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Nature offers a solution to the problem caused by arthritis wonder drugs

By Dale Keifer

Dual Inflammatory Pathway Blockade
Stimulation of TNF-alpha and IL-1 beta is not the only problem associated with COX-2 inhibitors. The body has two inflammatory pathways, both branching from the inflammatory precursor arachidonic acid. Blocking one pathway while leaving the other wide open is as imbalancing as it is incomplete. Pharmaceutical companies understand this shortcoming, and are developing drugs that block both branches of the inflammatory pathway.[16]


The problem with these drug candidates is that they block both forms of COX (COX-1 and COX-2) in addition to 5-LOX. Research has shown that indiscriminate COX inhibitors create a persistent โ€œrebound effectโ€ on proinflammatory signaling. Even two weeks after discontinuation of daily aspirin or ibuprofen, cytokine-stimulated production of TNF-alpha and IL-1 beta was increased from 270% to 538%.[17]

Thus indiscriminate inhibitors of COX cause the same end result discussed aboveโ€”potentiation of the two pivotal cytokines responsible for cartilage destruction and the inflammatory cascade in arthritis.

The balanced approach we have discussedโ€”selective inhibition of COX-2 combined with inhibition of TNF-alpha and IL-1 betaโ€”is, however, still incomplete. It is necessary to block the second inflammatory pathway, 5-lipoxygenase (5-LOX), which produces proinflammatory leukotrienes. Fortunately, an herbal inhibitor of 5-LOX has been discovered. 5-Loxinโ„ข is derived from Boswellia serrata, a tree native to India whose aromatic gum resins have been used by practitioners of the Ayurvedic system of medicine to treat arthritis for centuries.

Laboratory analysis of the gummy resin from Boswellia shows that one component, รŸ-boswellic acid, acts as a specific inhibitor of 5-LOX.[18]

Having isolated and concentrated the most active of the Boswellic acids, it is now possible to derive the benefits of 5-LOX inhibition without consuming large amounts of ordinary Boswellia serrata extracts.

A drug candidate under development by Shionogi, a Japanese pharmaceutical company, illustrates the potential of dual inflammatory pathway blockade. S-2474 is a dual inhibitor of COX-2 and 5-LOX. Not surprisingly, S-2474 significantly inhibited experimentally induced edema and arthritis while suppressing inflammatory mediators, all without ulcerogenic effects.[19]

Demonstrating the pervasiveness of dual inflammatory pathways in degenerative processes in the body, S-2474 also protected brain cells from amyloid beta induced neuronal death. Amyloid beta, which gives rise to the โ€œsenile plaquesโ€ characteristic of Alzheimerโ€™s disease, generates the proinflammatory prostaglandin D2 that was inhibited by S-2474.[20]

A common herb, ginger root, contains gingerols that also inhibit both the cyclooxygenase and lipoxygenase pathways, and the production of prostaglandins, thromboxane and leukotrienes.[21-23]

When COX-2 and 5-LOX inhibitors are used in tandem, inflammatory leukotrienes and prostaglandins are suppressed equally and balance is achieved safely.

Rebuilding Joints
Chondroitin and glucosamine sulfates are natural components of healthy joint tissue, and are readily available as dietary supplements. They work by supplying the natural raw materials cartilage needs to repair and rebuild itself, and by suppressing the natural enzymes that break cartilage down in the first place.

Glucosamine is a naturally occurring substance in the body, synthesized in the chondrocytes. In osteoarthritis, this synthesis is defective and insufficient, and supplementation with glucosamine has proven to be useful. The body uses supplemental glucosamine to synthesize the proteoglycans and the water-binding glycosaminoglycans (GAGs) in the cartilage matrix. In addition to providing raw material, the presence of glucosamine seems to stimulate the chondrocytes in their production of these substances. Glucosamine also inhibits certain enzymes that destroy the cartilage, e.g., collagenase and phospholipase. By blocking pathogenic mechanisms that lead to articular degeneration, glucosamine delays the progression of the disease and relieves symptoms even for weeks after termination of the treatment.[24]

Chondroitin sulfate is a major component of cartilage. It is a very large molecule, composed of repeated units of glucosamine sulfate. Like glucosamine, chondroitin sulfate has the ability to prevent enzymes from dissolving cartilage.

