CHONDROITIN SULFATE - General Discussion

Muller (1837) originally obtained a solution of chondrin by steaming cartilage at high pressures. The chief GAG of cartilage was found to be CS. Meyer (1955) identified the structure of CS as a repeating disaccharide, specifically glucuronic acid and sulfated N-acetylglucosamine, and coined the term "mucopolysaccharides" to describe CS.

Cartilage is a component of connective tissue and helps provide support and shape to tissues. Cartilage is distributed within the intervertebral discs, joints (articular cartilage), nasal septae, frontal rib cage and more. The principle solids of cartilage are collagen and proteoglycans (PGs). Cartilage PGs contain a central protein core to which GAGs are attached. Other GAGs in cartilage are hyaluronic acid, keratan sulfates, dermatan sulfates and heparin sulfates, all of which closely resemble CS in structure and function.

CS are arranged in a three-dimensional bottle-brush pattern in PGs. Because CS carry a high number of sulfate groups in an ordered array, the net electronegative charge favors a high affinity for water. The resulting gel gives a wet-cushion effect, accounting for compressibility, elasticity and fluidity of joint movement for cartilage.

Aging causes many changes of CS patterns in cartilage PGS. Age-related decreases in water content, CS chain size 'and amounts of CS relative to other GAGs are seen. Mechanical stress and loading hasten the age-related changes, and perhaps predisposes or causes undesirable responses to cartilage.

In adult connective tissues, CS and PGs are in a state of constant turnover (degradation and resynthesis). During repair of injured connective tissue, CS synthesis precedes collagen synthesis, and CS synthesis is essential for proper healing. Animals and humans treated with corticosteroids show decreased synthesis of CS and delayed healing. In addition, PGs and CS are degraded as a consequence of free radical damage during inflammatory conditions. Free radicals also inhibit the synthesis of CS and PGs.

CS are also structural components of vascular intima (inside artery walls), giving strength and elasticity to blood vessels. During aging, CS are gradually replaced by other GAGs, affecting vascular permeability. Deranged turnover and synthesis of CS in vascular intima are some of the earliest changes seen in this process. Another important role for CS is the activation of lipoprotein lipase on capillary endothelial cells, facilitating proper metabolism of blood lipids.

Synthesis of Chondroitin Sulfate from GLUCOSAMINE is inhibited by nutritional deficiencies of trace minerals (particularly manganese), ascorbate (Vitamin C) and retinol (Vitamin A). Anti-inflammatory drugs such as corticosteroids, salicylates, gold salts, ibuprofen, phenylbutazone and other NSAIDs can also reduce CS synthesis. Malnutrition, infection, trauma, excessive stress and collagen diseases are able to decrease CS synthesis and/or increase CS degradation and excretion from the body. This is why we suggest you use the end product -- CHONDROITIN SULFATE -- instead of its precursor.

A number of nutritional products being marketed as chondroitin sulfates are nothing more than dried trachea powder (15-20% CS), often times mixed with papain. This will yield only about 5 to 6% of bioavailable CS. However, the PURIFIED CHONDROITIN SULFATES that we use from Biotics Research Corporation, are isolated from trachea powder or other cartilage sources by a long process of digestion, washings, precipitations and dryings to remove collagen and other fibrous proteins from the CS. Oral uptake of CS from trachea powder is not known, but absorption from oral administration of purified CS is typically 90% or greater.

CHONDROITIN SULFATES AND
CONNECTIVE TISSUE REPAIR

Conditions Affecting Connective Tissue

. Almost any disease or degenerative process will be detrimental to connective tissue or GAGs to some extent, because they are found in, between and around every organ in the body. Indeed, connective tissue has more accurately been described as a body system of mesenchymal matrix.

Musculoskeletal Injuries and Clinical
Studies

We will concentrate on conditions commonly cared for by Chiropractors and Physical Medicine physicians for which evidence of effectiveness of CS supplementation exists - musculoskeletal injuries. Cardiovascular effects of CS are extensive enough to warrant a full installment in the next section below. Vertebral discs, joint cartilage, tendons, ligaments, muscle fascia, skin and bone itself are frequently involved in such injuries.

Needless to say, our bodies endeavor to repair injuries to the musculoskeletal system as quickly as possible, which still may take weeks to months. Without going into details, synthesis and deposition of CS, hyaluronic acid and other trace GAGs and proteoglycans are of utmost importance for healing to occur. When CS synthesis is blocked, healing is at best incomplete. Can supplemental CS accelerate the healing process? The answer appears to be affirmative. Since the research on CS and healing has been virtually ignored, some research results will be presented so that the reader can understand what to expect from CS supplementation.

Animal Studies

Animal studies on surgical wounds conducted since the 1950s have repeatedly found either 20-500/% greater strength or 20% faster recovery using injected or topical acid/pepsin-digested bovine trachea or shark cartilage extracts. Human chemical trials with topical applications of cartilage extracts on ulcers or surgical wounds also found acceleration of healing by 20-500%. Reversal of corticosteroid-induced inhibition of wound healing was also observed repeatedly. Also, soft tissue calcification and keloid formation were inhibited by CS. Further work showed that CS or its breakdown products accounted for much of the wound-healing effects. Even semi-synthetic CS (modified to appease government drug requirements for a purified, known, reproducible compound) showed enhanced repair of osteoarthritic cartilage by inhibiting the enzymes that degrade cartilage.

Human Trials

After two weeks of injections of semisynthetic CS, a clinical success rate of 94% (compared to 43% for indomethacin or Indocin) was found in a study on "jumper's knees" (apicitis patellae or patellar tendonitis). