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Not Just Joints

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Joint, muscles & connective tissue support

  • Helps comfort sore joints and muscles
  • Supports healthy cartilage and mobility
  • Promotes healthy inflammation management

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If you suffer from arthritis there is some additional information in this section which you may find helpful. We have put together some technical papers for our customers who would really like to gain a better understanding of why this product works so well.

Technical Paper 1 (introduction to Arthritis)
Technical Paper 2 (Not Just Joints Active Ingredients Information)
Additional Paper (Delivery System)


Technical Paper

Introduction to Arthritis
Xtend-Life Not Just Joints is a health supplement composition useful as a complement to medications for the treatment of a selected group of arthritic conditions.

Arthritic forms
Common forms of arthritis include osteoarthritis - a degenerative condition of the articular cartilage and bone, degenerative joint disease, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus, juvenile arthritis, rheumatoid arthritis and psoriatic arthritis - usually affecting only a few joints and following a rather episodic course with varying degrees of suffering and debilitation. The range of symptoms and duration of disease may extend to forms considered mild, acute, or even severe in extreme cases.

Treatment
For all forms of arthritis conventional therapy has included the use of corticosteroids, initially at a small dose and then continued and slowly increased, for a period of several years until the desired degree of control and mobility is attained. Prednisone is also often used.

For acute episodes of osteoarthritis an intra-articular injection of corticosteroids is often recommended. Other treatments have included the administration of salicylates, notably aspirin, gold salts, ibuprofen, indomethacin, oxyphenbutazone and the like (Harris, E.D., New England Journal of Medicine, Vol. 322, p. 1277-1289 (1990); and, Cash, J.M., et al., New England Journal of Medicine, Vol. 330, p. 1368-1375 (1994)).

Although substances such as aspirin inhibit prostaglandin production and thus pain and inflammation, they may cause stomach problems and ulcers. To address these problems drugs have been developed to target specific pain pathways in the hope of reducing some of the problems associated with aspirin, ibuprofen and other similar substances, if not completely eliminating them. One such drug is Celebrex®, which apparently targets such a specific pain pathway and thus does not have some of the disadvantages associated with substances such as aspirin.

NSAIDs (None-Steroidal Anti-Inflammatory Drugs) in particular prevent the production of prostaglandins by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway. However, drugs like Celebrex® distinguish between COX-1 and COX-2 and are touted as having less of the side effects associated with normal NSAIDs.

Rheumatoid Arthritis
The most common form of arthritis is rheumatoid arthritis, characterized by a chronic inflammatory condition affecting particularly the small joints of the hands and feet, although the larger joints may also be affected later.

Anatomical Explanation of Rheumatoid Arthritis
The synovial membrane typically swells forming pulpy masses or fringes causing the joints to be enlarged. A gradual destruction of the articular cartilage finally results in complete disability and fusion of the joint surfaces. Customary symptoms include pain and swelling of the joints together with increasing stiffness and disability as the condition continues. The joints may eventually become distorted, deformed and painful.
The cartilage of the joints is called hyaline cartilage (from the Greek "hyalos" which means glass); hyaline cartilage is found not only on all surfaces of bones that move (articular cartilage) but also in the nose, larynx, ribs and trachea. This cartilage consists of 70% water, about 10% collagen, type II, and the rest is various protein and specialized complex sugars called proteoglycans.

The articular cartilage provides resilience, a low friction surface and load-bearing distribution over the entire synovial joint. Even though the articular cartilage is very thin (about one eighth of an inch thick) it performs its function for the life of the individual (80-90 years or more) without any significant deterioration, unless it becomes injured or diseased.

The mechanism of pain first involves the stimulation of the nociceptors. When the nociceptors are stimulated the release of substance P, a neuropeptide that modulates cellular responses and increases the pain message, is increased. Substance P can stimulate the release of bradykinin, a neuropeptide that propagates slow pain. Histamine is also released, which evokes pain. Prostaglandins are released by damaged tissue during an inflammation response. Prostaglandin E series (PGEs), prostaglandin I2 (PGI2) and leukotriene B4 (LTB4) amplify pain by increasing the sensitivity of the nociceptors to the effects of other mediators or mechanical stimuli. This is called hyperalgesia. (Gilman A, Rail T, Nies A, Taylor P Ed, Goodman and Gilman's The Pharmacological Basis of Therapeutics, New York, Pergamon Press, 1990).

Causes
The etiology of rheumatoid arthritis is unknown. It is likely that many different causes trigger the development of what is diagnosed as rheumatoid arthritis. Regardless of the cause, once the joint becomes inflamed there is a well-documented immune mediated attack on one of the major structural components of the joints, collagen (Trentham, D. E., et al., J. Exp. Med. 146:857-868, 1977).
As stated above rheumatoid arthritis is an autoimmune disease and as such its etiology is much the same as the etiology of any other autoimmune disease. The body normally recognizes the difference between its own by-products and foreign invaders (i.e. bacteria, viruses, fungi and protozoans to name a few). When an immune cell (T or B lymphocyte) reacts to a "self-protein" during its development that cell is deemed defective and usually destroyed or inactivated. Sometimes however a "self-reactive" immune cell will escape destruction. At a certain later time that cell can be activated and trigger an immune response. Activation is thought to occur after infection with a common bacteria or virus containing a polypeptide and having a stretch of amino acids which match a stretch on the defective self-protein.

Several bacteria, such as Streptococcus, Borrelia, Yersinia, Salmonella, Shigella, Campylobacter or Chlamydia Mycoplasma have been implicated in the initiation of the disease, as well as certain viruses, namely retroviruses. Dr. Wyburn-Mason was able to isolate and identify heavy concentrations of free-living amoebae which he called the Limax Amoebae in the involved tissues of most of the so-called autoimmune or collagen diseases ((Anti-amoebic Treatment for Rheumatoid Disease, the Institute of Bio-molecular Medicine: Gus J. Prosch, Jr., 1985).

