A New Approach in OA: Dietary Management
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Figure 1
Recent News and Trends
With the recalls of selective COX-2 inhibitors and FDA’s recommendation to place a “black box” warning on the labels of
most Rx and OTC anti-inflammatory drugs, physicians are changing their prescribing habits due to heightened safety risks. 1
Many physicians have returned to prescribing older NSAIDs, including OTC products, even with their gastrointestinal side
effects. Some physicians have even stopped prescribing drugs for OA altogether. Patients are finding more information on
osteoarthritis (OA) from the media, often unbalanced or sometimes untrue, and many have chosen self-management without
much regard for potential side effects. Originally, OA was thought of as a degenerative disease associated with joint injury
and aging. However, recent insights have shown that after initial damage, OA progresses due to an excess of arachidonic
acid (AA) metabolism that increases inflammatory responses. Thus, OA is a metabolic deficiency disease which responds to
dietary management.
The Problem: Balancing Fatty Acid Metabolism to Manage Disease
While drugs focus on treating or masking symptoms, OA patients need help to manage the metabolic processes of OA,
thereby normalizing the levels of key metabolites. The initial event in the development of OA is damage to joints through
traumatic injury or overuse and release of phospholipids from damaged cell membranes which are converted to arachidonic
acid (AA) by phospholipase A2, a necessary fatty acid building block for membranes in the body. Metabolism of AA also
generates necessary fatty acid molecules for platelet aggregation, maintenance of stomach mucosa, organ function, proper
blood flow, urine production, blood pressure, tissue repair, and viral immunity.2-3 AA is metabolized via the COX
[cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2)] and LOX [5-lipoxygenase (5-LOX)] pathways into
thromboxanes, prostaglandins, prostacyclins, and leukotrienes (Figure 1)4. In addition, AA is converted via an oxidative
mechanism into F2-isoprostane, malondialdehyde, and 4-hydroxynonenal molecules, which directly degrade cartilage and
induce other inflammatory proteins.5 As aging occurs, however, AA both from the diet and the conversion of phospholipids
accumulates in excess in the body. The metabolism of excess AA to the above metabolites and its associated cyclical
inflammation is what propagates the disease and leads to cartilage degradation over time.6 In this metabolic sense,
inflammation is not merely a symptom of OA, rather this
inflammation cascade is the essence of the disease itself.
Managing the AA metabolic processes can ultimately
ease functional stiffness and inflammation, and restore
functional mobility.
The balance of AA metabolites is very important to
avoid deleterious effects on normal functions in the
body. As an example, two of the most important AA
metabolites for maintenance of normal kidney and
cardiovascular function are thromboxanes and
prostacyclins.7 Thromboxanes, produced by platelets via
the COX-1 enzyme, are involved in proper platelet
aggregation and also cause vasoconstriction in the
vasculature. Prostacyclins, generated from AA via COX-
2, are required for vasodilation of vessels and are
antagonistic to thromboxanes.8 If the production of
prostacyclins is selectively inhibited to a high level, then
thromboxanes dominate by constricting arteries and
arterioles causing decreases in urine perfusion in the
kidney and blood flow in the microvasculature around
the heart. Decrease in urine perfusion leads to increased
systolic blood pressure and peripheral edema, while
decreased blood flow to the heart can starve the tissue of oxygen and nutrients, especially if a person has plaque
accumulation. Both of these events lead to stress on the cardiovascular system, which contribute to increased incidence of
heart attack and stroke. These products of enzymatic AA conversion must remain balanced to allow the body to function
properly.9
A New Approach: Dual COX/LOX Mechanism of Action
A new approach on the market for OA is through dual COX/LOX mechanism of action (a.k.a. dual inhibition).10 This
approach helps to restore the balance of fatty acids, by damping AA metabolism non-selectively across the COX and LOX
A New Approach in OA: Dietary Management
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pathways, thereby minimizing common side effects. This balanced down-regulation, though weaker than traditional NSAIDs
and selective COX-2 inhibitor drugs, allows the body to produce AA metabolites at relatively equal levels to maintain
function within the body. Dual inhibitors may provide an answer for the imbalances that traditional NSAIDs (COX-1
imbalance) and selective COX-2 inhibitors (COX-2 imbalance) cause in AA metabolism. A prescription product utilizing
this new approach is a medical food product called Limbrel™. Medical foods are an FDA regulated class of foods meant to
provide distinctive nutrition requirements or to restore metabolic balances, and in this case, the balance between COX-1 and
COX-2 activity. Limbrel has been gaining wide acceptance based on its safety and ability to manage the metabolic processes
of OA using food-based ingredients. It contains concentrated levels of food-based ingredients called flavonoids which also
act as a potent antioxidant to limit oxidative conversion of AA to other damaging fatty acid products affecting cartilage
degradation. Licofelone from Merkle of Germany is currently the only prescription drug dual inhibitor in phase III trials,
and is not expected to be approved and marketed for a number of years. Its safety profile per published studies shows fewer
gastrointestinal events than NSAIDs and selective COX-2 inhibitors.10 Judging from the current spate of patents by major
pharmaceutical companies, we can expect to see more dual inhibitors as either drugs or medical foods in the future for the
treatment or dietary management of OA.
