- Nettle Leaf
- Chondroitin Sulfate
- Willow Bark
- Fish Oil
- Gamma-Linolenic Acid (GLA)
As noted, TNF-alpha and IL-1b have been identified as factors in the destruction of cartilage in both OA and RA. Studies show that the blockade of these aberrant immune factors can produce therapeutic results. Nettle leaf has been shown to reduce TNF-alpha levels and IL-1b. Nettle leaf also inhibits the genetic transcription factor that activates TNF-alpha in synovial tissue.
Antiarthritic drugs are being developed to suppress TNF-alpha, but similar effects may be obtained safely today using nettle leaf. Please note that nettle leaf extract contains different phytochemicals than the nettle root extract used to treat benign prostate disease.
Nettle leaf is an herb that has a long tradition of use as an adjuvant remedy in the treatment of RA in Germany. Nettle leaf extract has been found to contain a variety of active compounds, such as COX and lipooxygenase inhibitors and substances that affect cytokine secretion (Obertreis et al. 1996; Teucher et al. 1996).
A placebo-controlled trial by Feldman et al. (1997) provided the first convincing evidence that blockade of a specific cytokine could be effective treatment in human autoimmune or inflammatory diseases. Interesting results with TNF-alpha blockade have also been achieved in trials conducted on Crohn's disease, sepsis, and HIV/AIDS. A placebo-controlled human trial showed that leaves of the nettle exhibited a potent effect in lowering TNF-alpha levels in arthritis patients.
Another study conducted on 40 patients suffering from acute arthritis compared the effects of 200 mg of a NSAID (diclofenac) with 50 mg of the NSAID in combination with 50 grams of stewed nettle leaf a day (Chrubasik et al. 1997). Total joint scores improved significantly in both groups by approximately 70%. The addition of nettle extract made possible a 75% dose reduction of the NSAID, while still retaining the same anti-inflammatory effect with reduced side effects. The nettle leaf extract clearly enhanced the anti-inflammatory effect of the NSAID.
Not only does nettle leaf reduce TNF-alpha levels, but it has recently been demonstrated that it does so by potently inhibiting the genetic transcription factor that activates TNF-alpha and IL-1b in synovial tissue (Riehemann et al. 1999). This pro-inflammatory transcription factor, known as nuclear factor-kappa-beta (NF-KB), is known to be elevated in chronic inflammatory diseases and is essential to activation of TNF-alpha. Nettle is thought to work by preventing degradation of the natural inhibitor of NF-KB in the body. It has also been shown that TNF-alpha activates NF-KB in synovial cells, leading to the suggestion that a cycle of cross-activation between TNF-alpha and NF-KB may sustain and amplify the disease process in RA (Jue et al. 1999).
A study on healthy volunteers showed the anti-inflammatory potential of nettle. Irritants were used to stimulate and increase the secretion of proinflammatory cytokines. When nettle extract was given simultaneously in a dose-dependent manner, TNF-alpha and IL-1b concentrations were significantly reduced (Obertreis et al. 1996).
Because nettle leaf works at the level of anti-inflammation, it could also be tried on OA, although no studies have specifically been done with it on that condition.S-Adenosylmethionine (SAMe).
S-adenosylmethionine (SAMe) is the activated form of methionine. Because it has so many actions in different parts of the body, SAMe can have many health benefits that seem unrelated, but in fact all depend on SAMe.
A study was done on the effect of free radicals on RA. Researchers in The Netherlands discovered that the synovial fluid in RA patients contains nonfunctioning T-cells. The deficit is caused by a lack of IL-2, the cytokine crucial for T-cell activation. Free radicals are to blame, although all the science has not been worked out. However, researchers did find that N-acetyl-L-cysteine (NAC) restores T-cell activity (Maurice et al. 1997). (NAC naturally elevates the body's antioxidant, glutathione.)
Researchers theorize that SAMe, like NAC, protects synovial cells by reversing glutathione depletion. The reason researchers believe this, is that SAMe acts as a precursor to glutathione production (Lieber et al. 2002). (SAMe is naturally converted to cysteine in the body.) But in addition to its antioxidant protection, researchers believe SAMe has other important effects. It may protect synovial cells by blocking the enzymes that degrade cartilage. This would occur through its role in the polyamine pathway that leads to protein synthesis. It may also protect the important cartilage proteins and proteoglycans in the joint lining.
In a study published in the British Journal of Rheumatology, researchers demonstrated for the first time that SAMe reversed the effects of damage caused by TNF when added to cells at the same time as TNF (Gutierrez et al. 1997).