In addition to Rheumatoid Arthritis autoimmunity often results in such diseases as juvenile diabetes, multiple sclerosis, Grave’s disease, Menier’s disease, myasthenia gravis, lupus erythematosus and psoriasis. (Medical Sciences Bulletin, September, 1994).
There are bacterial infections that are known to result in the development of arthritis.
Free radicals affect the immune system causing rheumatoid arthritis and osteoarthritis. Free radicals are atoms or atomic groups that are by-products of normal metabolism, tobacco smoke, pollutants, car exhaust fumes, bacteria, radiation and chemicals which oxidize or damage otherwise healthy cells. They damage DNA, corrode cell membranes and may play a role in the development of cancer, heart and lung disease, cataracts and cause or accelerate the aging process.

Rheumatoid Inflammation
Inflammation in patients with rheumatoid arthritis probably involves the combination of an antigen (gamma globulin) with an antibody (rheumatoid factor) and a complement, causing the local release of chemotactic factors that attract leukocytes. The leukocytes phagocytose the complexes of antigen-antibody and complement and also release the many enzymes contained in their lysosomes. These lysosomal enzymes cause injury to cartilage and other tissues and this furthers the degree of inflammation. Cell mediated immune reactions may also be involved. Prostaglandins are also released during this process.

Prostaglandins, which are likely to be generated in inflammation, cause erythema and increased local blood flow. Two important vascular effects of prostaglandins that are not generally shared by other mediators of inflammation are a long-lasting vasodilator action and a capacity to counteract the vasoconstrictor effects of substances such as norepinephrine and angiotensin. Prostaglandin synthesis is accomplished in a stepwise manner by a ubiquitous complex of microsomal enzymes. The first enzyme in this biosynthetic pathway is prostaglandin endoperoxide synthase. This enzyme is also referred to as fatty acid cyclooxygenase. There are two isoforms of this enzyme known as cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), respectively (Smith, Am. J. Physiol., 268:F181-F191, 1992).

A number of mediators of inflammation increase vascular permeability (leakage) in the post-capillary and collecting venules. In addition, migration of leukocytes into an inflamed area is an important aspect of the inflammatory process.

The mechanism of inflammation typically involves 4 main symptoms: redness, warmth, edema (swelling), and pain. When tissue is damaged by mechanical, chemical, biological, or invading organisms, the first thing to happen is that mast cells release histamine. The histamine stimulates dilation of the blood vessels. The increase in blood volume to the area causes redness and the sensation of warmth. Kinins are released, which potentiate the vasodilatation. The vasodilatation causes plasma that contains mediators of acute inflammation (complement, C-reactive protein, antibodies, neutrophils, eosinophils, basophils, monocytes and lymphocytes) to leak into the surrounding tissue.

This causes the tissue to look swollen. The loss of plasma from the blood causes blood to become more viscous. The blood platelets and leukocytes start to stick together and clump. Platelet aggregation causes the platelets to release serotonin, which participates in the formation of pain. The damaged tissue and cell membranes cause an influx of calcium into the cells, which activates the enzyme phospholipase A2. Phospholipase A2 acts on the phospholipids to release arachidonic acid and produce the pro-inflammatory agent called platelet-activating factor. Neutrophils containing lipoxygenase create chemotactic compounds from arachidonic acid. This provokes the release of cytokinins that potently activate inducible cyclooxygenase 2 (COX-2) and inducible nitric oxide synthase (NOS). (Gilman A, Rail T, Nies A, Taylor P Ed, Goodman and Gilman's The Pharmacological Basis of Therapeutics, New York, Pergamon Press, 1990. Robak J, Gryglewski R J, Bioactivity of flavonoids, Pol J Pharmacol, 1996, 48:555-564).

Osteoarthritis
Although osteoarthritis does not always include the same intense inflammatory component as rheumatoid arthritis, it does involve damage to cartilage and other tissues, resulting in pain, deformity and limitation of motion of joints, in a similar fashion to rheumatoid arthritis.

Osteoarthritis is divided into two categories, primary and secondary osteoarthritis. In primary osteoarthritis, the degenerative wear and tear process generally occurs after the fifth and sixth decades, with no predisposing abnormality apparent. The cumulative effects of decades of use leads to the degenerative changes by stressing the integrity of the collagen matrix of the cartilage. Damage to the cartilage results in the release of enzymes that destroy collagen components. With aging there is a decreased ability to restore and synthesize normal collagen structures.

Secondary osteoarthritis is associated with some predisposing factor responsible for the degenerative changes. Various predisposing factors in secondary osteoarthritis include congenital abnormalities in joint structure or function (e.g. excessive joint mobility and abnormally shaped joint surfaces), trauma (obesity, fractures along joint surfaces, surgery, etc.), crystal deposition, presence of abnormal cartilage and previous inflammatory joint disease (rheumatoid arthritis, gout, septic arthritis, etc.)

Natural Solutions
As noted above, many consumers prefer natural substances to synthetic drugs. Therefore it is clear that there is a need for a natural acceptable composition for use in relieving or alleviating pain, inflammation and the symptoms associated with these conditions. In addition, there is a need for a natural composition that provides relief from pain and inflammation with minimal side effects to the gastrointestinal system.
Natural ingredients have been used to treat bone and joint inflammation. Such natural ingredients include, for example, cartilage, chondroitin, glucosamine, proteolytic and other enzymes and herbs. Although such natural ingredients generally do not lead to the kind of side effects observed with the steroidal and non-steroidal anti-inflammatory drugs (NSAIDs) discussed above, many of these natural ingredients do not always provide sufficient relief of pain, or restoration of significant function and use of inflamed tissue, e.g. joints. However, glucosamine and chondroitin have been found to contribute to restoring such function and use.

