Limbrel

CLINICAL PHARMACOLOGY

Mechanism of Action

LIMBREL (flavocoxid) acts on COX-1, COX-2 and 5-LOX pathways. LIMBREL (flavocoxid) is NOT selective for either COX-1 or COX-2 enzymes. LIMBREL (flavocoxid) acts by restoring and maintaining the balance of fatty acids in OA. LIMBREL (flavocoxid) dampens AA metabolism at relatively equal levels in the COX pathway (mediated by conversion of AA via the COX-1 & COX-2 enzymes), as well as inhibiting the metabolism of AA by the 5-LOX enzyme. This balanced inhibition of metabolism in the COX pathway yields relatively equal levels of thromboxanes, prostaglandins, and prostacyclins that are key mediators of systemic organ function. Inhibition of these mediators in the COX pathway, in conjunction with inhibition of leukotrienes in the LOX pathway, results in a ”dual inhibition“ mechanism that manages inflammation with minimal effects on organ function. Inhibition of 5-LOX has been shown in cell-based assays to reduce the production of LTB4, an agent that fosters WBC chemotaxis and the subsequent release of histamines, ROS, and pro-inflammatory cytokines. In addition, direct inhibition of the 5-LOX enzyme has been observed in enzymatic assays. This balanced down-regulation of these enzymatic pathways is relatively weak when compared to the effects of traditional NSAIDs and selective COX-2 inhibitors, thus allowing the body to produce AA metabolites at relatively equal levels to maintain physiologic function.

LIMBREL (flavocoxid) also acts as a strong antioxidant to limit the oxidative conversion of AA by ROS to other damaging fatty acid products including hydroxyl radicals, superoxide anion radicals and hydrogen peroxide. LIMBREL (flavocoxid) has demonstrated an oxygen radical absorbance capacity (ORAC) of 5,517 μmolTE/g, as compared to Vitamin E (1,100 μmolTE/g) and Vitamin C (5,000 μmolTE/g).

Through these enzyme inhibition and antioxidant mechanisms, LIMBREL (flavocoxid) is beneficial for the clinical dietary management of the metabolic aspects of osteoarthritis. Inflammation, joint discomfort, and reduced flexibility are shown in published studies to be clinical manifestations of OA. At a biochemical and metabolic level, inflammation is not simply a marker of the disease process, but also plays an important role in OA progression. Chronic inflammation with elevated metabolic production of inflammatory metabolites has an etiological role in the progression of OA. Thus, successful dietary management of the metabolic processes ofOA, results in a reduction of its characteristic inflammation by correcting OA's distinctive imbalance in AA metabolism.

Hepatic, Renal, and Gastrointestinal Histology

LIMBREL (flavocoxid) 's effect on hepatic, renal, gastric, and duodenal tissue histology was tested in four animal toxicity studies; two for acute use and two for sub- chronic use.

In the acute use studies, healthy juvenile male and female mice received a 2,000 mg/kg oral dose (10,000 mg per day human equivalent, or at least 10 times the recommended human use of 500 - 1,000 mg per day) or placebo daily for 14 days. In two different sub-chronic use studies, three groups of healthy adult male and female mice consumed either 50 mg, 250 mg or 500 mg/kg doses (250 mg, 1,250 mg and 2,500 mg per day human equivalent) for 28 and 91 days respectively.

In all studies, the test subjects were evaluated relative to placebo control groups of healthy subjects with similar ages and sexes. Observations across all groups revealed no organ or behavioral abnormalities, nor differences in weight gain. Neither study showed changes in hepatic, renal, gastric, or duodenal histology. Blood electrolytes were unchanged, and liver enzyme levels and markers of renal function were all within normal limits.

Food Effects

LIMBREL (flavocoxid) is safe taken with or without other foods. Taking LIMBREL (flavocoxid) one hour before or after meals may help to increase the absorption of LIMBREL (flavocoxid) 's key ingredients. This observation is based upon a pharmacokinetic study in humans, as well as in-market clinical experience in analyzing physician and patient product reports. Food does not affect the metabolism of LIMBREL (flavocoxid) and may buffer effects of slight indigestion.

