UMN Joint Lubrication Support

Joint Lubrication Support. A proprietary blend of fatty acid esters, antioxidants and natural Cox-2 inflammatory modulators, to support normal joint function and mobility.

Ingredients:

Proprietary blend 850mg

1. Cetyl myristoleate
a. Cetyl Myristoleate - A Unique Natural Compound Valuable in Arthritis Conditions.
b. Cetyl Myristoleate - Cases & Study
c. Clinical Study using Cetyl Myristoleate for improving range of motion and discomfort in patients suffering from chronic Osteoarthritis (OA)
d. U.S. Patents: Two patents: 1. Rheumatoid arthritis, 2. Osteoarthritis.

2. Curcuminoids
3. Tetrahydra Curcuminoids
4. Ursolic Acid

UMN Joint Lubrication Support Ingredient Rationale:

1. Ingredient Name: Cetyl myristoleate

Used For / Claims: Cetyl myristoleate is a substance isolated from mice that are immune to chemically-induced arthritis.

Cetyl myristoleate has been shown in research and clinical studies to:

· Improve lubrication of joints and muscles
· Cause the softening of hardened tissues
· Increase pliability of the joints and connective tissues
· Modulate the immune system
· Decrease inflammation

Orally, cetyl myristoleate is used for:

· Ankylosing spondylitis
· Back pain
· Behcet's syndrome
· Benign prostate hyperplasia (BPH)
· Emphysema
· Fibromyalgia
· Multiple sclerosis
· Osteoarthritis
· Psoriasis
· Reiter's syndrome
· Rheumatoid arthritis
· Silicone breast disease
· Sjogren's syndrome
· Systemic lupus erythematosus

Cetyl Myristoleate - A Unique Natural CompoundValuable in Arthritis Conditions. A Sponsored Article by Dr. Charles Cochran and Dr. Raymond Dent, September 1997 (Reprinted with permission from the author.)

Introduction

Arthritis is a disease of epidemic proportions, but it has been around for so many centuries that it is considered by most people as a part of growing old or a consequence of physical injury. Arthritis is in fact a far more complex disease than is generally known. For instance, Dorland's Medical Dictionary describes 27 different types of arthritis, and that does not include such diverse conditions as systemic lupus erythematosus, scleroderma, fibromyalgia, and numerous other conditions which some authorities consider to be types of arthritis.1 One authority states that there are approximately 100 causes for arthritis.

Arthritis is thought to affect more than 50 million Americans, and is generally accepted to be the leading cause of movement limitation and disability. It deserves and receives a great deal of research and medical attention. There are hundreds of drugs, procedures, and medical aids and devices directed at coping with the many manifestations of the disease. Given this degree of complexity, certainly no one agent alone could ever be expected to manage or cure "arthritis" in its entirety. New agents take their place in the spectrum and make a contribution. Now there is a relatively new discovery of a natural substance, cetyl myristoleate, which shows promise of making a great contribution in non-infective types of arthritis.

Cetyl Myristoleate

Cetyl myristoleate was discovered and isolated by one person, working alone, on a quest to find a cure for arthritis. Harry W. Diehl, while employed by the National Institute of Arthritis, Metabolism, and Digestive Diseases, specialized in sugar chemistry. He used his chemical knowledge and research instincts to great advantage, identifying and characterizing over 500 compounds, several of which were patented by the National Institutes of Health (NIH). His most significant discovery before cetyl myristoleate was a method of synthesizing 2-deoxydextroribose, a sugar used in the preparation of oral polio vaccine by Dr. Jonas Salk.

Diehl's interest in discovering a way to help victims of arthritis began over 40 years ago when his friend and next door neighbor, a carpenter, developed severe rheumatoid arthritis. His condition deteriorated over time until he became disabled. The neighbor had a family to support, but his arthritis made that impossible. Diehl is a deeply religious man whose feelings overwhelmed him as his friend's condition worsened. Harry thought, "Here I am working at the National Institutes of Health, and I have never seen anything that was good for curing arthritis."4 He decided to establish a laboratory in his home and embark on a search for something to relieve the pain and disability of his neighbor and the millions of people who suffer from arthritis. Unfortunately, he was too late to help the neighbor, but Diehl's research did lead to the discovery of cetyl myristoleate, which may someday be hailed as one of the significant nutritional discoveries of the 20th century.

The Quest

As a researcher, Diehl knew that finding a cure for arthritis first meant inducing the disease experimentally in research animals. He started with mice, and quickly realized that he was unable to induce arthritis in them. Diehl said he tried every way he could to give those mice arthritis, but they just would not get it. Then, he contacted a researcher in California who wrote to him, "If you or anyone else can give mice arthritis, I want to know about it, because mice are 100% immune to arthritis."5 At that moment, Diehl's research instincts told him that what he wanted was already somewhere in those mice.
It was a long, tedious job, working on his own in his spare time, but Diehl finally found the factor - cetyl myristoleate - that protected mice from arthritis. As Diehl said, "It didn't come on a silver platter to me, but after years of chemical sleuthing and just old-fashioned chemical cooking, I found it!" On thin layer chromatography of methylene chloride extract from macerated mice, Diehl noticed a mysterious compound, which was subsequently identified as cetyl myristoleate. As Diehl was to prove, cetyl myristoleate circulates in the blood of mice and makes them immune to arthritis.
Cetyl myristoleate is now known to exist in sperm whale oil and in a small gland in the male beaver. At this time no other sources in nature are known to contain cetyl myristoleate. While the first amounts of cetyl myristoleate for experimentation were extracted from mice, Diehl quickly developed a method for making cetyl myristoleate in the lab by the esterification of myristoleic acid.