The herbal extracts contain ingredients derived from six herbs that influence various immune functions, such as curtailing inflammatory responses, improving cellular functions (e.g. decrease production of IL-1, TNF, IL-6 and reducing T and B cell functions) and curtailing the production of pro-inflammatory cytokines. With these immunological changes a patient with arthritis is expected to physically improve in terms of pain and joint swelling within days on an oral therapeutic regimen. Reduction of pain and swelling and increased range of joint motion are expected over prolonged daily use of the product.

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Technical Paper 2 

Active Ingredients Enzyme and Enzyme Mixtures
Enzymes help break down food proteins, carbohydrates and lipids. Mammals digest all their food extra-cellularly. Digestive enzymes are secreted from cells lining the inner surfaces of the exocrine glands. The enzymes hydrolyze the macromolecules in food into small, soluble molecules that can be absorbed into cells.

Bromelain is the collective name for the proteolytic enzyme composition found in the tissues of the plant Bromeliaceae. Bromelain is a mixture of various moieties derived from the stem of the pineapple (Ananas comosus). It contains at least two proteolytic enzymes, but also non-proteolytic enzymes including an acid phosphatase and a peroxidase; it may also contain amylase and cellulase activity. In addition various other components are present, in particular organically bound calcium. The known proteolytic enzymes of Bromelain and Papain share a high degree of amino acid sequence homology around the active centre, and evidence suggests that Bromelain and Papain use the same catalytic mechanism. However, Bromelain differs from Papain in having a different specificity of cleavage. In addition the known proteolytic enzymes of Bromelain are glycoproteins, whereas Papain is a simple protein. Bromelain is reviewed by Taussig and Batkin (J. Ethnopharmacol. 22 191-203 (1988)).

Wild celery - we use celery seed extract (and it is cultivated). It is noted in the Ayurvedic pharmacopoeia for treatment for headaches and as a diuretic and spasmolytic (CRC Handbook of Ayurvedic Medicinal Plants, 1990, p 44, CRC Press Inc., Boca Raton). It is included in the 1983 British Herbal Pharmacopoeia as a treatment for arthritis and gout. The seed oil is used in perfumery, for flavouring food products and liqueurs, and also as a cercaricide. According to the Physician's Desk Reference for Herbal Medicines (1998, Medical Economics Company Inc, Montvale N.J.), "Preparations of celery are used as a diuretic, for blood purification, for regulating elimination of the bowels, for glandular stimulation, rheumatic complaints, gout, gall and kidney stones.

Cetyl Myristoleate, Cetyl-M, CMO

Cis-9-cetylmyristoleate
Cetyl myristoleate has the chemical formula of cis-9-cetyl myristoleate and is a non-toxic substance found naturally in nuts, vegetables and some species of animals.
Cetyl myristoleate works as an anti-inflammatory by modulating the prostaglandin balance and as an immune system modulator by inhibiting leukotriene, thereby reducing auto-immune responses. [Cochran and Dent, "Cetyl Myristoleate--A Unique Natural Compound Valuable in Arthritis Conditions" pp. 70-74. Townsend Letter for Doctors and Patients. (Jul. 1997).
Cochran, "Dr. Chuck Cochran Discusses Arthritis and Cetyl Myristoleate" entire publication. (.COPYRGT.1996).
Siemandi. "The effect of cis-9-cetyl myristoleate (cmo) and adjunctive therapy on the course of arthritic episodes in patients with various auto-immune diseases characterized by the common terminology, "arthritis" Manuscript, pp. 1-6 (1997)].

Chondroitin Sulfate

Chondroitins, e.g. chondroitin sulfate, have also been found to play a role in the preservation and rebuilding of joint tissues. In a similar fashion to glucosamine, chondroitins have been found to stimulate cartilage cells to produce the needed proteoglycans and to inhibit the enzymes that break down proteoglycans.
Chondroitin sulfate in particular also functions to draw fluid into the proteoglycan molecules. This fluid acts as a shock absorber for the joint tissue and also carries nutrients into the cartilage.

Chondroitin sulfate has a synergistic effect with glucosamine, but poorly absorbed by oral administration. Chondroitin sulfate is half galactosamine, which is made directly from glucosamine and has great water retaining ability (Theodosakis et al, in "The Arthritis Cure" St. Martin Press, New York, 1997).

Ginger (Zingiber officinale) gives relief from muscular discomfort and pain. It inhibits prostaglandin and leukotriene biosynthesis and histamine release. Thus it acts as an anti-inflammatory as well as an antacid agent. It is a dual inhibitor of the lipoxigenase and cycloxigenase system.

Ginger contains 1-4% essential oil (oleoresin). During the last 45 years many chemical investigations have been carried out on the constituents of the essential oil. Altogether more than 200 different volatiles have been identified in essential oil wherein the pharmacological activity is confined. The essential oil contains mixtures of various terpenes as well as some other non-terpenoid compounds.

Due to the large battery of compounds belonging to various chemical classes, it is likely that crude ginger powder intake brings about amelioration of symptoms by interfering with the production and release of products of lipid membranes (eicosanoids, reactive oxygen), peptides and proteins (lysosomal enzymes, growth factors, lymphokines, bradykinin), amino acids (histamine, serotonin) etc. (Kiuchi F. et al; Chemical and Pharmaceutical Bulletin, 1982, 30, 747-754). Although this is mostly speculative, the experimental data and observations suggest that ginger inhibits both the cyclooxygenase and lypoxygenase products, i.e. it can be a dual inhibitor of eicosanoid synthesis (Srivastava and Mustafa; Medical Hypotheses; 1992; 39 342-348).

Glucosamine sulfate is a naturally occurring substance in the body, synthesized in the chondrocytes. In failing joints this synthesis is defective and insufficient and the supplementation with glucosamine has proven to be beneficial. The body uses supplemented glucosamine sulfate to synthesize the proteoglycans and the water-binding glycosaminoglycans in the cartilage matrix. In addition to providing raw material, the presence of glucosamine sulfate seems to stimulate the chondrocytes in their production of these substances. Glucosamine sulfate also inhibits certain enzymes that destroy the cartilage, e.g., collagenase and phospholipase. By blocking pathogenic mechanisms that lead to articular degeneration glucosamine sulfate improves joint function.