Metabolism

LIMBREL (flavocoxid) is primarily carried bound to albumin in the blood and only a minor amount ( < 10%) is metabolized via glucuronidation and sulfation by hepatic metabolism involving cytochrome P450 isoenzymes (CYP). A primary ingredient constituent, baicalin, undergoes hydrolysis of the glucuronide moiety in the upper intestine via the action of intestinal flora and is absorbed as the aglycone, baicalein. Glucuronidation and sulfation of baicalein occurs intra-hepatically. In vitro CYP assays using a microsomal enzyme system demonstrated minimal CYP inhibition (see below).

Drug Interactions

In vitro studies indicated that LIMBREL (flavocoxid) is not a significant inhibitor of cytochrome P450 1A2, 2C9, 2C19, 2D6, or 3A4. These isoenzymes are principally responsible for 95% of all detoxification of drugs, with CYP3A4 being responsible for detoxification of approximately 50% of drugs. Based on the results of this assay, LIMBREL (flavocoxid) does not appear to have a pronounced effect on drug metabolizing enzymes.

LIMBREL (flavocoxid) was tested at a 10 μM concentration in human recombinant (sf9 cells) using spectrophotometric quantization of 7-benzyloxy-4-(trifluoromethyl)-coumarin as substrate. In this test model, if inhibition does not reach at least 50% at 10 μM, CYP inhibition is considered to be insignificant and no further development of titration curves is deemed necessary. Inhibition by LIMBREL (flavocoxid) ranged from 11% inhibition to 23% inhibition of selected isozymes when studied at a 10 μM concentration.

LIMBREL (flavocoxid) , therefore, does not appear to have a pronounced effect on the inhibition of hepatic drug metabolizing enzymes based on this 10 μM concentration. The data for CYP inhibition is shown below:

Table 1. Cytochrome P450 Assay

CYP Isoenzyme % Inhibition by LIMBREL
1A2 23%
2C9 11%
2C19 16%
2D6 15%
3A4 11%

Clinical Experience

LIMBREL (flavocoxid) has demonstrated significant functional improvements when used for the clinical dietary management of the metabolic processes of OA.

Double-blind, Randomized Clinical Study vs. Naproxen

LIMBREL (flavocoxid) 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 (flavocoxid) (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 thisstudy, both LIMBREL (flavocoxid) 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 (flavocoxid) 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 (flavocoxid) vs. naproxen in this study.

Figure 1. Improvement in WOMAC*

Improvement in WOMAC* Illustration

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

 Improvement in Physician VAS (Global Disease Assessment)**  Illustration

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

Improvement in Subject VAS (Global Disease Assessment) Illustration

Figure 4. Improvement in Subject VAS (Discomfort Assessment) ††

Improvement in Subject VAS (Discomfort Assessment) Illustration

Fisher's exact test was computed for improved vs. not improved (sum of unchanged and worsened) for all parameters (see Table 2). 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 (flavocoxid) arm and WOMAC in the naproxen arm.

Table 2. Percent of OA Patients with Improvement

  LIMBREL (flavocoxid)
500 mg BID
(N=52)
Naproxen
500 mg BID
(N=51)
p-value
WOMAC 79% 88% < 0.001
Physician VAS (global disease assessment) 83% 75% < 0.001
Subject VAS (global disease assessment) 87% 88% < 0.001
Subject VAS (discomfort assessment) 87% 88% ≤ 0.001

Double-blind, Randomized Clinical Study vs. Placebo

LIMBREL (flavocoxid) 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 (flavocoxid) 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 (flavocoxid) 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 3 and 4 below for a comparison of LIMBREL (flavocoxid) results to placebo for each noted measure.

Table 3. 90-day Functional Stiffness WOMAC Scores

  Mean % Change* p-value Conclusion
LIMBREL 250 mg/day -27.2% p=0.005 Significant improvement
LIMBREL 500 mg/day -38.0% p=0.002 Significant improvement
Placebo +3.1% p=0.324 No significant improvement
* Negative values indicated improvement in functional stiffness.

Table 4. 90-day Functional Mobility WOMAC Scores

  Mean % Change* p-value Conclusion
LIMBREL 250 mg/day +19.2% p=0.018 Significant improvement
LIMBREL 500 mg/day +28.4% p=0.001 Significant improvement
Placebo +2.3% p=0.895 No significant improvement
* Positive values indicated improvement in functional mobility.

Open Label Study

LIMBREL (flavocoxid) 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 (flavocoxid) .

Last reviewed on RxList: 7/24/2008
This monograph has been modified to include the generic and brand name in many instances.

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