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Inflammation Control Options from Nature

By Yousry Naguib, Ph.D.

Vitamin Retailer magazine (July 2003)

Inflammation is a localized response elicited by injury or destruction of tissues, which serves to destroy or sequester the injurious agent, often of microbial nature. Inflammation is derived from inflammatio and inflammare, meaning to set on fire. Inflammation is characterized by the classical signs pain, heat, redness, swelling, and loss of function.

Pain is partly caused by compression of the nerve endings that accompanies the welling and partly by irritation of the nerve endings by inflammatory mediators such as prostaglandins.

Inflammation can be described as acute or chronic based on its duration. The acute inflammation usually has a sudden onset (minutes, hours, a few days) after cellular injury, which may be caused by biological (microbes), physical (bums, trauma), chemical agents (toxins, caustic substances), and immunological reactions. Chronic inflammation is an inflammatory response of prolonged duration-weeks, months, or even years-whose extended time course is provoked by persistence of the causative stimulus to inflammation in the tissue.

If the agent causing acute inflammation is not removed, the acute inflammation may progress to the chronic stage. Examples of chronic inflammation include rheumatoid arthritis, inflammatory bowel disease, and tuberculosis.

Since the discovery of aspirin 100 years ago, non-steroidal anti-inflammatory drugs (NSAIDs) have become mainstays in the medical management of arthritis inflammation and pain relief. The market for NSAIDs and related analgesics is valued at more than $8 billion worldwide. NSAIDs don't address the underlying disease but rather alleviate its most bothersome symptoms.

Most of the NSAIDs, while relieving the symptoms of pain and arthritis, cause substantial gastrointestinal side effects and are commonly associated with renal toxicity and inhibition of platelet aggregation, resulting in patient compliance problems. The anti-inflammatory action, together with the common side effects of NSAIDs, is mediated through the inhibition of prostaglandin biosynthesis. Prostaglandins are a group of long chain fatty acids derived from arachidonic acid.

ARACHIDONIC ACID CASCADE

Arachidonic acid (AA) is a polyunsaturated C20 fatty acid bound to the membrane of almost all of the body's cells. AA is liberated from the phospholipids of cell membranes by the action of the enzyme phospholipase A2. The liberated AA is then metabolized through one of two principle pathways: the lipoxygenase pathway (which results in the production of leukotrienes) and the cyclooxygenase (COX) pathway (which results in the production of prostaglandins). Prostaglandins are hormone-like cellular modulators with a wide variety of physiological activities, including inflammation.

Aspirin and NSAIDs achieve their therapeutic effects by acting on the arachidonic acid cascade, by inhibiting the enzyme COX, and hence inhibiting the production of prostaglandins.

Research suggested the existence of different forms of COX, a constitutive form (COX-I), constantly produced in the body's cells, and an inducible form (COX-2), responsible for pain and inflammation, and produced in response to specific stimuli.

COX-l is involved in cellular "housekeeping functions" necessary for normal physiological activity, whereas COX-2 act primarily at sites of inflammation. The clinical corollary of this finding is that specific inhibition of COX-2 would exert beneficial anti-inflammatory effects without influencing the important physiologic functions of COX-I.

Since current NSAIDs, such as aspirin, inhibit both COX-l and COX-2 to varying degrees, their side effects might be related to their ability to inhibit COX-I, whereas their anti-inflammatory effects might depend on their ability to inhibit COX-2. Therefore, drugs designed to block COX-2, but not COX-I, would have anti-inflammatory properties and would not inhibit the synthesis of gastrointestinal prostaglandins (thereby avoiding ulcers) and platelet thromboxane (thereby avoiding bleeding) (1). Celebrex and Vioxx are selective COX-2 inhibitors that have been shown to have fewer ulcers and ulcer complications than traditional NSAIDs.

Recent studies also point to COX-2 as an important factor in cancer-cell growth. In tests carried out by researchers at Columbia University, an herbal mix, called Zyflamend from New Chapter Inc., (Battleboro, VT) was found to suppress the growth of prostate-cancer cells. The researchers noted that prostate cancer cells make COX-2.