Glucosamine provides strength, flexibility and elasticity to cartilage and connective tissue by stimulating the production of glycosaminoglycans. Glucosamine also decreases inflammation that can lead to joint destruction. Glucosamine is involved in the formation of nails, tendons, skin, eyes, bones, ligaments and heart valves. More importantly, glucosamine contributes to the strength and integrity of joint structures.

Connective tissue and cartilage naturally contain high concentrations of glucosamine. When sufficient levels of glucosamine are present cartilage retains its ability to hold water and act as a shock absorber. Glucosamine sulfate is a simple molecule composed of glucose, an amine and sulphur. The joints are naturally rich in sulphur molecules, which form important cross-linkages with other molecules. These cross-linkages provide cartilage with its strength, structure and shock-absorbing qualities. The strength, structure and shock-absorbing qualities along with glucosamine's absorbability makes glucosamine sulfate the preferred form of supplemental glucosamine.

Each person produces a certain amount of glucosamine. As people age the body no longer produces enough glucosamine causing musculoskeletal disorders such as arthritic conditions, deformed joints and limited joint and tendon movement. Numerous double-blind placebo controlled glucosamine studies have been published, all reporting that glucosamine was indeed very effective in treating osteoarthritis and reducing inflammation and that its use is long-term safe. The studies have also shown that glucosamine provided in liquid form is absorbed more quickly, much more fully and provides greater and longer lasting relief.

Although glucosamine generally does not provide the same rapid temporary relief of inflammation and pain as aspirin or other non-steroidal anti-inflammatory drugs, it plays several key roles in the preservation and rebuilding of joint tissues. Namely, it stimulates the cartilage cells to produce glycosaminoglycans and proteoglycans, which maintain healthy joints and contribute to rebuilding connective tissue. It is one of the main ingredients of the synovial fluid that lubricates and provides nutrients for the joint structures.

By participating in the preservation and rebuilding of joint tissues it is believed that glucosamine can contribute to long term relief of a wide range of degenerative and inflammatory conditions such as rheumatoid arthritis, osteoarthritis, degenerative spinal disc disease, tendonitis, bursitis and trauma to joints, tendons and ligaments, and in many cases may actually reverse the underlying disease process.

Indian Frankincense, Frankincense, Boswellia, Boswellin, Salai Guggal Boswellia serrata

Sallai Guggul (Boswellia serrata)
(Bursaceae) an oleo-gum-resin obtained from trees of Sallai Guggul as a stem exudate. Sallai Guggul contains Beta boswellic acid, which is a pentacyclic triterpene believed to be the active ingredient for anti-inflammatory activity. Beta boswellic acid has significant anti-inflammatory activity in acute inflammation models in animals using Carrageenan-induced paw edema and also in chronic rheumatoid arthritis (Singh et al; Indian Journal of Pharmacy, 1984 16, 51-53). It reduces triiodothyronine levels in acute and chronic inflammation.

In chronic conditions the acid increases thyroxine levels. It reduces both the volume and leucocyte population in pleural exudate. Sallai Guggul gives short time benefits to arthritis patients by reducing pain and inflammation without any ulcerogenic or other severe side effects (Pachanda et al; Indian Journal of Pharmacy 1981, 15, 65-67).

Methylsulfonylmethane (MSM) Is a natural form of organic sulphur found in all living organisms. MSM is prevalent throughout the human body. It is an important food that plays many roles in the body, including the stimulation of the growth of healthy bones, skin, hair and nails. MSM is needed by the body for healthy, connective tissues and joint function, proper enzyme activity and hormone balance, along with the proper function of the immune system.

As oxygen is transported from the lungs to the mitochondria, oxygen goes through a number of stages with continually decreasing oxidation potential or effective oxygen concentration. MSM easily and rapidly diffuses through the hydrophilic cell cytoplasm as well as the hydrophobic cell membranes as it has no barriers.
The human body has no other molecules naturally occurring in our bodies similar to MSM. Oxygen transport is handled by passing it between different molecules that are hydrophilic in the cytoplasm and hydrophobic in the cell membranes

New Zealand Green-Lipped Mussel
Perna Canaliculus
There is at the present time a significant medical need for new anti-inflammatory and anti-arthritic drugs with reduced side effects and prolonged in vivo activity and in particular for compounds which will moderate the progress of the arthropathies. Plants and other living cells offer a vast reservoir of compounds that have pharmacological effects on humans. Natural products have frequently been the source of effective drugs and lately there has been an increased interest in the analysis of these natural products, especially where a clinical benefit is claimed. Marine organisms contain metabolites that can act as pharmacological agents and aid in the treatment of inflammation.

An anti-inflammatory activity of Perna canaliculus (New Zealand Green Lipped Mussel) was first implicated as part of a pharmacological study on leukaemia. Initial assessment of the anti-inflammatory activity of Perna canaliculus was first attempted using a polyarthritis model in rats. These studies however failed to show the presence of any significant anti-inflammatory activity in the mussel preparation. In contrast, Miller and Ormrod, using a carrageenin-induced paw oedema assay, were able to show that mussel preparations, when administered intraperitoneally, gave a significant reduction in the swelling of a carrageenin-induced rat paw oedema. Subsequently, they fractionated a non-dialysable, water-soluble fraction from the mussel preparation that possessed anti-inflammatory activity. The aqueous extract showed a dose-dependent anti-inflammatory activity when administered intraperitoneally and could not be detected upon oral administration of the mussel powder. It was suggested that the water-soluble fraction therefore contained an irritant component possessing apparent anti-inflammatory activity [(Chemical and Pharmaceutical Bulletin, vol. 34, No. 11, 1986, Pharmaceutical Society of Japan, Tokyo, Takuo Kosuge et al., "Isolation of an Anti-histiminic Substance from Green Lipped Mussel (Perna canaliculus)," pp. 4825-4828 & Derwent Abstract Accession No. 89-333329/46, DE, 3814047, C (Fratzer) Nov. 16, 1989)].
Rainsford and Whitehouse (K.D. Rainsford et al. "Gastroprotective and Anti-inflammatory Properties of Green Lipped Mussel (Pera canaliculus) Preparation," pp. 2128-2132) also reported that freeze-dried powdered preparations of the whole mussel given orally to rats showed some modest anti-inflammatory activity in the carrageenin-induced paw oedema assay, and that this material strikingly reduced the gastric ulcerogenicity of several non-steroidal anti-inflammatory drugs in rats and pigs.