Medical Foods
FDA regulates “Medical Foods” as a discrete class of medical products for the dietary management of diseases or medical
conditions, when a nutritional or metabolic imbalance characterizing the disease or condition can be restored with nutrients,
specially formulated in an oral administration taken under a physician’s supervision. Therefore, medical foods are different
from drugs, because they work on the underling metabolic process of a disease or condition, instead of merely masking or
modifying its symptoms. The governing definition of medical foods is listed in Section 5(b) of the Orphan Drug Act (21
U.S.C. 360ee(b)(3)) which states that a medical food is “a food which is formulated to be consumed or administered
enterally [or orally] under the supervision of a physician and which is intended for the specific dietary management of a
disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established
by medical evaluation.”Medical foods are safe because one of their other statutory requirements is that their ingredients
have GRAS (Generally Recognized As Safe) status (see below). Medical foods have been distributed in hospitals as special
nutritional formulations containing vitamins, trace elements, minerals, fatty acids, flavonoids and amino acids for diabetes
mellitus, renal disease, pernicious anemia, gastrointestinal disorders, cachexia, chronic pancreatitis, elevated homocysteine,
etc. Medical foods are manufactured according to FDA cGMP (current Good Manufacturing Practices). FDA actively
enforces compliance with its medical foods regulations and performs regular inspections of medical foods manufacturing
facilities. Unlike dietary supplements which are intended for healthy populations, medical foods are intended to meet the
specific nutritional needs of a diseased patient population. Medical foods require physician supervision, and are required to
be distributed by prescription in many states prior to reimbursement.
GRAS (Generally Recognized As Safe)
GRAS is a strict safety standard set forth by the FDA, requiring technical demonstration of non-toxicity and safety, as well
as a general recognition and agreement by experts that the ingredients are safe for public consumption. Many ingredients
have been determined by the FDA to be GRAS, and are listed as such by regulation, in Volume 21 Code of Federal
Regulations (CFR) Sections 182, 184, and 186. Other ingredients may achieve self-affirmed GRAS status via a panel of
independent experts in the pertinent field who co-author a GRAS Report. Finally, a few ingredients have been specifically
permitted by FDA as safe medical foods ingredients, e.g., Folic acid, in Volume 21 CFR Section 172.345(f). Some experts
believe achieving GRAS status is an even higher standard of safety than the standard applied to drug products where a given
compound is considered safe for a particular indication in a particular patient population at a particular dose for a specified
duration of use, after a risk/benefit analysis. Dietary supplements, OTC drugs and prescription drugs are not required to
have GRAS ingredients. Limbrel contains GRAS ingredients that have been safely consumed by widespread populations
around the world.
1 http://www.fda.gov/cder/drug/infopage/COX2/default.htm (Accessed on July 19, 2005)
2 Goetzl EJ, An S, Smith WL. 1995. Specfficity of expression and effects of eicosanoid mediators m normal physiology and human diseases. FASEB J. 9:1051-1058
3 The Eicosanoids, Ed. Curtis-Prior P, John Wiley & Sons, New York, NY, 2004
4 Felson et al. 2000. Osteoarthritis: New Insights: Part 1: The Disease and Its Risk Factors. Ann Intern Med. 133(8): 635-46
5 Esterbauer, H, Schaur, RJ, Zollner, H. 1991. Chemistry and biochemistry of 4-hydroxynonenal, malondialdehyde, and related aldehydes. Free Rad. Biol. Med. 11:81–128;
Roberts, LJ, Morrow, JD. 1997. The generation and actions of isoprostanes. Biochim. Biophys. Acta, 1345:121–135.
6 McAlindon, T, Felson, DT. 1997. Nutrition: risk of osteoarthritis. Annal Rheum Dis, 56:397-402.
7 Bunting, S, Moncada, S, Vane, JR. 1983. The prostacyclin—thromboxane A2 balance: pathophysiological and theraputic implications. Br. Med. Bull. 39:271-6.