Almost all of the arthritis studies done with SAMe involve OA. In the test tube, SAMe increases the number of chondrocytes (cartilage cells) and proteoglycans (protein). This suggests that SAMe treatment may reverse the underlying process of OA by stimulating cartilage to grow (Barcelo et al. 1990; Kalbhen et al. 1990). The other main component of the joint is synovial fluid, which acts as a lubricant. The proinflammatory cytokine TNF-alpha has been found in the synovial fluid of people with RA, and it plays a role in bone and cartilage destruction (Bertolini et al. 1986). Until recently, scientists did not know the effects of SAMe on synovial fluid; it was discovered that SAMe reverses the damaging effects of TNF-alpha.
In 1987, the American Journal of Medicine published a series of articles on the use of SAMe for treating OA (as an example, see Tavoni et al. 1987). The SAMe provided for the studies was spread out among numerous physicians and clinics (in one case, 33 different medical centers). The studies confirmed that SAMe works as well as the most popular arthritis treatments on the market. The series is published under the title Osteoarthritis: The Clinical Picture, Pathogenesis, and Management with studies on a New Therapeutic Agent, S-Adenosylmethionine.
Many years earlier, studies had been done in Italy showing the benefits of SAMe. One of the studies involved approximately 22,000 patients. This large-scale trial lasted 2 months. Participants were not allowed to take any pain medication or other arthritis treatment during the study. Physicians found that patients taking SAMe improved steadily from the beginning. At the end of the study, about 80% of the subjects who took SAMe reported improvement: 70% of the subjects with the most severe knee pain improved significantly. Side effects were minimal, and only 2.3% of the group stopped taking it because it did not work. The most severe side effect reported was gastrointestinal upset.
In four double-blind studies, SAMe was compared either to placebo or to NSAIDs. SAMe was generally better tolerated than the NSAIDs (Glorioso et al. 1985; Maccagno et al. 1987; Vetter 1987; Domljan et al. 1989).
The latest study assessed the efficacy of SAMe against placebo and nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of OA. The investigators looked at 13 different human clinical trials to assess pain scores, functional limitation, and adverse side effects. When compared with placebo, SAMe was more effective in reducing functional limitation. When compared against NSAIDs, SAMe worked as well as NSAIDs with far fewer adverse effects. The conclusion of the researchers was: "SAMe appears to be as effective as NSAIDs in reducing pain and improving functional limitation in patients with osteoarthritis without the adverse effects often associated with NSAID therapies." Those with OA often resort to NSAIDs that can induce serious long-term side effects. Even COX-2 inhibiting drugs have demonstrated more side effects than anticipated. SAMe has shown itself to not only alleviate arthritic pain and functional limitation, but to also rebuild joint cartilage (Soeken et al. 2002).Nexrutine.
Nexrutine is a natural anti-inflammatory ingredient that has a unique mechanism of action: it is a COX-2 gene expression inhibitor without COX-1 inhibition. It inhibits the gene expression of COX-2, rather than inhibiting the COX-2 enzyme directly, achieving a broader inhibition of pro-inflammatory processes and a faster onset of action. Absence of COX-1 activity should result in limited gastrointestinal irritation, a common side effect of many NSAIDs.
Nexrutine was tested and found to be a safe, effective, and rapid-acting dietary supplement which helps avoid or relieve the general aches and pains associated with physical activity or overexertion. Fifty-three subjects were treated with Nexrutine for 2 weeks. Based on preclinical studies, Nexrutine was evaluated to help avoid or relieve the general aches and pains associated with physical activity or overexertion such as sore joints, sore muscles, muscle aches and pains, and stiff joints. Post-trial analysis revealed that 79% of the participants reported this effect. The efficacy parameters for Nexrutine included the following: it eases soreness in joints and muscles, makes everyday activities more comfortable, relieves aching joints, and relieves muscle aches. Additionally, the subjects were comfortable using the product. No significant side effects were reported. The product was judged to be gentle on the stomach by 86% of the subjects.
Nexrutine was compared to naproxen in a classic animal model for inflammation-induced pain. Naproxen is a well-known and widely used over-the-counter anti-inflammatory. The results observed were more dramatic than anticipated. Nexrutine demonstrated faster onset of analgesia than naproxen in one study while maintaining the same duration of activity as naproxen in another study. Nexrutine was shown to provide rapid onset and an extended duration of pain relief.