Use of the whole mussel extract in the treatment of both rheumatoid arthritis and osteoarthritis in human patients has also been reported [(New Zealand Medical Journal, vol. 95, No. 720, 1982, Dunedin, New Zealand, Crouch, RA.F. et al., "Anti-inflammatory activity in fractionated extracts of the green-lipped mussel," pp. 803-806 & Agents and Actions, vol. 39 (Spec. Conf. Issue), 1993, Basel, Switzerland, Miller, T.E. et al., "Anti-inflammatory activity of glycogen extracted from Perna canaliculus (NZ green-lipped mussel)," pp. C139-142].

Piperine, or mixtures containing piperine, have been shown to increase the bioavailability, blood levels and efficacy of a number of health products and drugs including ingredients of vasaka leaves (Bose, K. G., (1928) Pharmacopeia India, Bose Laboratories, Calcutta), vasicine (Atal et al., Journal of Ethnopharmacology, 4, 229-233 (1981)), sparteine (Atal et al., ibid), sulfadiazine (Atal et al., ibid), rifampicin (Zutshi, U. et al. (1984) Journal of the Association of Physicians of India, 33, 223-224), phenytoin (Bano et al., Planta Medica, 1987, pp. 568-569), pentobarbitone (Majumdar, A. N. et al. (1990), Indian Journal of Experimental Biology, 28, 486-487), theophylline (Bano et al., Eur. J. Clin. Pharmacol. (1991) 41:615-617) and propranolol (ibid). In summary, all of these examples clearly illustrate the role of piperine as a bioavailability enhancer.
There are two plausible explanations of the role that piperine may have in drug bioavailability:

1. non-specific mechanisms promoting rapid absorption of drugs and nutrients, e.g., increased blood supply to the gastrointestinal tract, decreased hydrochloric acid secretion which prevents breakdown of some drugs, increased emulsifying content of the gut, increased enzymes like gamma-glutamyl transpeptidase which participate in active and passive transport of nutrients to the intestinal cells; and

2. non-specific mechanisms inhibiting enzymes participating in biotransformation of drugs, preventing their inactivation and elimination.

See: Annamalai, A. R., Manavalan, R. (1990) Effects of `Trikatu` and its individual components and piperine on gastrointestinal tracts: Trikatu--a bioavailable enhancer. Ind. Drugs 27(12); pp. 595-604; Johri, R. K. et al. (1992) Piperine-mediated changes in the permeability of rat intestinal epithelial cells. Bioch. Pharmacol. 43; pp. 1401-1407; Atal, C. K. et al. (1985) Biochemical basis of enhanced drug availability by piperine: Evidence that piperine is a potent inhibitor of drug metabolism. J. Pharmacol. Exp. Therap. 232; pp. 258-262; and Singh, J. et al. (1986) Piperine-mediated inhibition of glucuronidation activity in intestine: evidence that piperine lowers the endogenous UDP-glucuronic acid content. J. Pharmacol. Exp. Therap. 2236; pp.448-493.

Anti-inflammatory activity of piperine:
Mujumdar AM, Dhuley JN, Deshmukh VK, Raman PH, Naik SR.
Jpn J Med Sci Biol. 1990 Jun;43(3):95-100.
Research & Development Division, Hindustan Antibiotics Limited, Pimpri, Pune, India.

Piperine (1-peperoyl piperidine) was isolated from Piper nigrum Linn for the evaluation of anti-inflammatory activity in rats. Different acute and chronic experimental models like carrageenin-induced rat paw edema, cotton pellet granuloma and croton oil-induced granuloma pouch were employed. Simultaneously, biochemical estimations were made to elucidate the underlying mechanism of the action. Piperine acted significantly on early acute changes in inflammatory processes and chronic granulative changes. It also acted partially through stimulation of pituitary adrenal axis. Exudative changes in both acute and chronic models, however, were insignificant.
PMID: 2283727 [PubMed - indexed for MEDLINE]

Permeability characteristics of piperine on oral absorption--an active alkaloid from peppers and a bioavailability enhancer:
Khajuria A, Zutshi U, Bedi KL.
Indian J Exp Biol. 1998 Jan;36(1):46-50.
Isotope Section, Regional Research Laboratory, Jammu-Tawi, India.
Piperine, [1-[5-[1,3-benzodioxol-5-yl]-1-oxo-2,4, pentadienyl] piperidine], is a pungent alkaloid present in Piper nigrum Linn, and P. longum Linn. It is shown to enhance the bioavailability of various structurally and therapeutically diverse drugs. A concise mechanism responsible for its bioavailability enhancing action is poorly understood. This study is an effort to understand the absorption dynamics of piperine in intestine on oral absorption. It encompasses intestinal everted sacs as an experimental model. Cycloheximide treatment and exclusion of Na+ salts from incubating medium were the variables used. Absorption half-life, absorption rate, absorption clearance and apparent permeability co-efficient were computed from the data. Experiments to denote physicochemical characteristics of this moiety exhibited that it is a weak base, highly lipophilic in nature with partial solubility in aqueous media. It exhibited passive diffusion constituting non-saturable absorption kinetics. Transport of piperine was not resisted by UWL and was proposed to be absorbed through transcellular pathway. It displayed short absorption clearance and high apparent permeability co-efficient. Data thus obtained suggested that piperine is absorbed very fast across the intestinal barrier. It may act as a polar molecule and form polar complex with drugs and solutes. It may modulate membrane dynamics due to its easy partitioning thus helping in efficient permeability across the barriers.
PMID: 9536651 [PubMed - indexed for MEDLINE]