Glucosamine alone or in combination with chondroitin sulfate is becoming recognized as the treatment of choice for osteoarthritis in the United States. Its ability to actually repair and improve joint function in addition to providing pain relief gives it a significant advantage over conventional treatment. Extensive studies have proven the ability of these natural tissue components to stimulate new tissue growth and suppress the enzymes that otherwise break down cartilage.

A new study analyzed glucosamine and chondroitin clinical trials for knee osteoarthritis from 1980 through early 2002 through a sophisticated statistical technique known as โ€œmeta-analysis.โ€ Glucosamine studies demonstrated a highly significant efficacy on all outcomes, including the WOMAC scale (Western Ontario MacMaster Univ. Osteoporosis Index) and joint space narrowing. Chondroitin was found effective on mobility, visual analog scale pain, the Lequesne Index of severity for osteoarthritis and responding status.[25]

In order to maintain optimal joint health well into your later years, itโ€™s important to maintain healthy weight and to exercise regularly. Overtaxed joints and weak muscles are a dangerous combination. Chondroitin and glucosamine sulfates can safely halt and reverse structural damage to joints, and promote the building of healthy new cartilage.

Just as arthritis is not one condition, no single treatment is likely to yield satisfactory results. A systemic approach targeting proinflammatory cytokines, the dual inflammatory pathways and cartilage destruction should more effectively address the multifaceted nature of the host of conditions that are known as arthritis.


References

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2. Plows D, et al. The role of tumor necrosis factor (TNF) in arthritis: studies in transgenic mice. Rheumatol Eur. 1995; Suppl 2: 51-4.

3. Bertolini DR, et al. Stimulation of bone resorption and inhibition of bone formation in vitro by human tumor necrosis factor. Nature. 1986; 319: 516-18.

4. Saklatvala J. Tumour necrosis factor alpha stimulates resorption and inhibits synthesis of proteogly- can in cartilage. Nature. 1986 Aug 7-13;322 (6079):547-9.

5. Penglis PS, et al. Differential regulation of prostaglandin E2 and thromboxane A2 production in human monocytes: implications for the use of cyclooxygenase inhibitors. J Immunol. 2000 Aug 1; 165(3): 1605-11.

6. Goldman G, et al. Thromboxane A2 induces leukotriene B4 synthesis that in turn mediates neu- trophil diapedesis via CD 18 activation. Microvasc Res. 1991 May; 41(3):367-75.

7. van den Berg WB. Anti-cytokine therapy in chronic destructive arthritis. Arthritis Res. 2001;3(1):18-26.

8. Dayer JM. Interleukin 1 or tumor necrosis factor- alpha: which is the real target in rheumatoid arthritis? J Rheumatol. 2002 Sep; Suppl 65:10-5.

9. Obertreis B, et al. Ex-vivo in-vitro inhibition of lipopolysaccharide stimulated tumor necrosis fact- or-alpha and interleukin-1 beta secretion in human whole blood by extractum urticae dioicae foliorum. Arzneimittelforschung. 1996 Apr;46(4):389-94.

10. Klingelhoefer S, et al. Antirheumatic effect of IDS 23, a stinging nettle leaf extract, on in vitro expression of T helper cytokines. J Rheumatol. 1999; 26(12):2517-2522.

11. Riehemann K, et al. Plant extracts from stinging nettle (Urtica dioica), an antirheumatic remedy, inhibit the proinflammatory transcription factor NF-kappaB. FEBS Lett 1999;442(1):89-94.

12. Jue DM, et al. Nuclear factor kappaB (NF- kappaB) pathway as a therapeutic target in rheumatoid arthritis. J Korean Med Sci. 1999 Jun;14(3):231-8.

13. Schulze-Tanzil G, et al. Effects of the antirheumatic remedy hox alphaโ€“a new stinging nettle leaf extractโ€“on matrix metalloproteinases in human chondrocytes in vitro. Histol Histopathol. 2002 Apr; 17(2):477-85.

14. Chrubasik S, et al. Evidence for antirheumatic effectiveness of herba urticae dioicae in acute arthritis: a pilot study. Phytomedicine.1997; 4:105-108.