An extensive literature review of the chemical constituents plus the use of the plant from which Nexrutine is extracted for hundreds of years suggests that this material is safe for its intended use. In addition, an acute toxicity study in rats (5 grams/kg) with 14-day observation revealed no untoward effects from Nexrutine. No side effects are expected at the recommended human dosage.Glucosamine.
Glucosamine is a naturally occurring substance in the body, synthesized by chondrocytes for the purpose of producing joint cartilage. In OA this synthesis is defective, and supplementation with glucosamine has proven to be useful. The body uses supplemented glucosamine to synthesize the proteoglycans and the water-binding glycosaminoglycans 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 such as collagenase and phospholipase, which destroy the cartilage. 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. Among the natural therapies for OA, glucosamine sulfate is probably the best known. It is extensively used as a drug for OA in Europe and is readily available in health food stores in the United States.
Research into glucosamine began in the early 1980s. To date there have been many significant positive studies regarding this treatment for OA. Studies have been double-blind and frequently have compared glucosamine either to a placebo or to one of the NSAIDs such as ibuprofen or piroxicam. Studies have been done on intramuscular glucosamine sulfate as well as oral and IV forms.
Glucosamine has been almost totally free of side effects, particularly when compared to the NSAIDs. Rovati et al. (1994) compared 310 patients with knee OA by randomizing them into four groups, each of which received oral treatment with glucosamine sulfate, piroxicam, both drugs, or a placebo. While piroxicam had a similar efficacy at the start of treatment, it was less well tolerated, and its effect wore off quickly. This study followed patients for 90 days plus another 60 days after treatment. While 24% had adverse effects with piroxicam, only 15% had adverse effects with glucosamine (Rovati et al. 1994). In one well-designed study of 178 patients with OA of the knee, one group was treated for 4 weeks with glucosamine sulfate, 1500 mg daily, and the other group was treated with ibuprofen at 1200 mg a day. Again, glucosamine relieved the symptoms as effectively as ibuprofen and was significantly better tolerated than ibuprofen. The safety and tolerability of glucosamine can easily be explained by the fact that it is a physiological substance normally used by the body (Qui et al. 1998).
As with most natural remedies, the therapeutic effect of glucosamine is not immediate. It usually takes 1-8 weeks to appear. Once achieved, it tends to persist for a notable time even after discontinuation of the treatment. The probable reason for this is that glucosamine is incorporated into rebuilding the cartilage itself. One study has shown through electron microscopy of the articular cartilage that patients treated with glucosamine show a picture more similar to healthy cartilage than that of the placebo-treated cartilage of the control group (Drovanti et al. 1980).
Given the amount of available evidence, the comparisons with NSAIDs, and the number of positive double-blind, placebo-controlled studies, glucosamine sulfate should be used as a first natural choice for OA. Certainly the evidence prevails that it is at the very least equal in efficacy to NSAIDs and that it has much fewer side effects. In most studies, the dose has been 500 mg 3 times daily. At least one study suggests that the sulfate salt of glucosamine is also an important component and that other salts such as glucosamine hydrochloride may not work as well. Sulfate is an important mineral in building cartilage (Hoffer et al. 2001).Chondroitin Sulfate.
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 attracts water into the cartilage matrix and stimulates the production of cartilage. Likewise it has the ability to prevent enzymes from dissolving cartilage. Although the absorption of chondroitin sulfate is much lower than that of glucosamine (10-15% versus 90-98%), a few studies have shown very good results from long-term treatment with chondroitin sulfate, reducing pain and increasing range of motion.
Uebelhart et al. (1998) performed a year long, double-blind clinical study including 42 patients with OA, showing that chondroitin sulfate was well tolerated and significantly reduced pain and increased joint mobility. The patients were given 800 mg of chondroitin sulfate a day or placebo. These results confirm that oral chondroitin 4- and 6-sulfate is an effective and safe, slow-acting supplement for the treatment of knee OA. In addition, it may be able to stabilize the joint space width and to modulate bone and joint metabolism. This is the first preliminary demonstration that chondroitin might influence the natural course of OA in humans.
In another double-blind study, 119 patients that had finger-joint OA were treated and then followed for 3 years (Verbruggen et al 1998). The chondroitin dosage was 400 mg 3 times daily. X-rays of the finger joints were carried out at the start and at yearly intervals. The number of patients that developed progression of the disease (i.e., decreased joint space and joint erosion) was significantly less in the group treated with chondroitin sulfate.
