Safety

FDA Advisory - Dear Doctor Letter
Safety in Post-Marketing Surveillance
Safety in GRAS Status
Safety in Unique COX/LOX Dual Inhibition
Safety in Clinical & Toxicology Studies

Safety in Post-Marketing Surveillance

Limbrel has been prescribed for osteoarthritis by physicians in the U.S. and Puerto Rico since mid 2004 across a wide variety of patient types. Generally, most patients have had mild to moderate osteoarthritis and have been over 40 years of age. Such practical daily use by physicians across various types of patients is really the ultimate proof of safety of any medical product.

With thousands of prescriptions, Limbrel has generated less than 0.1% product complaints or reports of adverse events by either physicians or patients. Please click here for the latest Post-Marketing Surveillance Report

Safety in GRAS Status

The ingredients in Limbrel have achieved Generally Recognized As Safe (GRAS) status. The standards for an ingredient to achieve GRAS status are listed in Volume 21 CFR.

These standards require not only technical demonstration of non-toxicity and safety, but also general recognition and agreement on that safety by experts in the field. 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 only after testing in a clinical trial. GRAS-level safety is often demonstrated in part through traditional use of the foods or food additives in a wider population.

Food ingredients for general consumption in the U.S. hold GRAS status and are therefore considered safe for public consumption. Examples of medical food based ingredients with GRAS status include Folic acid, ascorbic acid (Vitamin C), ferrous fumarate (iron), digestive enzymes, amino acids, and calcium carbonate.

To learn more about GRAS, please click here.

Safety in Unique COX/LOX Dual Inhibition Mechanism of Action

After the initial damage to joints, osteoarthritis progression is largely due to excess arachidonic acid (AA) metabolism via the COX and LOX pathways, producing inflammatory metabolites which degrade cartilage (1). A balance of AA metabolites produced by COX-1 and COX-2 enzymatic activities help regulate various body functions, including gastrointestinal, renal and cardiovascular functions (2). On the other hand, an imbalance or excess of AA metabolites produced by either enzyme results in organ dysfunction and side effects which can be severe (3-5).

Traditional NSAIDs primarily down-regulate COX-1 enzymatic activity, while selective COX-2 inhibitors generally down-regulate COX-2 enzymatic activity. Another pathway for the enzymatic metabolism of AA is the 5-Lipoxygenase pathway (also known as LOX), another activity involved in producing inflammation in joints (6). Neither NSAIDs nor selective COX-2 inhibitors down-regulate LOX activity. In fact, these well-known inhibitors have been shown to actually shunt AA metabolism down the LOX pathway thereby increasing overall inflammation in the damaged and osteoarthritis-ridden joint (7). Therefore, NSAIDs and selective COX-2 inhibitors cause imbalances in both the COX and LOX pathways, resulting in damage to the cartilage and progression of osteoarthritis, as well as side effects which can affect overall health (8).

How imbalances affect the ratio of AA metabolites in both COX and LOX pathways, and the resulting side effects, are detailed below:

• The COX-1 enzyme is involved in producing prostaglandins in the stomach that preserve the mucosa and thromboxanes in platelets that regulate clotting (9). In addition, thromboxanes act as vasoconstrictors in the arterioles and arteries of the cardiovascular system and kidneys (9).
• When traditional NSAIDs down-regulate prostaglandins in the stomach, there is a deterioration of the stomach mucosa. When this occurs, 5-LOX production increases in the stomach, which converts AA to LTB4. The LTB4 molecules attract white blood cells, causing inflammation that results in an ulcer (5).
• When traditional NSAIDs down-regulate thromoboxanes, activation of platelets is reduced, which causes a blood thinning effect (10). Therefore, traditional NSAIDs must be washed out of the system prior to surgery.
• The COX-2 enzyme is involved in producing prostaglandins which are involved in tissue and bone repair as well as prostacyclins which are required for vasodilation of arterioles and arteries in the cardiovascular system and kidneys (9).
• Prostacyclins are antagonistic to thromoboxanes requiring that the AA metabolite be balanced to maintain proper cardiovascular and kidney functions. When selective COX-2 inhibitors down-regulate prostacylcin production, thromboxanes dominate and constrict the arterioles in the kidney and in the worst case, the coronary arteries causing prothrombosis around plaques (4). Constriction of vessels in the kidneys causes a reduction in urine production, elevated systolic blood pressure, and peripheral edema, while prothrombosis can contribute myocardial infarction and stroke (3-4).
• When a patient has a minor ulcer, selective COX-2 inhibitors selectively down-regulate prostaglandins in the stomach as well. Reduction of these prostaglandins leads to expansion of the ulcer by up-regulating further 5-LOX activity thereby increasing inflammation in the stomach exacerbating the ulceration which can result in hospitalization and even death (11).

To avoid side effects related to an imbalance of COX-1 and COX-2 AA metabolites, the activity of the two enzymes must be balanced. This allows the body to maintain a near 1:1 ratio of prostacyclins to thromboxanes for proper cardiovascular and kidney function (8). In addition, a dual mechanism of action for inhibition of both COX and LOX activity can minimize 5-LOX production in the stomach to preserve stomach mucosa and reduce inflammation in the joints to lessen damage of cartilage and perhaps preserve cartilage (8,12). Therefore, to safely manage AA metabolism in osteoarthritis, a dual COX/LOX mechanism of action results in few gastric, cardiovascular, and renal side effects.

Limbrel is unique because dietary management with its flavonoid ingredients works across both COX and LOX enzymatic pathways. Limbrel balances the COX-1 and COX-2 enzymatic conversion of AA while down-regulating the production of LTB4 in the LOX pathway for the safe, dietary management of the metabolic processes involved in osteoarthritis. The unique COX/LOX dual mechanism of action is key to the safety of Limbrel in osteoarthritis patients.

Limbrel’s ratio of inhibitory activities for all three enzymes (COX-1 to COX-2 to 5-LOX) is 1.5 to 1.0 to 3.0 based on in vitro enzymatic comparisons of inhibitory activity (13). This broad-based, dual inhibition mechanism allows for balanced activity for safety while providing effectiveness in managing osteoarthritis.

Safety in Clinical & Toxicology Studies

In two randomized, double-blind, placebo-controlled human clinical studies, safety testing was performed on the Limbrel formula, monitoring 43 serum analytes, hematological and serological parameters, lipid profiles, liver enzymes, renal markers (BUN/creatinine ratios and creatinine clearance). One clinical trial studied 80 patients for 60 days and the other trial studied 60 patients over 90 days. In both clinical trials, Limbrel caused no change in any blood electrolytes, serology, liver enzyme, liver enzymes, or renal markers over the test period. Side- effects observed were comparable to placebo in both clinical studies as well (13).

The ingredients in Limbrel have also been tested in both acute and chronic animal toxicology studies at doses up to 20 times the equivalent human dose. In these acute and subchronic studies, no significant adverse events were reported and there were no significant changes in histology of the gastric, duodenal, hepatic, or renal tissue (14). Further, no LD50 has been established for Limbrel because, in testing, animals have not been able to consume enough (even by gavage) of Limbrel’s composition, flavocoxid, to create a lethal dose (13). Finally, Limbrel given at equivalent doses in Fisher 344 rats did not cause changes in the stomach lining by histological examination after two months whereas control NSAIDs, such as ibuprofen, yield significant gastric lesions at 100x’s lower doses within one week (13, 15). Notably, this particular strain of rats is known to be susceptible to gastrointestinal lesions (15).

References