Zyflamend contains 10 herbs: holy basil (Ocimum sanctum), turmeric, ginger, green tea, rosemary, hu zhang (Polygonum cuspidatum), Chinese goldthread, barberry, oregano, and Scutellaria biacalensis (2). Holy basil, turmeric, hu zhang, and scutellaria contain the COX-2 inhibitors ursolic acid, curcumin, resveratrol, and baicalin, respectively. Both Chinese goldthread and barberry contain the COX-2 inhibitorberberine. Green tea and rosemary contain polyphenols, which have been reported to reduce COX-2 activity. Zyflamendis also recommended as an arthritis alternative to block the enzyme COX-2 that triggers the joint inflammation responsible for arthritis pain. Almost all patients with arthritis or chronic pain will be prescribed an NSAID.

ARTHRITIS

Arthritis is an inflammatory joint disorder characterized by pain, swelling and limited movement. It can be caused by inflammation, infection in ajoint, degeneration of a joint. The most common forms of arthritis are rheumatoid (autoimmune disease), and osteoarthritis (brittle bone disease, a type of arthritis that occurs as a result of wear and tear on the joints as we age).

Osteoarthritis (OA) accounts for more than half of all arthritis cases in the United States. An estimated 20 million Americans, mostly women over age 45, suffer from this disabling disease. The onset of OA is gradual and results from progressive loss of cartilage proteoglycans (cartilage breakdown).

Cartilage is a highly differentiated tissue that cushions and protects joints against the friction caused by the rubbing together of bones. According to the Arthritis Foundation, rheumatoid arthritis (RA) affects 2 million Americans and usually strikes in middle age. Women are three times more likely than men to develop rheumatoid arthritis, in which joints stiffen and swell with fluid. Symptoms may also include fatigue, weakness, and fever.

RA occurs when the body's immune system turns against itself and starts to damage joint tissues. RA causes inflammation and deformity of the joints. Most treatments of arthritis combine medication, exercise, and rest, use of heat and cold, joint protection techniques, and sometimes surgery. Drugs most commonly prescribed are NSAIDs. While COX-2 selective inhibitors Celebrex (Celecoxib) and Vioxx (Rofecoxib), Bextra (Valdecoxib) effectively alleviate pain associated with inflammation, and reduce the risk of GI toxicity, they share the potential risks for adverse renal effects with the non-selective NSAIDs, such as aspirin, ibuprofen, naproxen.

Alternative therapies include herbs such as ashwagandha, Chinese barberry and goldthread, cayenne (topical, for pain only), devil's claw, ginger, nettle, willow; boswellia, cat's claw; and a variety of nutritional supplements: chondoitin sulfate, glucosamine sulfate, SAMe, fish oil, and methylsulfonylmethane (MSM).

ASHWAGANDHA

Ashwagandha (Withania somnifera) is a small shrub in the nightshade (Solanaceae) family, which grows prolifically in India as well as in parts of northern Africa and the Middle East. The roots and leaves of this plant are used in Ayurvedic medicine extensively to reduce the pain of arthritis (3). The recommended dosage of Ashwagandha is 1-2 g of whole herb standardized for 2-7 mg of "withanolides." It can also be taken as a tincture or fluid extracts of 2-4 ml three times per day.

CHINESE BARBERRY, GOLDTHREAD, AND AMUR CORK TREE

The genera Berberis and Coptis contain berberine, an alkaloid found to effectively inhibit COX-2 transcriptional activity in colon cancer cells (4). These results indicate the potential anti-inflammatory and chemo-preventive property of berberine against colon tumor formation.

Amur cork tree, huang bai (Phellodendron), has been used for centuries in China for abdominal pain and diarrhea. The bark of amur cork tree contains 0.8-1.0 percent berberine. A standardized extract of Phellodendron, sold under the trade name Nexrutine, has been shown to help in the management of inflammatory diseases.

Extracts from the roots and barks of various Berberis species are used in the treatment of various inflammatory ailments including rheumatism. An extract from the roots of Berberis crataegina exhibited potent anti-inflammatory effects in mice. Berberine isolated from the roots extract was shown to be the main active ingredient (5).

HOLY BASIL

The triterpene Ursolic acid, found in holy basil, was shown in a test tube experiment to significantly inhibit cyclooxygenase-2 transcription, and hence prostaglandin E2 synthesis, in human epithelial cells. These results suggest that holy basil might possess anti-inflammatory and anticancer properties (6,7).