The improvement in walking time was studied in 80 patients with OA in the knee. In this double-blind study, the treatment period was 6 months and the chondroitin sulfate dosage was 400 mg twice daily. The minimum time to perform a 20 m walk showed a constant reduction of time only in the chondroitin group. Lower consumption of pain-killing drugs and excellent tolerability was also observed (Bucsi et al. 1998).
Glucosamine alone or in combination with chondroitin sulfate is more and more becoming recognized as the treatment of choice for OA, even in the United States. Its ability to actually repair and improve joint function in addition to providing pain relief gives it a significant advantage compared to conventional treatment.Willow Bark.
Salicylic acid, the basis of aspirin, was first prepared from willow bark by an Italian chemist in 1838. The name of the compound is derived from Salix, the Latin name for the willow genus. Aspirin, acetylsalicylic acid, is a synthetic form of salicylic acid. Willow bark is rich in salicin and related salicylates that metabolize into salicylic acid. Many plants, such as meadowsweet and wintergreen, also contain these compounds. They have a long tradition of use in Europe and have far fewer side effects than aspirin.
While aspirin has been shown to have a lowering effect on some of the proinflammatory factors, it can also increase LTB4, which is a major inflammation-promoting mediator. An interesting study compared the effect on proinflammatory substances of aspirin alone with a combination of low-dose aspirin and fish oil (Engstrom et al. 1997). The results showed that the combination of fish oil and low-dose aspirin has significantly more favorable effects on the pattern of pro- and anti-inflammatory factors than the aspirin alone. LTB4 increased 19% when aspirin was taken by itself but decreased 69% after intake of aspirin and fish oil together.
This makes sense based on the fact that aspirin inhibits COX-2, but not lipooxygenase. Remember that arachidonic acid is converted into PGE2 and LTB4 by COX-2 and lipooxygenase, respectively. Since fish oil suppresses arachidonic acid levels, it reduces the precursor to both PGE2 and LTB4.Fish Oil.
It is established that dietary fatty acids determine the composition of lipids in the cell membranes which influence the production of prostaglandins and leukotrienes that regulate inflammation.
Omega-3 oils have been shown to suppress the production of PGE-2, which contributes to arthritis by degrading collagen needed for the cartilage that lines the joints. PGE-2 is also a proinflammatory prostaglandin that contributes to the arthritis inflammatory cascade. A large number of studies have confirmed the usefulness of omega-3 oils in relieving tender joints and morning stiffness, in some cases eliminating the need for NSAID medication. One study found that patients consuming fish oil were able to significantly reduce their NSAID dose compared with a control group (Lau et al. 1993).
Omega-3 oils, such as fish oil (which contain the essential fatty acids EPA and DHA) and perilla and flaxseed oils, have the ability to suppress the production of inflammatory mediators and thereby influence the course of chronic inflammatory diseases such as RA (Kremer et al. 1985; Kremer et al. 1992).
An enteric-coated fish-oil preparation was used in a 1-year, double-blind study of 78 patients with inflammatory bowel disease. The absorption rate and tolerability was high with this preparation, and after 1 year, 59% of the fish-oil group remained in remission compared to 36% in the placebo group, indicating an anti- inflammatory effect (Belluzzi et al. 1996).
In other studies, dietary omega-3 oils have shown a suppressive effect on the production of the cytokines IL-1b, IL-6, and TNF-alpha, in addition to PGE2 and LTB4 (Caugey et al. 1996; James et al. 1997). When fish oil supplementation was given to RA patients, inflammatory arachidonic acid levels were reduced by 33% compared to presupplement values (Sperling et al. 1987), suggesting that an increase of dietary omega-3 oils can be complementary in treating RA.
A large number of publications from around the world have confirmed the usefulness of dietary supplementation with omega-3 oils in relieving tender joints and morning stiffness in patients with RA, in some cases eliminating the need for NSAID medication (Kremer et al. 1995). Skoldstam et al. (1992) and Lau et al. (1993) found that patients consuming fish oil were able to significantly reduce their NSAID dose compared with a control group.
Of 12 published double-blind and placebo-controlled studies with a duration of 12-52 weeks, decreased joint tenderness was the most common favorable outcome reported. Fish oil supplementation significantly decreased the use of NSAIDs in the three studies in which NSAIDs were used. Unlike NSAID use, fish-oil consumption is not associated with GI toxicity. The results of the studies suggest that the effective dose of fish oil is approximately 3-6 grams a day. Higher dosages did not give better results (Robinson et al. 1989).
