limbrel and Osteoarthritis

Flavonoids, from Scutellaria baicalensis (Chinese skullcap) and Acacia catechu (black catechu), have been shown to exert a variety of therapeutic effects, including anti-inflammatory, antiviral, antibacterial, and anticancer activities. Flavocoxid is a mixed extract containing baicalin and catechin and it acts as a dual balanced inhibitor of cyclooxygenase-1 (COX-1) and COX-2 peroxidase enzyme activities with a significant inhibition of 5-lipoxygenase (5-LOX) enzyme activity in vitro. Flavocoxid downregulates gene or protein expression of several inflammatory markers and exerts also strong antioxidant activity in several experimental models. Controlled clinical trials and a postmarketing study have clearly shown that flavocoxid is as effective as naproxen in managing the signs and symptoms of osteoarthritis of the knee and it has better upper gastrointestinal, renal, and respiratory safety profile than naproxen. Flavocoxid may therefore provide a potential therapeutic approach to the treatment of chronic inflammatory conditions.

Topics: Acacia; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonate 5-Lipoxygenase; Catechin; Drug Combinations; Humans; Inflammation; Osteoarthritis; Scutellaria baicalensis

Osteoarthritis (OA) is the most common cause of musculoskeletal disability in the elderly, and it places an enormous economic burden on society, which will remain a major health care challenge with an aging population. Management of OA is primarily focused on palliative relief using agents such as nonsteroidal anti-inflammatory drugs (NSAID) and analgesics. However, such an approach is limited by a narrow therapeutic focus that fails to address the progressive and multimodal nature of OA. Given the favorable safety profile of most nutritional interventions, identifying disease-modifying pharmaconutrients capable of improving symptoms and also preventing, slowing, or even reversing the degenerative process in OA should remain an important paradigm in translational and clinical research. The goals of pharmaconutrition for metabolic optimization are to drive biochemical reactions in a desired direction and to meet health condition-specific metabolic demands. Applying advances in nutritional science to musculoskeletal medicine remains challenging, given the fluid and dynamic nature of the field, along with a rapidly developing regulatory climate over manufacturing and commerce requirements. The purpose of this article is to review the available literature on effectiveness and potential mechanism for OA of micronutrient vitamins; minerals; glycosaminoglycans; avocado-soybean unsaponifiable fractions; methylsulfonylmethane; s-adenosylmethionine; undenatured and hydrolyzed collagen preparations; phytoflavonoid compounds found in fruits, vegetables, spices, teas, and nuts; and other nutrients on the horizon. There also is a discussion on the concept of rational polysupplementation via the strategic integration of multiple nutraceuticals with potential complementary mechanisms for improving outcomes in OA. As applied nutritional science evolves, it will be important to stay on the forefront of proteomics, metabolomics, epigenetics, and nutrigenomics, because they hold enormous potential for developing novel therapeutic and prognostic breakthroughs in many areas of medicine, including OA.

Topics: Animals; Catechin; Dietary Supplements; Disease Progression; Drug Combinations; Epigenesis, Genetic; Harpagophytum; Humans; Hyaluronic Acid; Micronutrients; Osteoarthritis; Oxidative Stress; Peptide Hydrolases; Proteomics; S-Adenosylmethionine; Viscosupplements; Vitamins

Flavocoxid, a botanical, anti-inflammatory agent, nonspecifically inhibits the peroxidase activity of cyclooxygenase (COX-1 and COX-2) enzymes and 5-lipooxygenase (5-LOX). Due to the concomitant use of aspirin or warfarin in many osteoarthritis (OA) patients with increased cardiovascular risk, we felt it necessary to assess the anticoagulation properties of flavocoxid.. Three different studies were used: 1) a mouse model to assess effects on bleeding times when combined with aspirin; 2) the effect on platelet function as evaluated by platelet aggregation and bleed times in healthy human subjects; and 3) the effect on international normalized ratio in previously warfarinized patients with OA.. Flavocoxid at a human equivalent dose (HED) of 569 mg (within the standard human dosing range of 500 mg) produced no significant increases in bleeding time in mice. There was also no inhibition or synergistic increase in bleed times when flavocoxid was combined with aspirin (370 mg HED). Flavocoxid did not significantly inhibit thromboxane production or platelet aggregation, and did not increase bleeding times in healthy volunteers. Finally, flavocoxid did not inhibit or potentiate the anticoagulant effect of warfarin.. These results suggest that flavocoxid does not affect the primary or extrinsic pathways of secondary hemostasis and, by not inhibiting the anticoagulation effects of aspirin, may have utility in cardiovascular patients with OA.