15. Dennis and Company Research. Nexrutineยฉ human trial report. Next Pharmaceuticals, Inc. 2002; 13.

16. Boileau C, et al. Licofelone (ML-3000), a dual inhibitor of 5-lipoxygenase and cyclooxygenase, reduces the level of cartilage chondrocyte death in vivo in experimental dog osteoarthritis: inhibition of pro-apoptotic factors. J Rheumatol. 2002 Jul;29(7):1446-53.

17. Endres S, et al. Oral aspirin and ibuprofen increase cytokine-induced syntheis of IL-1 beta and of tumour necrosis factor-alpha ex vivo. Immunology. 1996 Feb; 87(2):264-70.

18. Safayhi H, et al. Mechanism of 5-lipoxygenase inhibition by acetyl-11-keto-beta-boswellic acid. Mol Pharmacol. 1995 Jun;47(6):1212-6.

19. Yagami T, et al. Effects of S-2474, a novel non- steroidal anti-inflammatory drug, on amyloid beta protein-induced neuronal cell death. Br J Pharmacol. 2001 Oct;134(3):673-81.

20. Inagaki M, et al. Novel antiarthritic agents with 1,2- isothiazolidine-1,1-dioxide (gamma-sultam) skele- ton: cytokine suppressive dual inhibitors of cyclooxygenase-2 and 5-lipoxygenase. J Med Chem. 2000 May 18;43(10):2040-8.

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To understand arthritis, itโ€™s important to understand how joints work. Healthy joints act as buffers between bones. They allow bones to move freely, without friction. They also protect bones from the often-enormous pressures generated by ordinary use. The knee, for example, allows for alignment between the thighbone, or femur, and the bones of the lower leg, so that we may stand. Tendons and ligaments connect bone and cartilage to muscle, allowing for changes in the position of two or more bones.

In order to walk, run, climb or, indeed, move at all, the knee provides a point at which the leg may bend. The ends of the femur and tibia (or lower leg bone) are capped not in bone, but in articular cartilage, a gelatinous, rubbery tissue that consists largely of water (65% to 80%) in a matrix of collagen, chondrocytes and proteoglycans. Collagen is an important structural protein that provides a fibrous framework to support proteoglycans, which are large molecules consisting of proteins and sugars. Collagen also provides elasticity and shock-absorption. Proteoglycans, specifically glycosaminoglycans (GAGs), attract and hold water, and water is crucial to cartilageโ€™s function in the joints. The entire joint is encapsulated, and contains synovial fluid, which fills the space between the cartilage-capped ends of the pivoting bones. Chondrocytes, or cartilage cells, manufacture new collagen and proteoglycans as needed, and generate enzymes that break down and recycle these materials when they deteriorate. Research has shown that when adequate glucosamine is available, chondrocytes produce plenty of collagen and water-loving proteoglycans.[26]

Consider what occurs when you take a few steps. As your foot hits the floor, the cartilage at the ends of the leg bones is compressed. Water is temporarily squeezed out of the cartilage matrix, only to rush back in during the โ€œrestingโ€ phase of the stride. This ingenious hydrostatic mechanism allows cartilage to absorb punishing forces, with virtually no friction and (ideally) no damage to either bone or cartilage.

Although there are more than 140 joints in the human body, allfall within three categories: fixed, partially moveable and highly moveable. Of these three, the joints of the latter categoryโ€”which see the most actionโ€”are most likely to cause problems. These joints are further categorized according to their function. For instance, moveable joints may be of the hinge type (e.g., the elbow), ball-in-socket (as in the hips) or gliding (as found in the hand), among others. Not surprisingly, the joints that bear the most weight, such as hip and knee joints, are the most common problem areas.

Unfortunately, as the years go by, the ability of chondrocytes to generate new constituents of healthy cartilage appears to decrease. The delicate balance between collagen, water and proteoglycans begins to shift, resulting in damaged cartilage and eventual grinding, cracking and arthritic pain. Bone may attempt to compensate by generating spurs, which further exacerbates the problem. Restoration of healthy articular cartilage is the key to restoring healthy, pain-free joint function.