Chemistry

Cetyl myristoleate, an oil, is the hexadecyl ester of the unsaturated fatty acid cis-9-tetradecenoic acid. The common name for the acid is myristoleic acid. Myristoleic acid is found commonly in fish oils, whale oils, dairy butter, and kombo butter. The chemical formula for cetyl myristoleate is (Z)-ROCO(CH2)7CH=CH(CH2)3CH3. Cetyl myristoleate was unrecorded in chemical literature until Diehl's discovery was reported. The current Merck Index of Chemicals does not list cetyl myristoleate. A search of Chemical Abstracts lists Diehl's method of extracting cetyl myristoleate from mice but contains no reference to cetyl myristoleate prior to his 1977 patent.

Experimentation

To test his theory that mice are immune to arthritis because of cetyl myristoleate, Diehl began to experiment on laboratory rats. This research was reported in an article written in conjunction with one of his colleagues at NIH in the Journal of Pharmaceutical Sciences.6 In summary, this paper reports that ten normal mice were injected in the tail with Freund's Adjuvant (heat-killed desiccated Mycobacterium butyricum) to which rats and certain other rodents are susceptible. In a period of 10-20 days, no noticeable swelling developed in the legs or paws. Mice in a second group were injected in the left hind paw. Again, after 10-20 days, no swelling was detected as determined by comparison of the measurements of paws at the time of injection.
Then, a group of rats was injected with cetyl myristoleate, and 48 hours later, they were given the arthritis-inducing Freund's adjuvant. A control group of rats was given Freund's adjuvant only. Both groups of rats were observed for a total of 58 days with respect to weight change, hind and front leg swelling, and general well-being. All rats receiving only Freund's adjuvant developed severe swelling of the front and hind legs, lagged in weight gain, and were lethargic and morbid. Those receiving cetyl myristoleate before receiving Freund's adjuvant grew an average of 5.7 times as much as the control group and had little if any evidence of swelling or other symptoms of polyarthritis.
The authors concluded that it was apparent that cetyl myristoleate gave virtually complete protection against adjuvant-induced arthritis in rats. Furthermore, a 1:1 mixture of cetyl myristoleate and a homologue, cetyl oleate, gave results not significantly different from administering cetyl myristoleate alone.

A Hiatus

Diehl patented his discovery in 1977, receiving a use patent for rheumatoid arthritis. He then sought pharmaceutical companies to conduct human trials with cetyl myristoleate, but none were interested in his discovery. Perhaps the lack of interest was because cetyl myristoleate was a natural substance and could not be granted a product patent, or maybe because drug companies know they will have to run through 25,000 to 35,000 substances before they find one that makes it to market. Diehl had made a major nutritional discovery, and no one was interested! Being a scientist, not a marketing expert, Diehl let his discovery lay dormant for about 15 years.

Cetyl Myristoleate Cures: Diehl's Arthritis

As Diehl got older, he began to experience some osteoarthritis in his hands, his knees, and his heels. His family physician tried the usual regimen of cortisone and non-steroidal anti-inflammatory drugs without much effect on the course of the disease. Finally his physician told Harry he could not have any more cortisone. "So," Diehl said, "I thought about my discovery, and I decided to make a batch and use it on myself." He did, and successfully cured himself of his osteoarthritis.

Many of his family members and friends became aware of the relief Diehl got from his discovery, and they wanted to try it too. Time after time, people with both rheumatoid and osteoarthritis received astounding relief with cetyl myristoleate. Before long, family members and friends grew into customers, and cetyl myristoleate appeared on the market as a dietary supplement in 1991.

Clinical Observations and Usage

In common with many other natural substances and drugs, the exact mechanism of cetyl myristoleate's physiologic activity is unclear. As a fatty acid ester, it appears to have the same characteristics as the essential fatty acids, linoleic and alpha linolenic acids, except stronger and longer lasting. These fatty acids are referred to as "essential fatty acids" because the human body cannot make them and we must ingest them in our diets. These EFA's truly are essential to normal cell structure and body function and function as components of nerve cells, cell membranes, and hormone-like substances known as prostaglandins. Many of the beneficial effects of a diet rich in plant foods is a result of the low levels of saturated fat and the relatively higher levels of EFA's. While a diet high in saturated fat has been linked to many chronic diseases, a diet low in saturated fat but high in EFA's prevents these very same diseases.7 The use of EFA's over an extended period of time has been shown to decrease the pain, inflammation, and limitation of motion of arthritis.

The difference between the activity of EFA's and cetyl myristoleate is that the quantity required and the period of time over which EFA's are taken are markedly longer. Cetyl myristoleate is taken in a one month course of about 13 grams, while EFA's must be taken over extended periods, sometimes many years, and intake varies widely from hundreds to thousands of grams. Cetyl myristoleate seems to have properties in common with EFA's, but it acts faster and lasts longer.

Because EFA's are necessary for normal functioning of all tissue, it is not surprising that the list of symptoms of EFA deficiency is a long one. In chronic inflammatory processes, the supply of EFA's is depleted. Cetyl myristoleate appears to have the ability to correct the imbalance created by chronic inflammation. Like EFA's, maybe cetyl myristoleate turns off the fires of chronic inflammation by serving as a mediator of prostaglandin formation and metabolism.

Venous blood from the gastrointestinal tract is carried to the liver via the portal vein. With the exception of intestinal chylomicrons that enter the lymphatics, all absorbed products pass initially through the liver, and in most instances are extracted or modified before passage into systemic circulation.9 Since all fatty acids enter systemic circulation through the liver, an oil like cetyl myristoleate would begin its systemic circulation from the liver also. It is speculated that cetyl myristoleate stimulates the production of immunoglobulins and series 1 and 3 prostaglandins, which could be one explanation for why cetyl myristoleate has such potent effect in auto-immune and inflammatory conditions.