Topics: Adult; Aged; Animals; Anticoagulants; Arachidonate 5-Lipoxygenase; Aspirin; Bleeding Time; Catechin; Cyclooxygenase 1; Cyclooxygenase 2; Drug Combinations; Drug Evaluation, Preclinical; Drug Interactions; Drug Therapy, Combination; Female; Humans; International Normalized Ratio; Male; Mice; Mice, Inbred ICR; Middle Aged; Osteoarthritis; Platelet Aggregation

Flavocoxid is a prescription medical food used to manage osteoarthritis (OA) symptoms. Safety concerns based on case reports raised an association with acute liver injury and hypersensitivity pneumonitis. We determined incidence rates (IR) of these safety events in a cohort of new users of flavocoxid and prescription non-steroidal anti-inflammatory drugs (NSAIDs).. MarketScan® claims data (2006-2017) was used to identify patients initiating flavocoxid or NSAIDs. Propensity score matching (1:2 ratio) was used to balance patient characteristics. Outcomes included hospitalization for hypersensitivity pneumonitis, liver injury, gastrointestinal bleeding, myocardial infarction, and acute kidney injury. Poisson regression was used to calculate IRs and Cox regression for calculating adjusted hazard ratios (aHR).. 3,337 flavocoxid and 6,674 NSAID users met eligibility criteria. Before matching, flavocoxid users were older (mean 57 vs 51 years), had more polypharmacy (68% vs 29% taking ≥11 medications). After matching, characteristics were well balanced. The rate of hypersensitivity pneumonitis was 1.1 (95% CI 0.0-5.9) per 1,000 PY for flavocoxid and 0.0 (95% CI 0.0-2.2) for NSAIDs. For hospitalized liver injury, it was 3.2 (95% CI 0.7-9.3) for flavocoxid and 2.4 (95% CI 0.7-6.1) for NSAIDs, aHR = 1.16, 95% CI 0.23-6.01. A lower rate of GI bleed was observed, IR: 5.3 (1.7-12.3) for flavocoxid and 10.2 (5.9-16.3) for NSAIDs, aHR 0.49 (0.18-1.68). There were no significant differences for MI or AKI.. The rate of hypersensitivity pneumonitis and liver injury associated with flavocoxid was low and minimally elevated compared to NSAIDs. Flavocoxid users had a significantly lower risk for hospitalized GI bleeding. The risk-benefit profile of flavocoxid may warrant reevaluation in light of these findings.

Topics: Acute Kidney Injury; Adult; Aged; Alveolitis, Extrinsic Allergic; Anti-Inflammatory Agents, Non-Steroidal; Catechin; Chemical and Drug Induced Liver Injury; Drug Combinations; Female; Gastrointestinal Hemorrhage; Hospitalization; Humans; Male; Middle Aged; Myocardial Infarction; Osteoarthritis; Polypharmacy; Proportional Hazards Models

Hypersensitivity pneumonitis (HP) is a rare adverse event with flavocoxid (Limbrel) use. Patients present with nonspecific symptoms after exposure to an inciting agent.. A 42-year-old female presented with worsening dyspnea on exertion and pleuritic midsternal chest pain. Her symptoms failed to abate with outpatient azithromycin for a diagnosis of community-acquired pneumonia. She was seen again at the emergency department (ED) due to symptom progression and exertional hypoxia. Chest reoentgenogram (x-ray) and computed tomography (CT) chest revealed bilateral infiltrates. Her history was significant for initiation of flavocoxid (Limbrel) two weeks prior, and a diagnosis of hypersensitivity pneumonitis was made. Once flavocoxid was discontinued, symptoms and radiologic studies improved without requiring biopsy or steroids.. Hypersensitivity pneumonitis is associated with many pharmacological agents and is challenging to diagnose, given nonspecific symptoms and radiologic findings. In the absence of specific indications to use corticosteroids, symptoms of HP might resolve with cessation of the offending agent, as proven by this case.