8 Solomon DH. 2005. Selective cyclooxygenase 2 inhibitors and cardiovascular events. Arthritis Rheum. 2005 Jul;52(7):1968-78.
9 Bing, RJ, Lomnicka, M. 2002. Why do cyclo-oxygenase-2 inhibitors cause cardiovascular events? J. Am Coll Cardiol. 39:421.
10 Martel-Pelletier, J, Lajeunesse, D, Reboul, P, Pelletier, JP. 2003. Therapeutic Role of Dual Inhibitors of 5-LOX and COX, Selective and Non-Selective Non-Steroidal Anti-
Inflammatory Drugs. Ann. Rhem. Dis, 62:501-09.
More detailed product information available at www.limbrel.com ISS.0905 #10005
Limbrel™ Product Profile
Distributed by Prescription #68040-601-16
“Safety That Works in Osteoarthritis”
Product Background
• Usage – For the safe, daily clinical dietary management of the metabolic processes of osteoarthritis (OA).
• Ingredients – Flavocoxid is a blend of primarily flavonoids, baicalin & catechin (from phytochemical food sources)
which are manufactured under prescription drug cGPM standards.
• Administration – Take one 250 mg capsule every 12 hours. This may be increased to two or more 250 mg
capsules every 12 hours under a physician’s supervision. Safe to be taken with or without other foods.
• FDA Regulated Product Class – Medical Food (not a drug or dietary supplement).
• Distribution – National distribution by prescription through retail pharmacies. National wholesaler order numbers:
(1) Amerisource 4774204; (2) Bergen 982722; (3) Cardinal 3568052; (4) McKesson 1256866.
• Promotion – Only via education and detailing to medical professionals (260+ detailing reps to MD/DO/PA/NP’s).
• Category – Arthritis affects 1 in 3 Americans and is the #1 cause of disability. Arthritis costs the U.S. economy
$82.5 billion annually, including over $6 billion in prescription product costs and growing at >10% annually with
aging population. Many products have had considerable cardiovascular and gastrointestinal safety concerns.
Product Benefits
• Safety – Across a range of critical parameters, Limbrel has been proven safe:
o Ingredients have GRAS (Generally Recognized As Safe) status; GRAS is the strict FDA safety standard
applied to food ingredients which designates “safe for public consumption”.
o In clinical studies, side effects were comparable to placebo.
o In safety and toxicology studies (animal & in-vitro), serological/hematological/histological measures are
comparable to placebo.
o In post marketing surveillance (n=16,452), side effects reported have been <0.25%. Predominant side effects
are: transient upper body rash (mild allergic reaction), indigestion, and synovitis.
• Effectiveness – Limbrel manages the distinctive nutritional requirements of OA by restoring the homeostasis of
OA metabolic processes in primarily two ways:
o Through inhibition of arachidonic acid (AA) metabolism down the 5-LOX (lipoxygenase) pathway, in addition to balanced inhibition across the COX-1 and COX-2 (cyclooxygenase) pathways. Limbrel is not a selective
COX-2 inhibitor. Limbrel is the first product with metabolic activity on both COX & LOX pathways.
o By acting as a powerful antioxidant to soak up reactive oxygen species (ROS) which convert AA to oxidative
products such as isoprostanes that directly degrade cartilage.
• Clinical & Scientific Support – Limbrel and its ingredients are supported by numerous medical and scientific
studies including:
Results of a Randomized, Double Blind, Placebo Controlled Study
Measure Limbrel Marketed Rx Control Placebo p-value
Functional Stiffness -41.5% -16.3% -2.3% p=0.001
Functional Mobility +34.3% +3.4% -6.8% p=0.002
Reimbursement Status
• Coverage – Presently, most U.S. healthcare plans and PBM’s reimburse Limbrel on a Tier-3 co-pay ($25-50 per
prescription). These include Aetna, United, Humana, Cigna (with prior authorization), Wellpoint and most Blue
Cross Blue Shield plans. Individual plans may vary.
• Cost Savings – Limbrel offers opportunities for lowering the cost of OA care in multiple ways:
o Daily Product Cost: Limbrel is on average 30% less expensive than leading branded Rx products.
o Total Cost of Care: Limbrel’s relatively low incidence of side effects can result in fewer complications such as
bleeding ulcers & cardiovascular events, which require additional costly drugs & hospitalization.
o Rebates: Attractive rebates to managed care organizations and buying groups are available.
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