1. Gout Elevation of serum uric acid level: hyperuricemia primary risk factor,predisposes to gout > 6.8mg/dl Deposition of uric acid crystals (monosodium urate) in the joint Acute inflammatory arthritis Management of the disease – Between flares Normalize urate level: goal below 6 mg/dl Maintain health joint – During flares: control and resolution of inflammation

2. Endogenous source: cellular break down nucleic acids Food rich in purine Purines: Hypoxanthine Guanine Xanthine Uric acid Allantoin Gastro-intestinal elimination 33% Renal elimination 66% Joint: Monosodium urate crystals Inflammation Gout Uricase: Non primates Xanthine oxidase Xanthine oxidase Guanine deaminase 2 major pharmaceutical targets: Inhibition of xanthine oxidase: e.g. allopurinol, febuxostat Increase renal uric acid excretion: e.g. probenecid Pathogenesis

3. Normalize urate level Gastro-intestinal tract: probiotics Inhibition of xanthine oxidase – Methanol extract of Chrysanthemum sinense (china) – Methanol extract of Larix laricinia ( North America) – Methanol extract of Coccinia grandis (India) – Methanol extract of Vitex negundo (India) – Chloroform extract of Erythrina stricta (India, China, Vietnam, Thailand) – Various plant extracts containing rutin and quercetin (Biota orientalis and others) – Cassia oil from Cinnamomum cassia Increase renal uric acid excretion: – Methanol extract of Orthosiphon stamineus – Lignans from Phyllanthus niruri ( Southeast Asia and Latin America) Mixed: (XOI and renal): Paedaria scandens ( China)

4. Maintain joint health DMOADs: glucosamine, chondroitin, insaponifiable fraction of soja and avocado Promotion of resolution of inflammation: DHA and EPA Plant derived anti-inflammatory agents – Curcuma – Meadowsweet – Black current

5. Normalize urate level Uricosuric agent and xanthase oxidase inhibitors GI tract health Probiotic Maintain joint health DMOADs DHA and EPA Plant anti-inflammatory Natural gout prevention program

6. Inflammation targets during gout flare Blood vessel Endothelium Synovium Resident macrophages Dendritic cells O 2 - Enzymes Complement Cytokines............. Apolipoproteins Clean up by macrophages Neutrophil migration Apoptosis TGFβ Monocytes Resident macrophages Inflammatory monosodium urate crystals Noninflammatory monosodium urate crystals Resolvins Protectins Maresins DHA + EPA Resolution of inflammation

7. Goals during flares for natural anti- inflammatory Inhibition of cytokine production: IL-1β, IL -6, IL-8 and TNF-α Neutralize oxygen radicals and enzymes produced by activated macrophages Promotes TGF β production Promote resolution of inflammation