Cases & Study

Cetylated fatty acids improve knee function in patients with osteoarthritis. J Rheumatol. 2002 Aug;29(8):1708-12.

Hesslink R Jr, Armstrong D 3rd, Nagendran MV, Sreevatsan S, Barathur R.
Hesslink Ventures, San Diego, California, USA.

OBJECTIVE: To determine the benefit of cetylated fatty acids (CFA) on knee range of motion and function in patients with osteoarthritis (OA). METHODS: Sixty-four patients with chronic knee OA were evaluated at baseline and at 30 and 68 days after consuming either placebo (vegetable oil; n = 31) or CFA (Celadrin; n = 33). Evaluations included physician assessment, knee range of motion with goniometry, and the Lequesne Algofunctional Index (LAI). RESULTS: After 68 days, patients treated with CFA exhibited significant (p < 0.001) increase in knee flexion (10.1 degrees) compared to patients given placebo (1.1 degrees). Neither group reported improvement in knee extension. Patient responses to the LAI indicated a significant (p < 0.001) shift towards functional improvement for the CFA group (-5.4 points) after 68 days compared to a modest improvement in the placebo group (-2.1 points). CONCLUSION: Compared to placebo, CFA provides an improvement in knee range of motion and overall function in patients with OA of the knee. CFA may be an alternative to the use of nonsteroidal antiinflammatory drugs for the treatment of OA.

Here are some cases involving the use of cetyl myristoleate from the author's practice.

Leona - She is a 64 year old mother of five who has been developing degenerative changes in her fingers over the last 15 years. She plays the piano frequently and had to reduce the amount of playing time as a result of the arthritis pain in her fingers. ANA titers have been mildly elevated over the years and rheumatoid disease has been diagnosed in several of her ancestors and one sibling. Leona's other medical problems are mild hypertension and chronic sacro-lumbar pain which appears to be attributable both to sciatic damage sustained in a water skiing accident 24 years ago and Shunerman's disease as teenager. Demonstrating both rheumatoid and osteoarthritis changes in her fingers, she has a mild nodular deformity at the terminal joints of the 3rd and 4th fingers on the left hand and fusiform swelling in the medial and distal joints of most of her fingers. Her thumbs were intermittently painful and swollen. She first took cetyl myristoleate in mid-January, 1997. There is now increased range of motion in all of the finger joints and visible reduction of the rheumatoid-like swelling. The nodular deformities have not changed noticeably. Her back problems demonstrated no improvement. Her sedimentation rate has run from 15 to 35, and is currently 16, with her ANA <1:360. Leona is now able to play the piano all she wants to without pain or swelling of her fingers.

Joyce - She is a 42 year old mother of three and a court reporter in good general health, suffering only from moderate hayfever in the spring. Recently Joyce developed a generalized stiffness and soreness in her fingers, which was worse on her right hand. The condition became so bad over a couple of weeks that she began making numerous mistakes in her court reporting and her speed was significantly reduced. She was diagnosed with tenosynovitis. Joyce shows no deformities of her hands associated with arthritis. She began a course of cetyl myristoleate during the last week of February and finished the last week of March, 1997. She reports complete restoration of her dexterity with return of her normal accuracy and speed, along with elimination of the associated pain.

Bob - He is a 67 year-old retired politician who suffered lumbar and pelvic fractures in WWII when his jeep struck a land mine. Over the years, these injuries produced increasing pain, which seriously affected routine daily activities like getting out of bed in the morning and his ability to play golf. X-rays demonstrate degenerative arthritic changes in the lumbar articulations and the right sacroiliac joint. At 6 feet tall and 185 pounds, he is otherwise in good health. Bob has been using anti-inflammatory drugs for over 20 years, including Voltaren, ibuprofen, Tylenol, and aspirin. He took a one-half course of 7.6 grams of cetyl myristoleate in September, 1996. He experienced moderately severe inflammation (breakthrough pain) on day two which lasted for three days. On the 4th day, the pain began to subside and was completely gone by the 5th day. He has been virtually pain-free since and is very happy with the increased comfort with which he can begin each day. He can now comfortably walk the golf course whereas before he was limited to a golf cart. In February, 1997, he perceived a slight return of his low back pain and decided to take another one-half course. He experienced no breakthrough pain this time and is currently pain-free. He has not taken any other medication for his back pain since taking cetyl myristoleate initially.

Virginia - She is an 85 year-old lady who still works part-time at the family-owned business and cares for her husband who has cancer. Virginia was diagnosed ten years ago with diabetes, and elevated triglycerides and cholesterol. Overweight all her life, she is now stable at 265 pounds. She suffers from long-standing osteoarthritis in her knees and ankles, for which she was placed on cetyl myristoleate. No other agents have been used by her for arthritis except for non-steroidal anti-inflammatory drugs, both OTC and prescription. After about 7.6 grams of cetyl myristoleate, she was able to walk without limping or experiencing significant pain. About three months following the initial course, some pain returned, but she has retained what she estimates to be 50% improvement. She also has gallstones and a recurrent problem with gout, both of which have been symptomless since her cetyl myristoleate course. She evidently did not receive enough cetyl myristoleate for her body weight and will be given another course of 13.25 grams.

