Osteoarthritis (OA) is a common, debilitating joint condition characterized by degeneration of cartilage. The early stages of OA feature synovial inflammation caused by sustained high levels of pro-inflammatory cytokines, which can be triggered by mechanical strain or age-related oxidative stress. Treatment options aim to reduce pain and improve function but do not affect disease progression. Some pharmacologic therapies, including nonsteroidal anti-inflammatory drugs, can cause side effects, and their long-term use poses safety concerns. LI73014F2 is a synergistic formulation of the extracts of chebulic myrobalan (Terminalia chebula, Combretaceae) fruit, turmeric (Curcuma longa, Zingiberaceae) rhizome, and boswellia (Boswellia serrata, Burseraceae) gum resin, which are used to treat inflammatory disorders in Ayurvedic medicine, in a 2:1:2 ratio. These authors conducted a placebo-controlled, double-blind trial to assess the clinical efficacy of two different doses of LI73014F2 on pain, joint stiffness, and mobility in patients with OA.
LI73014F2 was standardized to a minimum of 1% gallic acid, 0.5% ellagic acid, 2.0% total curcuminoids, and 0.6% 3-O-acetyl-11-keto-β-boswellic acid (AKBA). Phytochemical markers included gallic acid and ellagic acid for black myrobalan, curcuminoids for turmeric, and AKBA for boswellia. LI73014F2 and the excipients microcrystalline cellulose powder (8%), and Syloid (Grace Davison Discovery Sciences; Columbia, Maryland) silica (2%) were placed in hard gelatin capsules. Placebo capsules contained the excipients only.
Several studies have demonstrated that 5-lipoxygenase (5-LOX) pathway activation plays an important role in the onset and progression of OA by causing further deterioration of the synovial membrane. These authors conducted an in vitro study, which suggested strong 5-LOX inhibitory activities of LI73014F2 as shown by spectrophotometric assay. Preclinical efficacy of the formulation was proven in Sprague-Dawley rats with induced OA; improvements were seen in pain and weight-bearing capacity.
For the clinical study, 128 patients, both males, and females, were recruited from five study sites in India. Patients were 45-70 years old with a body mass index of 18-30 kg/m2 and had been diagnosed with grade II-III OA of one or both knees for at least six months. Patients were randomly assigned to take 200 mg LI73014F2, 400 mg LI73014F2, or placebo in two equally divided doses (one before breakfast and one before dinner) daily. Patients were prescribed 400 mg ibuprofen tablets (maximum dose, 400 mg three times daily) as rescue medication during the study.
Study visits took place at screening, at baseline (or randomization), at day 14 ± 3 days, at day 30 ± 3 days, at day 60 ± 3 days, and at day 90 ± 3 days. Each patient completed a demographics questionnaire and a medical history at baseline. At baseline and at each visit, pain and function scores were measured, and adverse effects and use of rescue medication were recorded. Patients were asked to refrain from taking ibuprofen for the three days before each visit. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the Lequesne Functional Index (LFI), and a visual analog scale (VAS) were used to measure functional disability. The WOMAC scale has subscores for pain, stiffness, and function, which were normalized to a scale of 100 units.
A total of 105 patients were recruited, with 35 each assigned to the low-dose, high-dose and placebo groups. Nine patients (one from the low-dose group, five from the high-dose group, and three from the placebo group) did not complete the study because they were not available for follow-up visits. [Note: these patients were not included in statistical analyses.] Both groups treated with LI73014F2 showed significant improvements in OA pain and physical function between baseline and day 90. Total WOMAC scores decreased by 25.1% compared with baseline in the low-dose group (P=0.001) and 32.7% in the high-dose group (P<0.001), versus 10.4% in the placebo group. Both LI73014F2 groups had significantly greater improvement than the placebo group in WOMAC pain, stiffness and function subscales, VAS, and LFI scores (for the low-dose group, P<0.001 to P<0.004; for the high-dose group, P<0.001 for all). In the high-dose group, all of those measures improved by more than 30%. After 14 days of supplementation, significant improvements in pain and function scores were seen in both the low-dose and high-dose groups compared with the changes in the placebo group (P<0.05 for all).
Ten patients (four from the low-dose group, three from the high-dose group, and three from the placebo group) reported minor adverse effects such as diarrhea, nausea, abdominal pain, mild fever, and general weakness; however, those effects subsided without any change in study intervention. Rescue medications were taken by three patients in the low-dose group, one patient in the high-dose group, and nine patients in the placebo group. No major changes were seen in hematological parameters, serum biochemical parameters, or urinalyses, suggesting that the herbal formulation is safe and tolerable.
The authors conclude that “preclinical and clinical data together strongly suggest that the herbal formulation LI73014F2 is a safe and effective intervention for management of joint discomfort, demonstrating efficacy as early as 14 days” in patients with knee OA.
The third author is an employee of Laila Nutraceuticals (Vijayawada, India), the apparent creator of the tested formulation, which supported the study, and the fourth author is an employee of a natural products ingredient supplier. No other conflicts of interest are reported.
Karlapudi V, Prasad Mungara AVV, Sengupta K, Davis BA, Raychaudhuri SP. A placebo-controlled double-blind study demonstrates the clinical efficacy of a novel herbal formulation for relieving joint discomfort in human subjects with osteoarthritis of the knee. J Med Food. May 2018;21(5):511-520. doi: 10.1089/jmf.2017.0065.