Effectiveness
Another principal benefit of Limbrel is that it provides effective management of the metabolic processes of osteoarthritis.  Limbrel’s effectiveness comes from:

Unique Dual Inhibition Mechanism of Action via Dietary Management
Antioxidant Activity
Clinical Experience

Unique Dual Inhibition Mechanism of Action via Dietary Management
After the initial damage to joints, osteoarthritis progression is largely due to excess arachidonic acid (AA) metabolism on both COX (cyclooxygenase) and LOX (lipoxygenase) pathways (1-2).

Limbrel’s approach for the dietary management of osteoarthritis is very different from other osteoarthritis products. Limbrel does not treat or mask the symptoms of osteoarthritis, but rather works by managing the underlying metabolic processes, which lead to as well as cause progression of the disease. Limbrel is designed to help restore the homeostasis of metabolic processes that are associated with osteoarthritis through dietary management. Limbrel manages the metabolic processes of osteoarthritis via a dual inhibition mechanism of action down both COX and LOX pathways providing highly demanded safety and effectiveness.

Implications of the inflammatory response in the LOX pathway is not widely-known:

• Both LOX and COX pathways convert AA into inflammatory mediators that, if chronically produced, can lead to progression of osteoarthritis (3-4).
• When either COX-1 or COX-2 or both enzymes are down-regulated, AA metabolism is shunted down the LOX pathway to generate inflammatory metabolites (5).
• The 5-LOX enzyme converts AA into an inflammatory mediator called leukotriene B4 (LTB4) that causes cell and fluid buildup in osteoarthritis joints (6-7).
• LTB4 acts as strong chemotactic attractants of white blood cells (WBC) to the site of injury (8). This can occur anywhere in the body including damaged joints.
• When traditional NSAIDs down-regulate prostaglandins required for maintenance of stomach mucosa, 5-LOX is up-regulated in the stomach mucosa converting AA to LTB4. This process is normally necessary for tissue repair. In the stomach, however, WBCs are attracted to the mucosa causing an increase in inflammation which contributes to ulceration (2, 9-10).
• Metabolism of AA in the COX pathway and inhibition of this process with traditional NSAIDs or selective COX-2 inhibitors affects metabolism of AA in the LOX pathway. COX inhibitors increase the production of LOX based inflammation both in the gastric and joint tissue (2, 5).
• Management of LOX pathway metabolism is essential in the dietary management of osteoarthritis.

The COX pathways and their roles in osteoarthritis are more widely understood:

• Metabolism of AA by COX-1 generates prostaglandins important for the preservation of stomach mucosa and thromboxanes for platelet function as well as vasoconstriction in vessels (11).
• Metabolism of AA by COX-2 generates prostacyclins, which is required for vasodilation of vessels, antagonistic to thromboxanes and prostaglandins involved in tissue repair (11).
• If COX-1 is selectively targeted, prostaglandins production in the stomach decreases, there is an increased incidence of ulceration (9-10).
• If COX-2 is selectively targeted, prostacyclins production decreases. Thromboxanes then dominate causing vasoconstriction of the arterioles in the kidney reducing urine output leading to elevated systolic blood pressure and peripheral edema (12). In extreme cases, this imbalance can cause a prothrombotic event which can result in a heart attack or stroke (13).
• Thus, balanced management of both COX-1 and COX-2 is crucial for the dietary management of osteoarthritis.

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With a balanced inhibition of COX-1 & COX-2, and the dual inhibition of COX & LOX, Limbrel dampens inflammation through its clinical dietary management of the metabolic aspects of osteoarthritis. Unique flavonoid ingredients in Limbrel are the key for exceptional safety and effectiveness in managing the metabolic processes of osteoarthritis.

References

Antioxidant Activity
Limbrel is a powerful antioxidant, which "soaks up" free radicals. Free radicals are also known as oxidative products, which are collectively called reactive oxygen species (ROS). ROS contribute to the breakdown of synovial tissue, and induce the pro-inflammatory protein signals that lead to cartilage degradation in osteoarthritis.

ROS generated by WBC influx into the joint cause increased production of the transcription factor NFκB at the cellular level which induces the production of pro-inflammatory cytokines such as TNFα which in turn induces IL-6 (14). TNFα, along with IL-1β and IL-6, are the initial signals that induce further expression of 5-LOX and COX-2 in osteoarthritis (15).

Limbrel has an antioxidant ORAC (Oxygen Radical Absorbency Capacity) score is 5517 umole TE/g, higher than Vitamin C and E (16). By reducing these key cytokines on a cellular level, via this antioxidant mechanism, Limbrel manages the production of excess inflammatory metabolites which contribute to osteoarthritis. Therefore, Limbrel's antioxidant capacity may reduce oxidative stress and minimize further cartilage damage caused over time by ROS produced by the action of WBCs or environmental influences.

