OA as a Metabolic Deficiency Disease
Metabolic processes are important in the progression of OA. After initial damage
to the joint due to trauma, overuse, or genetic factors, a cascade of inflammation,
triggered by the release of cytokines (e.g., TNFα, IL-β, IL-6), begins
the development of OA. These cytokines up-regulate the expression of COX-2 (cyclooxygenase-2)
and 5-LOX (5-lipoxygenase) enzymes, which metabolize fatty acids in the joint.
This process is both enzymatic as well as oxidative, and occurs at a cellular level where the essential fatty acid, arachidonic acid (AA), is converted into various inflammatory products. With age, elevated levels of AA accumulate both from the diet and increased conversion of phospholipids produced by further damage to cells in the joint. Therefore, OA is sustained by imbalanced AA metabolism.
Managing AA metabolism benefits OA patients by decreasing the damaging, metabolic inflammatory processes in the joint to improve functional mobility, reduce stiffness, and decrease joint discomfort.
When joint damage occurs, phospholipids released from damaged cell membranes are converted to AA. Enzymatic breakdown of AA then generates fatty acid metabolites
that are involved in platelet aggregation, maintenance of stomach mucosa, organ function, proper blood flow, urine production, blood pressure, viral immunity, bone turnover and tissue repair. AA is metabolized via the COX (COX-1 & COX-2) and LOX (5-LOX) pathways to thromboxanes, prostaglandins, prostacyclins, and leukotrienes. Balanced AA metabolism by COX-1 and COX-2 is essential to sustain proper levels of critical regulators for renal and cardiovascular function maintained by thromboxanes (vasoconstrictors) and prostacyclins (vasodilators).
An imbalance of these metabolites can result in high blood pressure, peripheral
edema and, in severe cases, myocardial infarction. AA, metabolized by 5-LOX, produces leukotrienes (particularly LTB4), that are strong chemoattractant molecules responsible for the migration of white blood cells (WBCs) to the site of injury. WBCs attracted to the joint by leukotrienes release histamines, produce reactive oxygen species (ROS) and cytokines, triggering additional inflammatory
processes not treated by traditional non-steroidal anti-inflammatory drugs (NSAIDs) or selective COX-2 inhibitors. Inhibition of either or both COX-1 and COX-2 has been shown to shunt AA metabolism down the 5-LOX pathway, thereby potentially increasing, rather than reducing, inflammation in cartilage. In addition, AA is converted via an oxidative mechanism mediated by reactive oxygen species (ROS) to the oxidized lipids F2-isoprostanes, malondialdehyde, and 4-hydroxynonenal that directly degrade cartilage and induce production of other inflammatory proteins.
LIMBREL (flavocoxid) consists of a proprietary blend of two types of flavonoids,
Free-B-Ring flavonoids and flavans, from Scutellaria baicalensis and
Acacia catechu, respectively. These ingredients in LIMBREL (flavocoxid) are Generally
Recognized As Safe (GRAS). For an ingredient to be recognized as GRAS, it requires
technical demonstration of non-toxicity and safety, general recognition of safety
through widespread usage, and agreement of that safety by experts in the field.
Many ingredients have been determined by the U.S. Food and Drug Administration
(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 experts in the
pertinent field who co-author a GRAS Report. Finally, the FDA has specifically
permitted a few ingredients as safe medical foods ingredients in Volume 21 CFR
Flavonoids are a group of phytochemical compounds found in all vascular plants,
including fruits and vegetables. They are a part of a larger class of compounds
known as polyphenols. Many of the therapeutic or health benefits of colored
fruits and vegetables, red wine, and green tea are directly related to their
The specially formulated flavonoids found in LIMBREL (flavocoxid) , or their related compounds
(i.e., other flavonoids, anthocyanins), cannot be obtained from conventional
foods in the normal American diet at the same level as found in LIMBREL (flavocoxid) . This
quantity of daily flavonoid intake generally would need to be significantly
greater for patients with hypochlorhydria or low intrinsic factor, both of which
occur most often in the elderly population. OA may not be managed simply by
a change to the normal diet due to the high volume of vegetable and fruit matter
that would need to be consumed.
The primary Free-B-Ring flavonoid is baicalin (5,6,7-trihydroxyflavone,7-O-β-D-glucuronopyranoside),
derived from the phytochemical food source material Scutellaria baicalensis,
with a molecular weight of 446.37. Its molecular formula is C21H18O11,
with the following chemical structure:
The primary flavan is composed of catechin (3,3',4',5,7-pentahydroxyflavan
(2R,3S form)), and its stereo-isomer, epicatechin (3,3',4',5,7-pentahydroxyflavan
(2R,3R form)) from the phytochemical food source material Acacia catechu
with a molecular weight of 290.27. Its molecular formula is C15H14O6,
with the following chemical structure:
LIMBREL (flavocoxid) contains the following “inactive” or other ingredients as
fillers, excipients, and colorings: magnesium stearate, microcrystalline cellulose,
Maltodextrin NF, gelatin (as the capsule material), titanium dioxide, FD&C
Blue #1, and FD&C Green #3. Capsules do not contain fructose, glucose, sucrose,
lactose, gluten or flavors.
Medical food products are often used in hospitals (e.g., for burn victims or
kidney dialysis patients) and outside of a hospital setting under a physician's
care (e.g., for PKU, AIDS patients, cardiovascular disease, osteoporosis) for
the dietary management of diseases in patients with particular medical or metabolic
needs due to their disease or condition. Congress defined "medical food" in
the Orphan Drug Act and Amendments of 1988 as "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.“ LIMBREL (flavocoxid)
has been developed, manufactured, and labeled in accordance with both the statutory
and the FDA regulatory definition of a medical food. LIMBREL (flavocoxid) is to be used under
a physician's supervision.
LIMBREL (flavocoxid) is a yellow to light brown powder. It is partially soluble in water
and glycerol, soluble in ethanol, methanol, and acetonitrile. It is practically
insoluble in hexane. Each capsule of LIMBREL contains 250 mg or 500 mg of flavocoxid,
as noted in the Primary Ingredients Section.
What are the possible side effects of bioflavonoids?
Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.
Less serious side effects are more likely to occur, and you may have none at all.
Tell your doctor, pharmacist, herbalist, or other healthcare provider about any unusual or bothersome side effect. You may report side effects to FDA at...
Read All Potential Side Effects and See Pictures of Limbrel »
What are the precautions when taking flavocoxid (Limbrel)?
Before taking flavocoxid, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.
This product should not be used if you have certain medical conditions. Before using this product, consult your doctor or pharmacist if you have: a history of stomach ulcers, active stomach ulcers.
Before using this product, tell your doctor or pharmacist your medical history.
This product is not recommended for use during pregnancy. Consult your doctor for more details.
It is not known whether this product passes into breast milk. Therefore, breast-feeding is not recommended while using this product....
Read All Potential Precautions of Limbrel »
Last reviewed on RxList: 7/24/2008
This monograph has been modified to include the generic and brand name in many instances.