Topics: Adrenal Cortex Hormones; Adult; Alveolitis, Extrinsic Allergic; Biopsy; Catechin; Diagnosis, Differential; Drug Combinations; Female; Humans; Osteoarthritis; Tomography, X-Ray Computed

Flavocoxid is a prescription medical food that is used to treat osteoarthritis. It is a proprietary blend of 2 flavonoids, baicalin and catechins, which are derived from the botanicals Scutellaria baicalensis and Acacia catechu, respectively.. To describe characteristics of patients with acute liver injury suspected of being caused by flavocoxid.. Case series.. Drug-Induced Liver Injury Network Prospective Study ongoing at multiple academic medical centers since 2004.. Four adults with liver injury.. Clinical characteristics, liver biochemistry values, and outcomes.. Among 877 patients enrolled in the prospective study, 4 had liver injury suspected to have been caused by flavocoxid. All were women; ages ranged from 57 to 68 years. All developed symptoms and signs of liver injury within 1 to 3 months after initiating flavocoxid. Liver injury was characterized by marked elevations in levels of alanine aminotransferase (mean peak, 1268 U/L; range, 741 to 1540 U/L), alkaline phosphatase (mean peak, 510 U/L; range, 286 to 770 U/L), and serum bilirubin (mean peak, 160.7 µmol/L [9.4 mg/dL]; range, 34.2 to 356 µmol/L [2.0 to 20.8 mg/dL]). Liver biochemistry values decreased to the normal range within 3 to 12 weeks after flavocoxid was stopped, and all patients recovered without experiencing acute liver failure or chronic liver injury. Causality was adjudicated as highly likely in 3 patients and as possible in 1 patient.. The frequency and mechanism of liver injury could not be assessed.. Flavocoxid can cause clinically significant liver injury, which seems to resolve within weeks after cessation.

Topics: Aged; Alanine Transaminase; Alkaline Phosphatase; Bilirubin; Catechin; Chemical and Drug Induced Liver Injury; Dietary Supplements; Drug Combinations; Female; Humans; Middle Aged; Osteoarthritis; Prospective Studies

Topics: Catechin; Chemical and Drug Induced Liver Injury; Dietary Supplements; Drug Combinations; Humans; Legislation, Food; Osteoarthritis; United States; United States Food and Drug Administration

Topics: Aged; Alanine Transaminase; Alkaline Phosphatase; Bilirubin; Catechin; Chemical and Drug Induced Liver Injury; Dietary Supplements; Drug Combinations; Female; Humans; Middle Aged; Osteoarthritis; Prospective Studies

The multiple mechanisms of action for flavocoxid relating to arachidonic acid (AA) formation and metabolism were studied in vitro. Flavocoxid titrated into rat peritoneal macrophage cultures inhibited cellular phospholipase A2 (PLA(2)) (IC(50) = 60 μg/mL). In in vitro enzyme assays, flavocoxid showed little anti-cyclooxygenase (CO) activity on COX-1/-2 enzymes, but inhibited the COX-1 (IC(50) = 12.3) and COX-2 (IC(50) = 11.3 μg/mL) peroxidase (PO) moieties as well as 5-lipoxygenase (5-LOX) (IC(50) = 110 μg/mL). No detectable 5-LOX inhibition was found for multiple traditional and COX-2 selective NSAIDs. Flavocoxid also exhibited strong and varied antioxidant capacities in vitro and decreased nitrite levels (IC(50) = 38 μg/mL) in rat peritoneal macrophages. Finally, in contrast to celecoxib and ibuprofen, which upregulated the cox-2 gene, flavocoxid strongly decreased expression. This work suggests that clinically favourable effects of flavocoxid for management of osteoarthritis (OA) are achieved by simultaneous modification of multiple molecular pathways relating to AA metabolism, oxidative induction of inflammation, and neutralization of reactive oxygen species (ROS).

Topics: Acetaminophen; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Arachidonate 5-Lipoxygenase; Arachidonic Acid; Catechin; Cells, Cultured; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Drug Combinations; Gene Expression Regulation, Enzymologic; Ibuprofen; In Vitro Techniques; Lipoxygenase Inhibitors; Macrophages, Peritoneal; Male; Membrane Proteins; Osteoarthritis; Peroxidases; Phospholipase A2 Inhibitors; Phospholipases A2; Rats; Rats, Sprague-Dawley