References

Clinical Experience

Double-blind, Randomized Clinical Study vs. Naproxen^§ (Click Here for the complete paper in pdf format)
LIMBREL was evaluated in a double-blind, randomized, active comparator (naproxen) controlled clinical study that enrolled 103 subjects with moderate or moderate-severe OA of the knee. Subjects were randomly assigned to receive either LIMBREL (500 mg BID) or naproxen (500 mg BID) for 4 weeks. Primary endpoints were the short WOMAC composite index (Western Ontario and McMaster Universities Osteoarthritis Index), investigator VAS for global response, subject VAS scales for global response and discomfort. Subjects were sex-matched and recruited from ages 35 to 85 years with an average age of 57-60 years per arm. There were no differences in demographic characteristics or in baseline WOMAC or VAS scores between the two arms. Subjects taking NSAIDs and/or gastroprotective medication underwent a 2-week washout period before beginning the trial. Subject activity was not restricted, and subjects were free to withdraw from the trial at any time for any reason. Dropouts were minimal in both arms. Two subjects, one from each arm, failed to complete the trial for personal reasons unrelated to the study.

In this study, both LIMBREL and naproxen arms noted significant reduction in the signs and symptoms of knee OA. All within-arm improvements in efficacy endpoints were statistically significant (p≤0.001). The LIMBREL and naproxen arms performed nearly identically, and the between group differences were not statistically significant for any efficacy endpoint. See Figures 1-4 below for efficacy results of LIMBREL vs. naproxen in this study.

Figure 1. Improvement in WOMAC*

Figure 2. Improvement in Physician VAS
(Global Disease Assessment)**

Figure 3. Improvement in Subject VAS
(Global Disease Assessment)

Figure 4. Improvement in Subject VAS
(Discomfort Assessment)

Fisher's exact test was computed for improved vs. not improved (sum of unchanged and worsened) for all parameters (see Table 1). Both arms had a large percentage of subjects with significant improvement (75% to 88%). Differences were not significant between arms for percent of patients with improvement. There was a slight, non-significant trend toward greater improvement in physician global disease assessment VAS in the LIMBREL arm and WOMAC in the naproxen arm.

§Levy R, Saikovsky R, Shmidt E, Khokhlov A. 2007. Safety, efficacy and acceptability of flavocoxid (Limbrel™) compared with naproxen in subjects with osteoarthritis of the knee: a pilot study. Osteoarthritis and Cartilage. 15(suppl B):B91

Double-blind, Randomized Clinical Study vs. Placebo
LIMBREL was evaluated in a 90-day randomized, double blind, placebo-controlled clinical trial of 60 subjects. Subjects were sex-matched and recruited from ages 40 to 75 years with an average age of 55-57 years per arm. Subjects taking NSAIDs engaged in a two-week washout period before beginning the trial. Subject activity was not restricted, and subjects were free to withdraw from the trial at any time for any reason. Three subjects withdrew from the study for personal reasons unrelated to study procedures or products.

In patients with OA, use of LIMBREL at 125 mg and 250 mg BID resulted in significant improvements in WOMAC functional endpoints of stiffness and mobility over those scores of placebo users. In this study, patients using LIMBREL 250 mg twice daily experienced greater improvements in functional stiffness and functional mobility at 90 days than did patients using 125 mg twice daily. See Tables 2 and 3 below for a comparison of LIMBREL results to placebo for each noted measure.

Open Label Study
LIMBREL has been shown to be effective in an open label human trial with a mean duration of use of 6.5 months. This trial consisted of 24 subjects: 13 males and 11 females ranging from 26 to 60 years of age. The primary endpoints were WOMAC functional mobility (65% improvement; p=0.002) and functional stiffness (62% improvement; p=.001) scores before vs. after taking LIMBREL.

Special Populations

Patients Anticoagulated with Warfarin
LIMBREL was administered to 59 patients who were taking warfarin chronically. Prothrombin times measured 2 weeks after the addition of LIMBREL were unchanged in the majority of patients. In 2 patients the prothrombin time was lengthened and in 2 patients was shortened beyond 2 standard deviations. It is not known whether these represented variation in laboratory testing or reflect a CYP450 polymorphism affecting warfarin metabolism. Because of this, physicians are advised to check prothrombin time one to two weeks after initiating LIMBREL in patients anticoagulated with warfarin.

Clinical studies have not been performed to assess the safety and efficacy of LIMBREL in pediatric, geriatric, hepatic insufficiency, renal insufficiency, and immunologically compromised patient populations.

New and Ongoing Clinical Studies
Various randomized, double-blind, placebo-controlled clinical trials of large sample sizes including mild and moderate osteoarthritis patients are underway by independent investigators.

These new and ongoing clinical studies will provide further long term safety and effectiveness results for Limbrel versus other marketed osteoarthritis products. All studies have been IRB approved.

Long-term Clinical Experience
The constituent ingredients in Limbrel have been extensively studied individually and are available as prescription medical products in numerous countries around the world(17). For example, in Japan, which has exceedingly rigorous standards for prescription products, the primary constituent ingredients of Limbrel have been available in prescription anti-inflammatory products and reimbursed by Japan's national health insurance for decades. Both Scutellaria baicalensis and Acacia catechu are listed in the Official Japanese Pharmacopoeia(18). Finally, millions have safely consumed the extracts of these plants as traditional medicines worldwide for generations.

References

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