Rose - Rose is a 46 year old mother of four who works as a legal secretary. She was diagnosed five years ago as having an atypical form of multiple sclerosis. She had MRI exams of the skull and spinal cord, which demonstrated several areas of non-specific degenerative changes in the brain with several "bright spots" in the cervical spinal cord. She had periodic visual aberrations as well as constant fatigue and fibromyalgia-like pains focused in her trapezius (bilaterally), and in her upper arms and legs below the knees. She also complained of burning sensations in her hands and feet. All of the symptoms worsened with elevated stress. There was no sign of pernicious anemia or diabetes. She was receiving chiropractic therapy. Joyce was started on numerous naturopathic therapies in March, 1996 without significant benefit over an eight month period. In November, 1996, she started on cetyl myristoleate and indicated that she felt more fatigued for the first three days but that the pain in her upper back and extremities was completely gone. She further reported that the tingling/burning sensation in her feet and hands was also gone. Rose felt this was the most striking aspect of the treatment as those areas were the ones most constantly affected. This improvement lasted until she had to travel out of state to tend to her mother who was diagnosed with a rapidly advancing malignancy. Over the next three weeks, her symptoms began to reappear. After the death of her mother, she returned home in as bad shape as before first taking cetyl myristoleate. She decided that she wanted to take another half course of cetyl myristoleate, which completely duplicated the relief from the initial dosage with the exception that she feels slightly less relief from her tendencies to fatigue than she did after the first course. Rose will be taking another half course to see if she can improve her stamina.

J.P. - He is a 60 year old male who has been a farmer his entire life. Diagnosed with rheumatoid arthritis 15 years ago, he has been on various pharmacologic protocols during that time. The most recent includes Plaquenil, methotrexate, and prednisone, with daily non-steroidal anti-inflammatory drug dosing. J.P. has fusiform swelling involving most of the joints of his fingers and moderate ulnar deviation of both hands. He suffered severe pain most of the time, which limited the labor he could perform. He began cetyl myristoleate during the last week of February, 1997, at which time he terminated his methotrexate and Plaquenil (not recommended except in consultation with a qualified physician). He has also reduced his prednisone from 15 milligrams per day to 5 mg, but he still maintains his NSAID dosing on a daily basis. J.P. experienced a mild increase in pain during the first four days of taking cetyl myristoleate, but since then he has been pain free and the swelling in his hands is reducing. J.P. will be monitored over the next month to determine his stability, with checking of his serum parameters by an MD. If he continues to remain symptom-free, his steroid and NSAID therapies will be terminated. J.P. does not smoke, eat chocolate, nor drink alcohol or caffeinated beverages. He was advised at the onset of his cetyl myristoleate dosage to avoid sugar. He is also taking Glucosaplex (a mix of glucosamines) and Lyprinol (fatty acid extract of green lipped mussel) as an additional natural anti-inflammatory agent.

Optimizing the Effects of Cetyl Myristoleate

Since the days of Paracelsus, physicians have been combining therapeutic agents for synergistic effects, or to achieve potentiation of several compounds. As powerful a nutrient as it is, the effects of cetyl myristoleate can be helped by combining it with other natural substances, such as curcuminoids, and ursolic acid. [In certain cases, we find an improved response with the combined use of the UMN Joint Support and UMN Joint Lubrication formulas. Added by Dr. Pouls]

Reported Results

Both osteoarthritis and rheumatoid arthritis sufferers report striking improvement with cetyl myristoleate. Numerous private correspondence describes decreased stiffness and pain, and increased flexibility and range of motion with cetyl myristoleate. Swelling and redness is reduced in rheumatoid arthritis. Writers describe other health benefits, including positive effect of cetyl myristoleate on emphysema, hepatitis, hypertension, diabetes, eczema, psoriasis, colds, allergies, low back pain, and headaches. These reported improvements in general health status are not surprising since each of these conditions could be associated with deficiency in the balance of EFA's.

Like everything else, cetyl myristoleate does not work 100% of the time. Failure to work can be associated with failure to follow the dietary recommendations; failure to use lipase in conjunction with each capsule of cetyl myristoleate; failure to take a sufficient amount of cetyl myristoleate; failure of the liver to uptake and respond to the cetyl myristoleate; and, misdiagnosis in which the condition is not really an arthritis-type condition.

Dosage

Cetyl myristoleate is taken in a one month course. A total dose of 12 to 15 grams appears to be indicated. This is usually enough for most people, but for osteoarthritis sufferers, the dose appears to be related to the number of sites in which cartilage has worn away. For example, a patient with osteoarthritis of the knees could expect 10 to 15 grams to be sufficient in most cases, while a patient with osteoarthritis of 5 or 6 spinal discs, both hips, and both knees may require an additional 5 to 10 grams, or even a full second course. Some of the patients treated by the author would likely have benefited even more from their cetyl myristoleate usage with the larger doses now recommended.

Contraindications and Toxicity

With the tens of thousands of people who have taken cetyl myristoleate there have been no confirmed reports of adverse side effects. In common with fish oils, it may produce some mild burping in some people which passes within an hour. There have been no reported interactions with other medications or natural substances, and other substances (except those mentioned above as diet considerations) do not interfere with cetyl myristoleate.

While teratogenicity of cetyl myristoleate is probably the same as for EFA's, as a safety matter cetyl myristoleate should not be used by pregnant or lactating women until studies of cetyl myristoleate's effects on fetuses and infants have been done. As with any substance being added to the diet of anyone with asthma or a history of severe allergic reactions, caution is advised and cetyl myristoleate should be used in these cases under the direct supervision of a health care professional.

Toxicity studies have been performed on cetyl myristoleate and the lack of toxicity is evident. Test results deemed cetyl myristoleate a non-toxic material in accordance with Federal regulations. Mega-doses were given to test animals with no ill effects. Necropsy of test animals showed no ill effects on their internal organs.13 The LD50 of cetyl myristoleate was not established, but it can be presumed to far exceed 10 grams per kilogram of body weight.

References:

Dorland's Medical Dictionary, 25th Ed.