FRANKINCENSE (Boswellia serrata)

The gum resin of the ancient herb frankincense has been used in India for the treatment of a variety of health conditions, including ulcers, dyspepsia, pain, and inflammation. Boswellia serrata has been found to block the synthesis of leukotrienes, which can trigger inflammation. A number of chronic inflammatory diseases are perpetuated by leukotrienes. In clinical trials, boswellic acids (components of frankincense) showed promising results in patients with rheumatoid arthritis, chronic colitis, ulcerative colitis, and Crohn's disease (8).

CAYENNE

Cayenne obtained from the dried, ground fruit of various red pepper species (especially Capsicum frutescens) was found to stimulate circulation, aid digestion, and promote sweating (9). Cayenne is used topically for pain relief since the active chemical, capsaicin, alters the action of compounds in the body that transfer pain messages to the brain, thus reducing pain and inflammation.

CURCUMIN

Curcumin, the anti-inflammatory yellow coloring agent contained in turmeric (Curcuma longa L, Zingiberaceae) has been proven in a test tube experiment to be a specific inhibitor of COX-2, and an effective chemo preventive agent against colon cancer with minimal gastrointestinal toxicity (10,11).

In a test tube experiment, curcumin was found to markedly inhibit protein (factor NF- kappaB) expression of COX-2, but not COX-I, in a concentration-dependent manner. These data suggest that curcumin specifically inhibits COX-2 expression, and may have a value as a safe chemo-preventive agent for colon cancer (12).

DEVIL'S CLAW

Devil's claw (Harpagophytum procumbes) is an African plant whose fruit looks like a giant claw. The root and tuber have been used in traditional medicine to treat inflammatory conditions such as arthritis, rheumatism, and lower back pain, allergies, and headache.

In a randomized, double-blind pilot study involving patients with nonspecific low back pain, 44 patients received a daily dose of Doloteffin containing 60 mg of harpagoside for 6 weeks and 44 patients received 12.5 mg/day of Vioxx (NSAID). Forty-three Doloteffin patients and 36 NSAID patients completed the study. Ten (23 percent) of Doloteffin patients and five (14 percent) of NSAID patients reported no pain for at least five days of the sixth week of treatment (13).

A recent review of two clinical trials found that people who took capsules containing either 335 mg or 400 mg of devil's claw extract three times a day, for either three weeks or two months, experienced pain relief. People with moderate OA were more likely to experience relief, but some with severe arthritis also felt an improvement (l4). Devil's claw preparations with 50-100mg of harpagoside or willow bark extract with 120-240mg salicin proved efficacious as anti-rheumatics in clinicaltrials (15).

GINGER

6-Gingerol, a pungent ingredient in ginger (Zingiber officinale, Zingiberaceae) possesses anti-carcinogenic activities, effects associated with its anti-oxidative and anti-inflammatory activities (16). In a test tube experiment, pungent oleoresin constituents of Ginger showed strong inhibitory effects on COX-2 enzyme activity (17).

STINGING NETTLE

Stinging nettle (Urtica dioica) is effective when used as a topical treatment for arthritis and rheumatism. In vitro addition of a commercial preparation of nettle leaf (IDS 23, Rheuma-Hek) to whole human blood resulted in an inhibition of lipopolysaccharide-stimulated secretion of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin-l beta (IL-I beta) in human blood (18).

In another study involving 37 patients with acute arthritis, the effects of 200 mg of diclofenac (NSAID) were compared with 50 mg of diclofenac plus 50 g of stewed nettle leaf per day. Clinical improvement of the signs of acute arthritis was observed in both groups to a similar extent (l9).

THUNDER GOD VINE

The roots of thunder god vine (Tripterygiumwilfordii Hook), a plant whose leaves and flowers are highly toxic, have been used for years in China as a treatment to reduce pain in people with arthritis.

In a randomized, double-blind, placebo-controlled trial, 21 rheumatoid arthritis patients were assigned to one of three treatments: placebo, low-dose (180 mg/day) or high dose (360 mg/day) extract of vine root After four weeks, 80 percent of patients in the high dose group and 40 percent in the low-dose group showed marked improvement in symptoms. The study suggested that the vine root extract reduces inflammation by turning off inflammatory genes (20).

