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Natural Anti-inflammatory Agents
Since ancient times our ancestors have used phytochemicals found in plants to curtail the inflammatory process. For example, the bark of the willow tree was used as an analgesic and antipyretic medication more than 2400 years ago by the Greeks and Romans. The discovery of aspirin in 1899 was based on this observation.
The emergence of today's pharmaceutical industry, in large part, has been based on natural products. Drugs such as digoxin, Taxol, artemisinin, and scores more have been developed from phytochemicals.Not only have many medical breakthroughs been based on compounds of natural origin, but these also represent a large share of the drug market. In 1999, close to 50% of the 20 best-selling drugs were derived from natural products, and their sales amounted to approximately $16 billion. According to a survey by the National Cancer Institute, 61% of the 877 small molecules, which are new chemical entities introduced as drugs worldwide from 1981 to 2002, were inspired by natural products. The following is a discussion of the most commonly used natural antiinflammatory agents and their mechanism of action.
Omega-3 EFAs (Fish Oil)
The use of fish oil (in the form of cod liver oil), an omega- 3 EFA, for the treatment of muscular, skeletal, and discogenic diseases can be traced back to the late 18th century. As detailed by Curtis, et al., Dr. Thomas Percival recommended 1 to 3 tablespoons of cod liver oil two to four times per day for the treatment of "obstinate chronic rheumatisms, sciaticas of long standing, and in those cases of premature decrepitude, which originate from immoderate labor, repeated strains and bruises, or exposure to continuous dampness and cold; by which the muscles and tendons become too rigid, and the flexibility of the joints is impaired, so as to crackle for want of a due secretion of synovia." Unfortunately, because of the rapid onset of rancidity of this polyunsaturated oil when exposed to air and hence its disconcerting odor, cod liver oil fell out of favor.
With recently developed extraction techniques, which are performed under a nitrogen blanket, and with enhanced oxygen-free encapsulation methods, which prevent oxidation, the therapeutic benefits of fish oil can now be realized without the regurgitation and odor of previous products. Research has shown that the omega-3 polyunsaturated fatty acids are some of the most effective natural antiinflammatory agents available. With the discovery that vascular inflammation is the underlying cause of coronary artery disease, fish and fish oil supplements are now recommended by the American Heart Association for the prevention of this disease. Countries in which the highest fish consumption occurs have populations with a lower incidence of neurodegenerative disease and depression. The biological basis for the effectiveness of fish oil in treating arthritis has been well documented, with many positive clinical studies when compared with traditional pharmaceutical antiinflammatory agents.
The active ingredients in fish oil, EPA and DHA, enhance the conversion of COX to prostaglandin E3. A natural antiinflammatory agent, prostaglandin E3 competitively inhibits the effects of the arachidonic acid conversion to prostaglandin E2, a highly inflammatory substance. Prostaglandin E3 also inhibits the synthesis of TNFá and IL-1â, both of which are inflammatory cytokines. The EPA and DHA can inhibit the 5-LOX pathway, which converts arachidonic acid to inflammatory leukotrienes, also by competitive inhibition. When EPA and DHA are incorporated into articular cartridge chondrocyte cell membranes, there is a dose-dependent decrease in the expression and activity of the proteoglycan-degrading aggrecanase enzymes.
Omega-3 EFA, found in fish oil, can directly reduce the degenerative enzymes aggrecanase and matrix metalloproteinase, as well as IL-1, TNFá, and COX-2 to reduce the inflammation in synovial cartilage. A recent study of 250 patients with cervical and lumbar disc disease who were taking NSAIDs revealed that 59% could substitute fish oil supplements as a natural antiinflammatory agent for the NSAIDs. The recommended dosage is a total of 1.5 to 5 g of EPA and DHA per day, taken with meals. Rare side effects include steatorrhea and occasional belching if the supplements are not taken with meals. Typically, persons on a regimen of anticoagulant medications should not take omega-3 EFAs because of the possibility of increasing the bleeding potential.
White Willow Bark
Bark from the white willow tree is one of the oldest herbal remedies for pain and inflammation. It has been used by the ancient Egyptian, Roman, Greek, and Indian civilizations as an analgesic and antipyretic agent. In fact, the first record of its use is found in the Ebers papyrus, written more than 3500 years ago. Because the drug caused gastric irritation, the French chemist Charles Gerhardt neutralized salicylic acid and created acetylsalicylic acid. In 1897, Felix Hoffmann used the agent to treat his father's rheumatoid arthritis, and because of his success, the Bayer Corporation marketed the product under the trade name of aspirin, which is now one of the most widely prescribed nutraceutical agents in the world.