Shils, Olson, and Shike. Modern Nutrition in Health and Disease. Lea & Febigen, 1994. Philadelphia, PA. p. 1480

Hunter KW Jr, Gault RA, Stehouwer JS, Tam-Chang SW., Synthesis of cetyl myristoleate and evaluation of its therapeutic efficacy in a murine model of collagen-induced arthritis. Pharmacol Res. 2003 Jan;47(1):43-7.

Wright, M.D., J., and Gaby, M.D., A, Nutrition and Healing, August, 1996, Vol.3, Issue 8, paraphrase from page 5.

Private correspondence to H. W. Diehl, Rockville, Md. from Dr. Fay Wood, Univ. of Cal., Berkeley, 1969

Diehl, H. W. and May, E. L., Cetyl Myristoleate Isolated from Swiss Albino Mice: An Apparent Protective Agent against Adjuvant Arthritis in Rats. Jour. of Pharmaceutical Sciences, Vol. 83, No. 3, Mar, 94 pp296-299.

Hesslink R Jr, Armstrong D 3rd, Nagendran MV, et al. Cetylated fatty acids improve knee function in patients with osteoarthritis. J Rheumatol 2002;29:1708-12.

Murray, M. T. Encyclopedia of Nutritional Supplements, Prima Publishing, Rocklin, CA 1996 p. 237

Sobel, D. and Klein, A. C.. Arthritis: What Works. St. Martins Press, New York, NY. pp. 221-225

Clinical Study using Cetyl Myristoleate for improving range of motion and discomfort in patients suffering from chronic Osteoarthritis (OA).

The following presentation was presented at the Federation of American Societies for Experimental Biology (FASEB) on March 31st - April 4th 2001 in Orlando, Florida. The study was performed by ClinCyte, 11055 Flintkote Ave., Suite H, San Diego, CA 92121. The researchers and presenters were Raj Barathur, Ph.D. and Jack Bookout, Ph.D..
Introduction

Osteoarthritis (OA), the most common form of arthritis, is widespread with incidence rising among the elderly. It is estimated that by the year 2020, 60 million persons in the U.S. will be affected by arthritis. Therapy for OA is mostly palliative and based on the use of analgesic or anti-inflammatory agents and physical modalities.

There is a new class of agents (COX2) that are used for treating OA. However, it is undecided whether their benefits outweigh the known contraindications. Many individuals are seeking natural remedies for treating this disease in the hope of limiting the side effects.

There is substantial data showing that OA is associated with an inflammatory model of disease, although the exact mechanism is still debated. There are new studies showing that non-pharmaceutical interventions improve patient outcomes in both OA and rheumatoid arthritis that included poly-unsaturated fatty acids such as gamma-linolenic acid.

The present study investigated the efficacy of a cetylated-fatty acid complex (CMC) for the treatment of OA.

Methods
Subjects - Participants were associated with medical clinics in India. All subjects were classified as having chronic OA (avg 9.2 yrs). Subject age range was 30 to 70 years with a median of 50 to 59 years. Ratio of men to women averaged 60:40.

Patients were excluded if they were currently using systemic corticosteroids, had inflammatory or autoimmune arthritis, or had their gall bladder removed.
Medications for other medical complications were permitted as long as the drugs were mild and medical condition under control. Patients currently consuming aspirin and NSAIDs were enrolled as long as their treatment remained stable and unchanged during the course of study.

Clinical Assessment - Subjects were evaluated by their physicians for the assessment of pain, range of motion, and joint changes. A standard goniometer was used on each affected joint. Starting from a flat, prone position, the subject was asked to bend his/her knee until slight discomfort.

Functional Assessment - Participants were asked to complete standard questionnaires during each visit. The MACTAR questionnaire was used to measure global and discrete function. Subjects were asked a series of questions related to their daily activity, pain, and discomfort. The Lequesne Indices of OA severity was used for subjective assessment of knee pain, function, and daily activity.

Design - The subjects provided informed consent prior to baseline assessment. Subjects returned to their physicians for assessment after 30 and 68 days.

Study Intervention - Subjects were randomized into two groups:
* Placebo - a mixture of soy lecithin (500 mg)
* CMC - a proprietary blend of naturally occurring cetylated fatty acids (eg. cetyl myristate, cetyl myristoleate, cetyl palmtoleate, cetyl laurate, cetyl palmatate and cetyl oleate; 350 mg) in a base of fish oil (75 mg) and soy lecithin (50 mg).
Subjects consumed a total of 6 soft gels per day with meals. The study lasted a total of 68-days.

Statistics
The MACTAR and Lequesne responses were analyzed using an ordinal logistic regression. This technique estimates the cumulative probability of being at or below each individual response level. The data was analyzed using a repeated measures design due to the three time periods of collection.

Range of motion was analyzed using a repeated measures ANOVA. When a significant F-ratio was found, Scheffe was used to determine significance between means.

Results
There were 11 participants dropped from the study due to protocol violation, non-compliance, or elected withdrawal. Subjective assessment from the questionnaires showed that the CMC group reported an improvement in independence, pain reduction, and mobility. Table 1 shows the average MACTAR responses for the two groups. The CMC group tended (p < 0.07) to respond more favorably overall to the questions than placebo participants. Representative question responses are shown in Figures 1 and 2.

Table 1 - Average responses to the MACTAR questionnaire

                 Baseline     30 days       68 days
CMC        15.06           9.64             9.3
Placebo  14.42          12.58           12.58

Each subject's response for the MACTAR questions were summed and then averaged. The CMC group tended to respond more favorably with less discomfort compared to placebo, while the placebo tended to remain within the standard deviation.