WHITE WILLOW BARK

Since the discovery of aspirin 100 years ago, non-steroidal anti-inflammatory drugs (NSAIDs) have become mainstays in the cal management of arthritis inflammation and pain relief.

The centuries-old natural remedy of using white willow bark (Salix alba) to provide some pain relief led to the discovery of aspirin, and eventually to NSAIDs. Willow bark extract with 120-240 mg salicin in the daily dosage proved efficacious in a number of clinical studies (21).

Fatty Acids

Borage oil is rich in the essential fatty acid gamma-linolenic acid (GLA), also found in black currant and evening primrose oils. GLA is converted by the body to prostgalndin E1, which may account for its ability to reduce inflammation.

In a recent study, GLA administered to patients with arthritis was shown to suppress the release of the pro-inflammatory cytokine interleukon-1beta from human monocytes stimulated with lipopolysaccharide (22).

Fish oils EPA and DHA have been shown to reduce joint tenderness and morning stiffness, and to reduce the dose of NSAIDs in patients with rheumatoid arthritis (23).

Enzymes

Some enzymes have shown promise in alleviating symptoms associated with osteoarthritis. Proteolytic enzymes, such as bromelain and papain (protein-digesting enzymes from pineapple and papaya), have analgesic, anti-inflammatory, and swelling-reducing properties.

Phlogenzym is a mix of the enzymes bromelain (90 mg), from the stem of the pineapple plant (Ananas comosus Merr.), and trypsin (48 mg), usually taken from hog pancreases, and 100 mg of the antioxidant rutin, derived from citrus fruits. The efficacy of an oral enzyme therapy with phlogenzym was compared to diclofenac in patients ages 40-75, with OA of knee joints. Patients received either phlogenzym (2-3 tablets) or diclofenac for three weeks. At the end of the study, reduction in joint tenderness was greater in the phlogenzym as compared to the diclofenac group (24).

Glucosamine and Chondroitin

Chondroitin sulfate (CS) is an important component of the body’s natural building blocks for the cartilage found in joints. CS is found in the proteoglycans of cartilage. Glucosamine on the other hand acts as the building block for the biosynthesis of glycosaminoglycans needed to form proteoglycans that are important constituents of the cartilage. Glucosamine sulfate can not only relieve arthritis symptoms but also help the body repair damaged joints (25).

The first U.S. six month trials on the efficacy of CS in the treatment of knee osteoarthritis was reported in 2000. In a randomized, placebo-controlled study, 93 patients with OA of the knee were given a combination of low molecular weight sodium CS (800 mg), glucosamine hydrochloride (1000 mg), and manganese ascorbate (152 mg) twice daily. After six months, a significant improvement in severity of mild to moderate OA was observed (26).

MSM

Methyl sulfonyl methane, also known as dimethyl sulfone, is a naturally occurring sulfur compound found in a variety of foods. MSM has been claimed to play an important role in collagen synthesis, which helps arthritis. In a double-blind study, Ronald Lawrence at UCLA School of Medicine found that about 80 percent of arthritis patients who ingested 2,250 mg of MSM a day for six weeks showed improvement in their pain symptoms, while 18 percent of those on the placebo experienced an improvement at six weeks (27).

S.ADENOSYLMETHIONINE (SAMe)

SAMe appears to act like glucosamine in the treatment of OA (28). In a recent meta-analysis of randomized controlled trials of SAMe versus placebo or NSAIDs for the treatment of OA, SAMe was found to be as effective as NSAIDs in reduceing pain and improving activity limitation in patients with OA without the adverse effects (29).

HYALURONIC ACID (HA)

HA is a polysaccharide composed of repeating units of N-acetyl-glucosamine and D-glucuronic acid. The main source of HA is rooster combs. Another important source of HA is from microorganisms, through a fermentation process. In humans, HA is found in the soft connective tissue, and the synovial joint fluid (the fluid secreted by the lining of the joint to nourish and lubricate the joint).

In OA, the concentration of HA is decreased in both the cartilage and synovial fluid. In 1997, the FDA approved HA for the treatment of OA of the knee. Clinical studies have shown that intra-articular injections of HA produce rapid pain relief and improved mobility in OA (30).

REFERENCES

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[23] Kremer JM. N-3 fatty acid supplements in rheumatoid arthritis. Am J Clin Nutr 2000; 71(1 suppl):349S

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