Because of the side effects of aspirin, there has been a resurgence in the use of white willow bark for the treatment of inflammatory syndromes. Salix alba, or white willow, is the species most commonly used for medicinal purposes. The mechanism of action of white willow bark is similar to that of aspirin in that it is also a nonselective inhibitor of COX-1 and COX-2, thus reducing the inflammatory prostaglandins. Various randomized placebocontrolled studies comparing white willow bark with nonsteroidal agents have show an efficacy comparable to these agents and aspirin. Salicin from white willow bark is converted to salicylic acid by the liver and is considered to have fewer side effects than aspirin. However, it is more costly than aspirin, and should not be used in children (to avoid the risk of Reye syndrome), or in patients with peptic ulcer disease, diabetes, hepatic or renal disorders, or other conditions in which aspirin would be contraindicated. The usual dose of white willow bark is 240 mg per day.
Curcumin is a naturally occurring yellow pigment derived from turmeric (Curcuma longa), a flowering plant in the ginger family. It has traditionally been used as a coloring and flavoring spice in food products. Curcumin has long been used in both Ayurvedic and Chinese medicine as an antiinflammatory agent, a treatment for digestive disorders, and to enhance wound healing. Several clinical trials have demonstrated curcumin's antioxidant, antiinflammatory, and antineoplastic effects. In a recent article in the New England Journal of Medicine, Zandi and Karin suggested that curcumin might be efficacious in the treatment of cystic fibrosis because of its antiinflammatory effect. Curcumin is known to inhibit inflammation by suppressing NF-êB, restricting various activators of NF-êB as well as stemming its expression. Curcumin has been suggested as a treatment for colitis, chronic neurodegenerative diseases, arthritis, and cancer. In addition, it regulates the activity of several enzymes and cytokines by inhibiting both COX-1 and-2. Most studies to date have been performed in animals, but given the centuries of use of curcumin, as well as its now demonstrated activity in the NF-êB, COX-1, and COX-2 inflammatory pathways, it may be considered a viable natural alternative to nonsteroidal agents for the treatment of inflammation.
The usual dosage of standardized turmeric powder is 400 to 600 mg taken three times per day. Side effects are few, but with extended use this agent can cause stomach upset, and in extreme cases gastric ulcers may occur at very high doses. Caution should be used if the patient is taking anticoagulant medications or high doses of nonsteroidal drugs. Studies have shown that curcumin may be used in combination with lower doses of nonsteroidal medications. Curcumin's therapeutic effects are considered comparable to pharmaceutical nonsteroidal medications such as phenylbutazone, but with a major difference in that this compound is relatively nontoxic and free of side effects.
Green tea has long been recognized to have cardiovascular and cancer preventative characteristics due to its antioxidant properties. Its use in the treatment of arthritic disease as an antiinflammatory agent has been recognized more recently. The constituents of green tea are polyphenolic compounds called catechins, and epigallocatechin- 3 galate is the most abundant catechin in green tea.
Epigallocatechin-3 galate inhibits IL-1-induced proteoglycan release and Type 2 collagen degradation in cartilage explants. In human in vitro models, it also suppresses IL-1â and attenuates activation of the transcription factor NF-êB. Green tea also inhibits the aggrecanases, which degrade cartilage.
From various studies, the molecular basis of the antiinflammatory and chondroprotective effects of green tea is being discovered. A recent review article from Yale University regarding green tea as the Asian paradox summarizes its currently recognized therapeutic effects: as a cardiovascular and neuroprotective agent, an inhibitor of carcinogenesis, and an antiinflammatory agent. The usual recommendation is 3 to 4 cups of tea a day. If the patient is taking green tea extract, a dosage of 300 to 400 mg is typical. Green tea can cause stomach irritation in some, and because of its high caffeine content, a decaffeinated variety should be considered
Pycnogenol (Maritime Pine Bark)
Pycnogenol, like white willow bark, is a nutraceutical material that has been used since ancient times. Pycnogenol is derived from the bark of the maritime pine tree (Pinus maritima) and has been used for more than 2000 years. Hippocrates mentions its use as an antiinflammatory agent. It has been considered helpful for wound healing, treating scurvy, healing of ulcers, and reducing vascular inflammation. It contains a potent blend of active polyphenols that includes catechin, taxifolin, procyanidins, and phenolic acids. It is one of the most potent antioxidant compounds currently known. Pycnogenol inhibits TNFá-induced NF-êB activation as well as adhesion molecule expression in the endothelium. Grimm and colleagues recently reported that oral intake of pycnogenol inhibited NF-êB activation in lipopolysaccharide- stimulated monocytes as well, thus decreasing the inflammatory response. It also statistically significantly inhibited matrix metalloproteinase-9. This matrix-degrading enzyme is highly expressed at sites of inflammation, and contributes to the pathogenesis of various chronic inflammatory diseases.