The Lequesne Index is shown in Table 2.
Participants were similar at baseline. After 30 days, the CMC group reported improvement in all areas of assessment. These improvements were significantly (p < 0.01) different than placebo. Typical question responses are shown in Figure 3.
Range of motion (ROM) did not differ at baseline. The response after intervention illustrates the improvement in the CMC subjects. The placebo group did not change over the course of the 68-day treatment. See Figure 4.

Figure 1 - MACTAR Question: Recently, are you able to walk up a flight of stairs?

Figure 2 - MACTAR Question: Recently, are you able to stand up from a straight chair without using your arms for support?

Table 2 - Lequesne Index of Severity of Knee OA
                    CMC Placebo
                    0           30          68         0          30         68
Total          15.58   10.66     10.39   15.83   13.88   13.87
Pain           6.22     4.09       3.94      6.13     5.10      5.13
Walking    4.73      3.48       3.36     4.93      4.59      4.55
Activity       4.64      3.09       3.09     4.77      4.19      4.19

Each value is the average sum of the Lequesne questions for each subject. The CMC group noted improvement resulting in a lower total response compared to the placebo.

Figure 3 - Lequesne Question: Maximum distance you can walk (with or without pain)?
A- More than 1 Km B - About 1 Km C - 500 to 900 m
D - 300 to 500 m E - 100 to 300 m F - Less than 100 m

Figure 4 - Knee range of motion in OA patients

Data presented as mean plus/minus S.E. * = Significance p < 0.001

Summary
The present study is the first to characterize the effectiveness of CMC for improving range of motion and discomfort in patients suffering from chronic OA. While the actual mechanisms for these results are unknown, we believe that this fatty acid complex functions at some cellular level. The cellular action may be related to membrane stability, immune modulation, and/or may serve as some cellular signal for a cascade of events.

U.S. Patents: (Two patents are presented below)

1. United States Patent: 4,113,881

Diehl September 12, 1978

Method of treating rheumatoid arthritis

Abstract
A method is described for relieving and inhibiting the symptoms of inflammatory rheumatoid arthritis in mammals using cetyl myristoleate.

Claims

A method of relieving and inhibiting the symptoms of inflammatory rheumatoid arthritis in mammals which comprises the oral administration to a mammal of aneffective amount of cetyl myristoleate.

2. United States Patent 5,569,676

Diehl October 29, 1996

Method for the treatment of osteoarthritis

Abstract
A method is described for alleviating the symptoms of non-rheumatoid arthritis by administering to the afflicted subject a therapeutically effective amount of cetyl myristoleate either orally, topically, or parenterally.
Other References
Primary Examiner: Criares; Theodore J.
Attorney, Agent or Firm: Brown; James J.
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Claims
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What claimed is:

1. A method for treating osteoarthritis arthritis in mammals which comprises administering a therapeutically effective amount of cetyl myristoleate to a mammal having osteoarthritis arthritis.
The present invention is directed to a method for treating non-rheumatoid arthritis. More specifically, the present invention is directed to a method for treating the symptoms of various forms of non-rheumatoid arthritis in mammals by administering either orally, topically, or parenterally a therapeutic effective amount of cetyl myristoleate to the subject mammal.

EXAMPLE I
12 ml of dimethyl sulfoxide solution containing 1 gram of cetyl myristoleate were administered twice daily for 10 days topically to the hands of an approximately 80 year old male diagnosed as suffering pain in his hands and knees due to osteoarthritis. A dramatic decrease in this pain resulted in 3 to 5 weeks and the individual continued to experience relief from this pain for about four years without requiring further application of medication.

EXAMPLE II
A 250 pound, age 75 year old male diagnosed as suffering from osteoarthritis received four 1 cc capsules of cetyl myristoleate orally, twice with about a two month interval between the dosages. The result was at least a 75% alleviation of pain in the afflicted joints. Only minimal pain persisted following medication in the lower back and hips with the knees, elbows and other joints being almost completely pain free.

EXAMPLE III
A female suffering severe back pain from osteoarthritis applied a 10% solution of cetyl myristoleate in dimethyl sulfoxide topically twice a day until a total of 11 cc had been used. Approximately 90% of the back pain relieved within about a week.

EXAMPLE IV
A 48 year old male suffering from severe osteoarthritis received two 1 c.c injections of liquified cetyl myristoleate at about a two year interval. Prior medication had resulted only in limited relief of the pain resulting from the osteoarthritis. Almost total and persistent relief of pain followed each of the cetyl myristoleate injections.

EXAMPLE V
A 72 year old male diagnosed as having osteoarthritis took three capsules, each containing 1 cc of cetyl myristoleate, followed five months latter by four more of the same capsules. His osteoarthritis was alleviated sufficiently that he was able to discontinue other arthritis medication and resume playing the guitar.

EXAMPLE VI
A 65 year old female suffering from osteoarthritis received four capsules containing 1 cc each of cetyl myristoleate orally. She experienced complete recovery from the osteoarthritis within a short time of taking the medication.

Dosage/Safety: With the tens of thousands of people who have taken cetyl myristoleate there have been no confirmed reports of adverse side effects. In common with fish oils, it may produce some mild burping in some people, which passes within an hour. There have been no reported interactions with other medications or natural substances, and other substances do not interfere with cetyl myristoleate.

References:

The merck Manual, Sixteenth Edition, Merck Research Loaboratories, Merck & Co., Rahway, NJ, pp. 1338-1342 1992.

Diehl HW, May EL. Cetyl myristoleate isolated from Swiss albino mice: an apparent protective agent against adjuvant arthritis in rats. J Pharm Sci 1994;83(3):296-9.

Hesslink R Jr, Armstrong D 3rd, Nagendran MV, et al. Cetylated fatty acids improve knee function in patients with osteoarthritis. J Rheumatol 2002;29:1708-12.