Phellodendron Amurense
Phellodendron Bark, also known as cork-tree has been reported to contain palmatine, magnoflorine, guanidine, jateorrizine, phellodendrine, candicine, menisperine and, as bitter substances, obakunone, obakulactone and beta-sitosterol. The Boncho Kangmok and the Pharmacopoeia (Pharmacy) state that these components act on bone diseases and jaundice due to antibacterial, antihypertensive, central nerve inhibitory, acetylcoline increasing and anti-inflammatory effects. Phellodendron Bark also acts on typhoid and gastrointestinal disease and the bark has been used as bitter stomachic, intestinal agent and astringent anti-inflammatory agent against gastroenteritis, abdominal pain and jaundice.

Phellodendron Bark extract is used for analgesic and anti-inflammation against chronic gastritis, arthralgia, benign prostate hyperplasia, chronic and recurrent cystitis, cervical disc, degenerative joint arthritis, rheumatoid arthritis, tennis elbow, osteoportotic pain, migraine, diabetic neuropathy pain, Rt. flank pain, etc. Also Hozumi et al. disclose the bark extract of Phellodendron amurense as antiherpesviral, antipolioviral, anti-measles virus, anti-varicella-zoster virus, and anti-CMV agents, as well as an anti-DNA virus and anti-RNA virus agent. See T. Hozumi, T. Matsumoto, H. Ooyama, T. Namba, K. Shiraki, M. Hattori, M. Kurokawa, & S. Kadota, U.S. Pat. No. 5,411,733, issued on May 2, 1995

Suppressive effects of a Chinese herbal medicine qing-luo-yin extract on the angiogenesis of collagen-induced arthritis in rats:
Li S, Lu AP, Wang YY, Li YD.
Am J Chin Med. 2003; 31(5):713-20.
The Key Laboratory of Bioinformatics of Ministry of Education, Institute of Bioinformatics, Tsinghua University, Beijing 100084, People's Republic of China. shaoli@mail.tsinghua.edu.cn
Qing-Luo-Yin (QLY), a traditional Chinese herbal medicine for the treatment of rheumatoid arthritis, is a combination of the extracts of Sophora flavescens Ait, Phellodendron amurense Rupr, Sinomenium acutum Rehd. ET Wils. and Dioscorea hypoglauca Palib. The suppressive effect of QLY on the development of angiogenesis was investigated in a rat model of collagen-induced arthritis (CIA). QLY (0.3 g/kg) was orally administered daily for 27 days. Neo-angiogenesis, pannus and cartilage damage, the expression of metalloproteinases (MMP)-3 messenger RNA (mRNA) and the level of the tissue inhibitor of matrix metalloproteinase (TIMP)-1 in the synovium were examined by histology, in situ hybridization and immunohistochemical assays respectively. It was observed that the articular morphological alterations, the over-expression of MMP-3 mRNA and the reduced production of TIMP-1 in CIA rats were significantly ameliorated by QLY. QLY performed about as effectively as tripterygium glycosidorum tablets (0.1 g/kg) extracted from Tripterygium wilfordii Hook. f.. These results indicate that QLY exerts a suppressive effect on the angiogenesis of CIA rats, and suggest that the therapeutic effect of QLY could be due to restoring the balance of MMP-3 and TIMP-1 in rheumatoid synovium.
PMID: 14696674 [PubMed - indexed for MEDLINE]

The pharmacological and pathological studies on several hepatic protective crude drugs from Taiwan (I):
Chiu HF, Lin CC, Yang CC, Yang F.
Am J Chin Med. 1988; 16(3-4):127-37.
Department of Pharmacology, School of Medicine, Kaohsiung Medical College, Taiwan.
This study is to investigate the hepatic protective effect of several Taiwan crude drug extractions on the carbon tetrachloride (CCl4)-induced hepatotoxicity in rats. The pharmacological and pathological effects of Bupleurum chinense, Phellodendron wilsonii, Clematis chinensis and Hedyotis corymbosa were analyzed by liver enzyme function test and pathological studies. However, the results of amine transferase SGOT and SGPT have shown a significant hepatic protective effect after treatment with Bupleurum chinense (P less than 0.005), Phellodendron wilsonii (P less than 0.001), Clematis chinensis (P less than 0.005) and Hedyotis corymbosa (P less than 0.005, SGPT only). The fatty degeneration around the central vein area and necrosis of the central lobule can be significantly improved by P. wilsonii and moderately changed by B. chinense or C. chinensis. Although fatty metamorphosis has been affected by H. corymbosa, various inflammatory cell infiltrations in the cytoplasm were noted.
PMID: 3245533 [PubMed - indexed for MEDLINE]

Poly-NAG (Chitin) consists of a non-collagenous protein core to which long-chain polysaccharides (glycosaminogylcans, GAGs) are linked. Poly-NAG is a key component of cartilage, which accounts for its biomechanical properties. Type II collagen is the other principle component of cartilage. These two components are thus often used, alone or in combination, as in vitro surrogate markers for cartilage synthesis and degradation. Beekman R. (1998) Articular chondrocytes: synthesis and MMP-mediated degradation of extracellular matrix. Thesis from the Gaubius Laboratory of TNO Prevention and Health, Leiden, The Netherlands (ISN 90-9011354-1) & Beekman et al., "Matris degradation by chondrocytes cultured in alginate: IL-1.beta. induces proteoglycan degradation and proMMP synthesis but does not result in collagen degradation", Osteoarthritis and Cartilage, 1998, pp. 330-340, vol. 6:5, Osteoarthritis Research Society).

Rutin
The anti-inflammatory activities of rutin flavonoid were investigated in animal models of acute and chronic inflammation. Rutin was only effective in the chronic process, principally in adjuvant arthritis, also acting as a free radical scavenger in rheumatoid arthritis.