A study by James et al. (1997) emphasized the potential for increased efficacy of anti-inflammatory drugs when using omega-3 oils in the diet. It was observed that diets rich in omega-3 oils and low in omega-6 fats had a drug-sparing effect with decreased side effects. Drug toxicity is estimated to contribute 60% of the total cost of treating RA patients in the United States (Prashker et al. 1995). Use of omega-3 oils in the diet would appear to offer a simple, safe, and inexpensive way to reduce toxicity and side effects from OA and RA medications.Antioxidants.
Oxidative stress or free-radical damage is a factor of importance in the development of OA, just as it is a major cause of most chronic degenerative diseases as well as aging. There is also strong evidence that oxidative damage occurs in RA patients (Jikimoto et al. 2002). Increased oxidation of lipids (peroxidation) as well as depletion of ascorbate in serum and synovial fluid has been observed (Vijayalakshmi et al. 1997; Sakai et al. 1999). High doses of vitamin E, an antioxidant, are reported to diminish pain (Edmonds et al. 1997). Most importantly, TNF-alpha which plays a key role in RA and is a well-known cause of oxidative stress, is reduced by vitamin E.
Increased selenium was given over a period of 3 months to RA patients whose red blood cells showed significantly lower selenium levels than the normal populations. At the end of the 3 months, selenium levels were not restored despite supplementation higher than the RDA. However, the patients showed improvement with less tender or swollen joints and less morning stiffness. The patients using selenium needed less cortisone and NSAIDs than the control group. Laboratory indicators of inflammation were also reduced (Heinle et al. 1997).
In order to counteract free-radical damage, antioxidants are needed. A diet rich in vegetables and fruits is likely to add important antioxidants to the body. However, this may not always be enough. Vitamin C and vitamin E supplements have been studied and found to be important in the treatment of OA. Deficient vitamin C intake, which is common with elderly people, impairs the synthesis of collagen, the main protein of cartilage (Bates 1977). Studies on vitamin E have shown its ability to stimulate the production of cartilage components, such as glycosaminoglycans, as well as to inhibit the breakdown of cartilage.
Healthy food and a minimum of toxins may be more important for our health than we want to believe. The body strives to heal itself, whether it is a cut finger, a cold, or a damaged or inflamed joint. It makes sense to find ways to support the body with natural substances that the body can use in the healing process.
Recent research has provided us with new insights into the mechanisms of arthritis and has left us with a scientific understanding of how natural remedies work in harmony with the body rather than against it.Gamma-Linolenic Acid (GLA).
GLA is a fatty acid found in evening primrose oil, borage oil, and black currant seed oil that has been used to suppress chronic inflammation. In the Annals of Internal Medicine (1993), the findings of a 24-week, double-blind, placebo-controlled trial with GLA derived from borage oil were reported. The patients receiving the borage oil experienced a 36% reduction in the number of tender joints, a 45% reduction in the tender joint score, a 41% reduction in the swollen joint score, and a 28% reduction in the swollen joint count. The placebo group showed no benefits (Leventhal et al. 1993).
A paper in the British Journal of Rheumatology (1994) reports the findings of a 24-week, double-blind, placebo-controlled trial in RA patients treated with black currant seed oil rich in GLA and alpha-linolenic acid. Patients receiving black currant seed oil showed reductions in the signs and symptoms of the disease. The placebo group showed no change in disease status. According to the researchers, the study showed that black currant seed oil is a potentially effective treatment for active RA. No adverse reactions were observed, although some people dropped out of the trial because of the size and number of capsules they were required to take (Leventhal et al. 1994).
In Seminars in Arthritis and Rheumatism (1995), there was a review of all published literature on the use of GLA for the treatment of RA. GLA reduced the effects of autoimmune disease on joint linings, although more research was needed to determine the ideal dose of GLA for arthritis (Rothman et al. 1995).Methylsulfonylmethane (MSM).
MSM is a natural sulfur compound found in all living things. It should not to be confused with sulfur (sulfa) drugs or dimethyl sulfoxide (DMSO) to which some people are allergic. It is one of the most prominent compounds in our bodies after water and sodium. MSM has been shown to produce a multitude of actions including pain relief, reducing inflammation, dilating blood vessels and increasing blood flow, reducing muscle spasms, and promoting immune normalizing effects (Jacob et al. 1999). In a double-blind study of patients with degenerative joint disease, MSM was administered at a dose of 2250 mg daily. At the conclusion of the study, the overall improvement in pain of those taking MSM was 82% after 6 weeks (Lawrence 1998).Continued
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