2. Curcuminoids

Used For / Claims: Curcuminoids are the yellow pigment, and major active constituent of the herb turmeric.

Curcuminoids have been shown in research and clinical studies to:

· Possess anti-inflammatory properties
· Possess antioxidant effects
· Possess immunostimulatory effects
· Inhibit cyclooxygenase-2 (COX-2) prostaglandins and leukotrienes

Curcuminoids are used for:

· Reducing the symptoms associated with rheumatoid arthritis (RA)
· Protection from oxidative destruction of the joints and connective tissues
· Stomach pain
· Indigestion
· Gall bladder conditions
· Liver conditions
· Headache

Dosage/Safety: Orally, turmeric is well tolerated if taken as recommended. It has been safely recommended at up to 2 grams per day. In some individuals, it can cause diarrhea and/or nausea.

References:

Deodhar SD, Sethi R, Srimal RC. Preliminary study on antirheumatic activity of curcumin (diferuloyl methane). Indian J Med Res 1980;71:632-4.

Thamlikitkul V, Bunyapraphatsara N, Dechatiwongse T, et al. Randomized double blind study of Curcuma domestica Val. for dyspepsia. J Med Assoc Thai 1989;72:613-20.

Blumenthal, et al. Herbal Medicine, Expanded Commission E Monographs. Austin: American Botanical Council; 2000.

Antony S, Kuttan R, Kuttan G. Immunomodulatory activity of curcumin. Immunol Invest 1999;28:291-303.

Ravindranath V, Chandrasekhara N. Absorption and tissue distribution of curcumin in rats. Toxicology 1980;16:259-65.

Araujo CC, Leon LL. Biological activities of Curcuma longa L. Mem Inst Oswaldo Cruz 2001;96:723-8.

Zhang F, Altorki NK, Mestre JR, et al. Curcumin inhibits cyclooxygenase-2 transcription in bile acid- and phorbol ester-treated human gastrointestinal epithelial cells. Carcinogenesis 1999;20:445-51.

3. Tetrahydra curcuminoids

Used For / Claims: Tetrahydra curcuminoids are a highly purified colorless hydrogenated nutrient derived from the yellow curcuminoids, which are the biologically active constituents from the root of Curcuma longa, and possess superior antioxidant and anti-inflammatory properties to other curcumin products. Numerous independent studies have confirmed the significant antioxidant and anti-inflammatory effects of Tetrahydra curcuminoids. Tetrahydra curcuminoids are more bioavailable and stable in the body due to their molecular structure, and their increased water solubility, which improves absorption, circulation and biological effects in the bloodstream.

Tetrahydra curcuminoids are used for:

· Antioxidant protection from oxidative free radicals
· Anti-inflammatory properties
· Improved absorption and bioavailablity of active constituents

Dosage/Safety: Tetrahydra curcuminoids are safe if used appropriately. In some individuals, at high doses, it can cause diarrhea and/or nausea.

References:

Reprinted with permission from the authors:
Lakshmi Prakash, Ph,D., & Muhammed Majeed, Ph.D., Tetrahydracurcuminoids: Bioactive Antioxidant Compounds From Curcuminoids. © Sabinsa Corporation, 2000.

Majeed, M. et al, 1995. Curcuminoids: Antioxidant Phytonutrients. Nutrascience Publishers, New Jersey.

Pan, M. H., et al., 1999. Biotransformation of curcumin on tumorigenesis in mice. J Cell Biochem Suppl, 27:26-34.

Osawa, T., et al., 1995. Antioxidant activity of the tetrahydracurcuminoids. Biosci. Biotechnol. Biochem, 59(9):1609-12.

Sugiyama, Y., et al., August 23,1996. Involvement of the beta-diketone moiety in the antioxidative mechanism of tetrahydracurcumin. Biochem Pharmacol, 52(4):519-25.

Nakamura, Y., et al., 1998. Inhibitory effects of curcumin and tetrahydracurcuminoids on tumor-promoter-induced reactive oxygen species generation in leukocytes, in vitro and in vivo. Jpn J Cancer Res, 89(4):361-70.

Holder, G.M., et al., 1978. The metabolism and excretion of curcumin. (1-7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) in the rat. Xenobiotica, 8(12):761-8.

Mukhopadhaya, A., et al., 1982. Anti-inflammatory and irritant activities of curcumin analogues in rats, Agents and Action. 12:2287

Rao, T.S., et al., 1982. Anti-inflammatory activities of curcumin analogues. Ind J Med.Res., 75:574-578.

Research Report No. 786, Sabinsa Corporation, U.S.A., 1995.

Bonte, F., et al., 1997. Protective effects of curcuminoids on epidermal skin cells under free oxygen radical stress. Planta Med. 63(3):265-266.

Kim, J.L., et al., 1988. Chemoprotective effects of carotenoids and curcumins on mouse colon carcinogenesis after 1,2-dimethylhydrazine irritation. Carcinogenesis 19(1):81-85.

4. Ursolic Acid

Pharmacological actions of ursolic acid:

· Anti-inflammatory
· Anti-ulcer
· Anti-tumor
· Anti-microbial
· Anti-viral
· Anti-hyperlipidemic
· Hepatoprotective

Used For / Claims: Ursolic Acid is medicinally active both topically and internally. Its anti-inflammatory, antitumor (skin cancer), and antimicrobial properties make it useful in numerous applications.

Introduction

Ursolic acid, is a pentacyclic triterpenoid compound which naturally occurs in a large number of vegetarian foods, medicinal herbs, and plants1,2. For a long time, it was considered to be pharmacologically inactive3. Thus, ursolic acid and its alkali salts (e.g. potassium or sodium ursolates) were exclusively used as emulsifying agents in pharmaceutical, cosmetic, and food preparations3,4. However, upon closer examination, ursolic acid was found to be medicinally active both topically and internally1. Its anti-inflammatory, antitumor (skin cancer), and antimicrobial properties make it useful in numerous applications1.