Anti-inflammatory properties of plant flavonoids. Effects of rutin, quercetin and hesperidin on adjuvant arthritis in rat:
Guardia T, Rotelli AE, Juarez AO, Pelzer LE.
Farmaco. 2001 Sep; 56(9):683-7
Departamento de Farmacia, Facultad de Quimica, Bioquimica y Farmacia, Universidad Nacional de San Luis, Argentina.
The anti-inflammatory activities of three flavonoids were investigated in rats using the Mizushima et al. model of acute and chronic inflammation. Intraperitoneal administration of rutin, quercetin (flavonols) and hesperidin (flavanone), given at daily doses equivalent to 80 mg/kg, inhibited both acute and chronic phases of this experimental model of inflammation. Rutin was the most active in the chronic phase.
PMID: 11680812 [PubMed - indexed for MEDLINE]

Oxidative stress in rheumatoid arthritis leukocytes: suppression by rutin and other antioxidants and chelators:
Ostrakhovitch EA, Afanas'ev IB.
Biochem Pharmacol. 2001 Sep 15; 62(6):743-6.
Russian State Medical University, Ostrovityanova 1, 117513, Moscow, Russia.
The enhanced production of superoxide ion and peroxynitrite by bloodstream neutrophils and of superoxide ion by monocytes from rheumatoid arthritis (RA) patients was registered. It was suggested that NADPH oxidase together with NO synthase were the major sources of superoxide ion in RA neutrophils, while in RA monocytes superoxide ion was produced by NADPH oxidase and mitochondria. Among the different free radical inhibitors studied (antioxidant enzymes, SOD and catalase; free radical scavengers, bioflavonoid rutin and mannitol; and the iron chelator desferrioxamine), SOD and rutin were the most efficient suppressors of oxygen radical overproduction by RA neutrophils, while mannitol and desferrioxamine were inactive. Thus, in contrast to Fanconi anemia (FA) leukocytes (Korkina LG et al., J Leukocyte Biol 1992; 52:357-62), iron-catalyzed hydroxyl radical formation was unimportant in RA leukocytes, which mainly produced superoxide ion. Natural non-toxic bioflavonoid rutin (vitamin P) inhibited oxygen radical overproduction in both RA and FA in an equally efficient manner and therefore may be considered as a useful supporting pharmaceutical agent for the treatment of "free radical" pathologies.
PMID: 11551519 [PubMed - indexed for MEDLINE]

SAM-e
S-adenosyl-L-methionine
Other additives can be used in the supplement, such as naturally occurring sulfur compound like s-adenosylmethionine. Many biochemical processes in the body are related to s-adenosylmethionine, such as the production and break down of serotonin, melatonin, dopamine and Vitamin-B12. S-adenosylmethionine also aids in the production of genetic material such as DNA and cartilage. The essential amino acid methionine, administered as S-adenosyl-methionine, was shown to be superior to ibuprofen (Motrin®) in the treatment osteoarthritis in a double-blind clinical trial. The positive effect in this trial is consistent with several other clinical studies.

Turmeric

Curcuma longa, Curcuma domestica

Relatively few compounds exhibiting anti-angiogenic properties useful in the treatment of cancer have been investigated. Curcumin (diferuloylmethane), the aromatic yellow pigment in curry, turmeric and mustard, is known to have anti-angiogenic, anti-tumor and anti-tumor promoting properties. In addition, Curcumin exhibits numerous other therapeutic effects including anti-oxidative, anti-thrombotic, anti-inflammatory, anti-cholesterol and anti-diabetic properties.

The anti-inflammatory effects of Curcumin isolated from Curcuma longa were reported in Srimal and Dhawan, Pharmacology of Diferuloyl Methane, a Non-steroidal Anti-inflammatory Agent, J. Pharm. Pharmac. 25:447-452 (1973). Significant anti-inflammatory activity comparable with phenylbutazone and hydrocortisone was observed by Arora et al. (Indian Journal of Medical Research 1971, 59, 1289-1291). Curcumin, an alkaloid (diferuloyl methane) isolated from the alcoholic extract of turmeric has been shown to be a potent anti-inflammatory agent and is considered to be its active ingredient. Further work on anti-inflammatory and anti-arthritic activity has also been carried out by Thatte et al (Indian Journal of Pharmacology 1986, 18 (1), 19-21). Turmeric has been found to have significant anti-inflammatory activity both in acute and chronic models. Curcumin not only has anti-inflammatory properties but also has anti-oxidant anti-tumour and other valuable properties. When used in low concentrations, Curcumin can inhibit nitric oxide synthase (NOS), and therefore inhibit nitric oxide production. For example Brouet et al. (Biochem. Biophys. Res. Commmun., Jan. 17, 1995; 206 (2); 533-40) have reported that NOS activity in soluble extracts of macrophages activated for 6-24 hours in the presence of Curcumin was significantly lower than that of macrophages activated without Curcumin. Northern-blot and immunoblotting analyses demonstrated that significantly reduced levels of the mRNA and 130-kDa protein of inducible NOS were expressed in macrophages activated with Curcumin, compared to those with Curcumin. Inhibition of NOS induction was maximal when Curcumin was added together with lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) and decreased progressively as the interval between Curcumin and LPS/IFN-gamma was increased to 18 hours. Therefore, Curcumin, when used in an effective amount, may be used to effectively control overproduction of saliva by virtue of its property of acting as a NOS inhibitor.

Vitamins

Vitamin B3
Niacinamide--Dr. William Kaufman has reported very good clinical results in the treatment of hundreds of patients with rheumatoid and osteoarthritis using high dose niacinamide (i.e. 900 mcg to 4 g in divided dose daily). At this high dose Niacinamide can result in significant side effects (glucose intolerance, liver damage) and should therefore be instituted under strict medical supervision. Niacinamide is one of the water-soluble B-complex vitamins. It has multiple functions such as inhibition of poly-ADP-ribose synthetase, inhibition of inductible nitric oxide synthase, free radical scavenging, suppression of major histocompatibility complex class II expression and ICAM-1 expression on endothelial cells and inhibitory effect on the production of TNF-alpha. Fukuzawa M, et al, Immunol Lett October 1997; 59(1):7-11.