In a recently published review article on pycnogenol and its effect on the cardiovascular system, investigators concluded that due to its antiinflammatory activity, this agent has the potential to counteract major cardiovascular risk factors, including reducing platelet activity and reducing the inflammatory process that underlies coronary artery disease. With the mounting evidence of its antiinflammatory effects and its virtual absence of toxicity, pycnogenol may play a larger role in the treatment of the pain from arthritic conditions in athletes as well as in degenerative disease of all kinds. Due to its potent antioxidant effects, enhancement of sports endurance was indicated in a recent study in which athletes took 200 mg per day of pycnogenol. Vigorous sports activity dramatically increases oxygen consumption, by 10- to 20-fold over the resting state. Hence, an increased number of free radicals is generated during exhaustive exercise. Pycnogenol is thought to counteract the deleterious effects of these free radicals and improve blood flow to muscle, as was demonstrated by Pavlovic in a double-blind cross-over study of 24 recreational athletes.
Studies have shown that this agent is 50 to 100 times more potent than vitamin E in neutralizing free radicals and that it helps recycle and prolong the activity of vitamins C and E. Studies have shown pycnogenol to be effective in reducing blood pressure and reducing the risk of venous thrombosis by its effect on vascular endothelium. The usual dosage is 100 to 200 mg daily. Few side effects from the use of pine bark extracts have been reported, the most frequent being mild gastrointestinal effects such as diarrhea and upset stomach. Pycnogenol should not be taken by patients who are being treated with immunosuppressants or by those receiving corticosteroid drugs, because it can enhance immune system function and interact with drugs that are supposed to suppress the immune system.
Boswellia Serrata Resin (Frankincense)
The Boswellia species are trees located in India, Ethiopia, Somalia, and the Arabian peninsula that produce a gum resin called olibanum, better known in the western world as frankincense. This resin possesses antiinflammatory, antiarthritic, and analgesic properties. It is known to inhibit the leukotriene biosynthesis in neutrophilic granulocytes by inhibiting 5-LOX. Various inflammatory diseases are perpetuated by leukotrienes, hence some of the antiinflammatory activity of this agent. Clinically, the substance is used in the treatment of degenerative and inflammatory joint disorders. It reduces the total white blood cell count in joint fluid, and it also inhibits leukocyte elastase, which is released in rheumatoid arthritis. In one recent study, a statistically significant improvement in arthritis of the knee was shown after 8 weeks of treatment with 333 mg B. serrata extract taken three times a day. The treatment improved function, but radiographically there was no change in the affected joints. Another study by Kulkarni, et al., demonstrated a significant drop in pain severity and disability. A combination of Boswellia and curcumin showed superior efficacy and tolerability compared with nonsteroidal diclofenac for treating active osteoarthritis. Boswellia typically is given as an extract standardized to contain 30 to 40% boswellic acids (300- 500 mg two or three times/day). Boswellia has been well tolerated in most studies, although some people may experience stomach discomfort, including nausea, acid reflux, or diarrhea.
Uncaria Tomentosa (Cat's Claw)
Uncaria tomentosa and U. guianensis100 are Peruvian herbs derived from woody vines with small clawlike thorns (hence the vernacular name, cat's claw) at the base of the leaf that allows the plant to climb to heights of up to 100 ft. Traditionally, a decoction of the bark of the cat's claw is used to treat arthritis, bursitis, and intestinal disorders. The active ingredients appear to be polyphenols (flavonoids, proanthocyanidins, an tannins), alkaloids, and sterols Various studies indicate that this Peruvian herb induces a generalized reduction in proinflammatory mediators.
This herb has been shown to prevent the activation of the transcriptional factor NF-êB and it directly inhibits TNFá production by up to 65 to 85%. It inhibits the expression of inducible genes associated with inflammation, specifically negating the expression of inducible nitric oxide synthase, and hence attenuates nitrous oxide production. Side effects may include nausea, although it has shown an impressive protective effect on indomethacin- induced enteritis in laboratory studies. Although toxicity and side effects are usually minimal, two case reports of acute renal failure in a patient with lupus erythematosus have been recorded. Cat's claw can be consumed as a tea (1000 mg root bark to 8 oz water), or as a dry, standardized extract in a capsule (20-60 mg daily).
Capsaicin (Chili Pepper)
Capsicum annum is a small spreading shrub originally cultivated in the tropical regions of the Americas but now is grown throughout the world, including the US. The small red fruit commonly used to accentuate chili owes its stinging pungency to the chemical capsaicin. This was isolated by chemists more than a century ago and constitutes approximately 12% of the chili pepper. This fruit has been used for medicinal purposes by the native peoples of the American tropics for hundreds of years.
More recently, various preparations have become available over the counter for the treatment of peripheral neuropathies and chronic musculoskeletal pain. Capsaicin produces highly selective regional anesthesia by causing degeneration of capsaicin-sensitive nociceptive nerve endings, which can produce significant and long-lasting increases in nociceptive thresholds. Capsaicin potently activates transient receptor potential vanilloid 1, which is a main receptor underlying nociception. It also inhibits NF-êB, thus producing an antiinflammatory effect. Capsaicin can cause a burning sensation when it comes in contact with human flesh, and also in the digestive tract. This herb is rarely used alone but is generally mixed into other natural antiarthritic preparations. There are topical capsaicin formulations now available to treat postherpetic neuralgia.
credit: Medscape Today