Botanical Sources

Like most triterpenoids, ursolic acid is ubiquitous in the plant kingdom5. Ursolic acid and its derivatives are constituents of numerous plants which have diversified phylogenetic origins and taxonomic positions. It has been isolated from the protective wax-like coatings of apples, pears, cranberries, prunes, and other fruits6. Seaweeds are rich in ursolic acid derivatives6.

Chemistry

Ursolic acid [(3?)-3-Hydroxyurs-12-en-28-oic acid] rarely occurs without its isomer oleanolic acid [(3?)-3-Hydroxyolean-12-en-28-oic acid]. They may occur in their free acid form, as shown in Figure 1, or as aglycones for triterpenoid saponins which are comprised of a triterpenoid aglycone linked to one or more sugar moieties. Ursolic and oleanolic acids are similar in pharmacological activity1.


Figure 1. Structures of Ursolic and Oleanolic Acids.
Several ursolic acid derivatives, both natural and synthetic, have been reported. Novel ursolic acid derivatives, including ursane-type triterpenoid saponins, naturally occur as secondary metabolites through complex metabolic processes in different parts of the plant5,8-12 Synthetic derivatives obtained from ursolic acid have been reported and evaluated for their pharmacological action3,13-16.

Pharmacological Actions of Ursolic Acid

Medicinal plants containing ursolic acid have been used in folk medicine before it was known which constituents were responsible for their therapeutic effectiveness. Contemporary scientific research which led to the isolation and identification of ursolic acid revealed and confirmed that several pharmacological effects, such as antitumor, hepatoprotective, anti-inflammatory (oral and topical), antiulcer, antimicrobial, anti-hyperlipidemic, and antiviral, can be attributed to ursolic acid1.

Reprinted with permission from the authors:
Muhammed Majeed, Ph.D. & Yvonne Nujoma, Ph.D., Ursolic acid., © Sabinsa Corporation, 2000.

References:

Liu, J. (1995) Pharmacology of oleanolic and ursolic acid. J. of Ethnopharmacology 49, 57-68.

The Merck Index (1996) 12th edition, Merck Research Laboratories, Whitehouse Station, NJ, 1686-1687.

Mezzetti, T., Orzalesi, G., and Bellavita, V. (1971) Chemistry of ursolic acid. Planta Medica 20(3), 244-252.

Harry, R.G. (1963) Cosmetic Materials. Their Origin, Characteristics, Uses, and Dermatological Action. Chemical Publishing Co., Inc., New York, NY.

Price, K.R., Johnson, I.T., and Fenwick, G.R. (1987) The chemistry and biological significance of saponins in foods and feedingstuffs. CRC Critical Reviews in Food Science and Nutrition 20(1), 27-135.

D’Amelio, F.S. (1999) Botanicals- A Phytocosmetic Desk Reference. CRC Press, Boca Raton, Fl.

Leung, A.Y. and Foster, S. (1996) 2nd edition Encyclopedia of Common Natural Ingredients Used in Food, Drugs, and Cosmetics. John Wiley and Sons Inc. New York, NY.

Kraemer, K.H., Taketa, A.T., Schenkel, E.P., Gosmann, G., and Guillaume, D. (1996) Matesaponin 5, a highly polar saponin from Ilex paraguariensis. Phytochemistry 42(4), 1119-1122.

Miyase, T., Melek, F.R., El-Gindi, O.D., Abdel-Khalik, S.M., El-Gindi, M.R., Haggag, M.Y., and Hilal, S.H. (1996) Saponins from Fagonia arabica. Phytochemistry 41(4), 1175-1179.

Miyase, T., Shiokawa, K.I., Zhang, D.M., Ueno, A. (1996) Arliasaponins I-XI, triterpene saponins from the roots of Aralia decaisneana. Phytochemistry 41(5), 1411-1418.

Nakanishi, T., Tanaka, K., Murata, H., Somekawa, M., and Inada, A. (1993) Phytochemical studies of seeds of medicinal plants III. Ursolic acid and oleanolic acid glycosides from seeds of Patrinia scabiosaefolia Fischer. Chem. Pharm. Bull. (Tokyo) 41(1), 183-186.

De Tommasi, N., De Simone, F., and Pizza, C. (1992) Constituents of Eriobotrya japonica. A study of their antiviral properties. J. Nat. Prod. 55(8), 1067-1073.

Finlay, H., Honda, T., Gribble, G.W., Benoit, N.E., Suh, N., and Sporn, M.B. (1997) Novel A-Ring cleaved analogs of oleanolic and ursolic acids which affect growth regulation in NRP.152 prostate cells. Bioorganic and Medicinal Chemistry Letters 7, 1769.

Finlay, H., Honda, T., Gribble, G.W., Suh, N., and Sporn, M.B. (1997) New enone derivatives of oleanolic and ursolic acid as inhibitors of nitric oxide production in mouse macrophages. Bioorganic and Medicinal Chemistry Letters 7, 163.

Lee, K., Lin, Y., Wu, T., Zhang, D., Yamagishi, T., Hayashi, T., Hall, I.H., Chang, J., Wu, R., Yang, T. (1988) The cytotoxic principles of Prunella vulgaris, Psychotria serpens, and Hyptis capitata: ursolic acid and related derivatives. Planta Medica 54, 308-311.

Takechi, M., Uno, C., and Tanaka, Y. (1996) Structure-activity relationships of synthetic saponins. Phytochemistry 41(1), 121-123.