GOAL (Gauging Osteoarthritis [OA] with Limbrel*), an open-label, post-marketing study was performed to determine the overall efficacy and gastrointestinal (GI) tolerability of flavocoxid, a novel, plant-based, anti-inflammatory medication, in a 'real world' clinical practice setting. To this end, the study enrolled several unique patient types including nonsteroidal anti-inflammatory drug (NSAID) naïve patients, those who had used NSAIDs in the past, regardless of outcome (positive or negative), and those who had previously taken a gastroprotective medication to improve GI tolerability or continued to take it as a precautionary measure to prevent NSAID-associated GI damage.. A total of 1067 individuals at 41 rheumatology practices were enrolled and prescribed flavocoxid, 500 mg b.i.d., for 60 days. The Physician Global Assessment of Disease (PGAD) visual analog scale (VAS) was used as a global measure to assess the signs and symptoms of OA, including joint discomfort, functional stiffness, functional mobility and quality of life. In addition, overall tolerability and upper GI tolerability were assessed by individual questions scored on a 5-part Likert scale. The physicians also monitored any interruption in, or cessation of use of flavocoxid due to a GI issue as well as changes in the use of gastroprotective medications. Adverse event (AE) monitoring was also conducted.. Of the 1005 patients who completed all follow-up visits, physicians recorded an average improvement in VAS scores from 60.1 +/- 18.8 at baseline to 42.5 +/- 21.9 at 8 weeks (p < 0.001) in 65.8% of patients. The PGAD VAS noted the most significant improvement in those patients with moderate to severe OA (baseline VAS [0 = least severe, 100 = most severe]: 0-25 mm, -3.5 +/- 6.9; 26-50 mm, -10.1 +/- 17.0; 51-75 mm, -19.3 +/- 19.5; 76-100 mm, -29.6 +/- 23.6; p < 0.001) and in those patients who were historically non-responders to NSAIDs (40.3 +/- 21.1 vs. 66.3 +/- 17.7 at baseline; p < 0.001). Patients who had previously responded well to NSAIDs had VAS scores of 42.6 +/- 19.8 vs. 58.0 +/- 18.0 (p < 0.001) and NSAID naïve subjects showed improvement in VAS scores from 60.5 +/- 18.0 at baseline to 46.3 +/- 23.7 (p < 0.001). The study recorded a low incidence ( approximately 10%) of AEs reported to physicians and good overall tolerability to flavocoxid. Flavocoxid showed improved upper GI tolerability in almost 50% of previous NSAID users (p < 0.001) and reduced therapy interruption in approximately 90% of previous NSAID users with a history of GI-related therapy interruptions (p < 0.0001). Finally, the use of flavocoxid resulted in a >30% reduction in or cessation of the use of gastroprotective medications such as proton pump inhibitors (PPI) or histamine-2 receptor antagonists (H2s) in subjects (p < 0.001).. Within a 'real world' clinical rheumatology practice setting, flavocoxid demonstrated significant efficacy in the management of OA in multiple patient types and displayed significant potential for reducing the possibility of adverse GI side-effects and use of gastroprotective agents associated with more traditional OA medications. A limitation of this study was that it was open-label and not rigorously controlled. The large population may compensate for this lack of control.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Catechin; Drug Combinations; Gastrointestinal Tract; Humans; Movement; Osteoarthritis; Product Surveillance, Postmarketing; Quality of Life

Flavocoxid is a medical food used for the clinical dietary management of osteoarthritis (OA). The acquisition cost of flavocoxid is higher than most traditional, generic NSAIDs. However, flavocoxid may have more favorable gastrointestinal (GI) toxicity resulting in lower overall costs. These costs have not been previously examined. This study provides a decision analytic model to assess the net costs of using flavocoxid for OA from a Medicare perspective.. A decision model was developed to estimate the total costs associated with flavocoxid versus naproxen for the management of Medicare patients with mild to moderate OA. Probabilities were obtained from literature and expert opinion, and costs were obtained from Medicare. Sensitivity analyses were conducted by varying probabilities and costs within clinically relevant ranges.. The base case resulted in flavocoxid having lower total annual costs ($1482 per patient) compared to naproxen ($1592). Flavocoxid remained the lowest cost option when the cost inputs were varied by 25% (above and below the base case), and when the probability of GI events with flavocoxid were varied by 25%. However, when GI rates from the literature and implied relative risks from the expert panel were used, or if the cost of PPIs was $0, then naproxen was the less costly alternative, though saving less than the annual cost of flavocoxid. Key limitations were the limited outcomes in the model (only GI events), lack of consideration of adherence or combination therapy, and the reliance on expert opinion due to a lack of data for flavocoxid.. In patients over 65 years of age who suffer from mild to moderate OA, flavocoxid may result in lower overall costs, despite a higher acquisition cost. Managed care organizations should consider total health care costs in the decision to include flavocoxid as a covered benefit.

Topics: Aged; Aged, 80 and over; Algorithms; Anti-Inflammatory Agents, Non-Steroidal; Catechin; Comorbidity; Costs and Cost Analysis; Drug Combinations; Hospitalization; Humans; Models, Economic; Naproxen; Osteoarthritis; Severity of Illness Index