Vitamin D3
Vitamin D (cholecalciferol) is essential for formation of the skeleton and for mineral homeostasis. Without vitamin D the small intestine cannot absorb adequate calcium regardless of how much calcium is available for absorption. Thus, vitamin D is indicated as a component of a nutritional supplement to help build strong bones.

Vitamin E
Vitamin E is an antioxidant that protects cell membranes and other fat-soluble parts of the body. Vitamin E also plays a role in the body's ability to process glucose. In the last ten years studies have clarified the function of Vitamin E in the cells. In addition to its antioxidant functions Vitamin E is now known to act through other mechanisms, including direct effects on inflammation, blood cell regulation, connective tissue growth and genetic control of cell division, improve circulation and allow the muscles to use oxygen.
A clinical trial using 600 IU of vitamin E in patients with osteoarthritis demonstrated significant benefit from the vitamin E. The benefit was thought to be due to vitamin E's antioxidant and membrane stabilizing actions. Later studies have shown that vitamin E has an ability to inhibit the enzymatic breakdown of cartilage as well as stimulate cartilage synthesis

Minerals
The Arthritis supplement includes minerals such as selenium, boron, manganese, magnesium potassium, silicone, copper, strontium and zinc.

Selenium and zinc are a powerful combination of antioxidants that neutralize harmful free radicals. It is well proven free radicals cause oxidation and damages the body. These same free radicals can destroy your joints and cartilage. These combinations, forms and levels are unique and provide far greater protection from free radicals when compared to other single nutrients or formulations.

The role of manganese in driving metalloenzyme manganese-superoxide dismutase (Mn-SOD) has been clearly identified, along with a similar role in other metalloenzyme systems (glutamine synthetase, arginase, and pyruvate carboxylase). Numerous enzyme systems have also been shown to undergo manganese activation, even though they are not manganese metalloenzymes. The manganese-SOD connection may be of special clinical importance since this form of the metalloenzyme appears to be the sole operative form within the cell's mitochondrial membranes, and thus may play a unique role in protection of the mitochondria and assurance of the body's oxidative energy production system. The inclusion of manganese in a dietary supplement would be desirable.

Newnham suggests that dietary boron is related to the incidence of arthritis. See Newnham, "The Role of Boron in Human Nutrition," Journal of Applied Nutrition, Vol. 46, No. 3 (1994). Newnham has studied various geographies and soil conditions and has indicated a relationship between a higher incidence of arthritis and low boron levels in soils and foods grown in such conditions. Accordingly, boron would be a useful mineral for inclusion in products, which are useful for the treatment of arthritis and related conditions, either alone or in combination with other chondroprotective agents such as glucosamine and chondroitin. However, its precise mechanism is not known. It is possible that boron acts by inhibiting the activated kallikrein-kinin system which appears to be operative in chronic inflammatory arthritis (Colman et al, Proc Assoc Am Physicians, 109:10-22, 1997).

Zinc and Copper are required for the synthesis of normal collagen and maintenance of cartilage structures. A deficiency of any one of these would allow accelerated joint degeneration.
Zinc plays a physiological role in the regulation of bone metabolism by stimulating bone formation and mineralization and an inhibitory effect on bone resorption. Zinc activates aminoacyl-tRNA synthetase in osteoblastic cells, stimulates cellular protein synthesis and inhibits osteoclast-like cell formation in marrow cells. Bone zinc content is decreased by development, with aging, skeletal unloading and postmenopausal conditions. Zinc plays a role in the preservation of bone mass. Most zinc compounds, such as zinc sulfate, are useful for the prevention of osteoporosis, but a recent study confirmed that--Alanyl-L-histidinato zinc (AHZ) has a potent effect on bone formation and calcification. Yamaguchi M, Role of Zinc in Bone Formation and Bone Resorption, J of Trace Elements and Experimental Medicine 1998; 11:119-135. The thickening of subchondral bone in osteoarthritis may be a prelude to cartilage breakdown. The phosphate-to-protein and carbonate-to-protein ratios rise with increasing severity of symptoms in osteoarthritis. Lewis R A, Biophotonics International 2001; January-February: 67.
Zinc compounds have anti-inflammatory and anti-infective properties. In Current Therapeutic Research, 1998; 59/9: 595-607, the inventor served as chief investigator for a randomized, double-masked, placebo-controlled clinical study of the effectiveness of zinc acetate lozenges on common cold symptoms in allergy-tested subjects. Those subjects who used the zinc lozenges had both a shorter duration and severity of common cold symptoms. Those subjects, who were positive for allergies, were more responsive to zinc by having a shorter duration of nasal symptoms. The study cited many references that reported the benefits and effects of zinc compounds.

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Additional Paper

Delivery System - Enteric Coated Tablets:

The use of enteric-coated & controlled release tablets to deliver the arthritis composition to the gastrointestinal tract with a desired level of the active health supplements without the adverse gastrointestinal effects is well known in the art.

Enteric coatings are used to deliver drugs to the small intestine and to protect drugs from inactivation by gastric enzymes or the acidic environment of the stomach (low pH). Targeted delivery is based upon the pH differences between these two parts of the alimentary canal. Enteric coatings are selectively insoluble substances that are insoluble in a low pH medium, typically having a value less than about 5.5, but are soluble in a higher pH medium, typically having a value greater than about 5.5.

In summary, enteric coatings are pH sensitive polymers designed to remain intact, but to dissolve in the more alkaline environment of the intestine. The coatings provide an impermeable barrier that will not readily dissolve or disperse at the low pH of the gastric juices of the stomach. However, at the higher pH of the intestinal fluids the enteric coating will dissolve or disperse allowing for absorption of the drug.

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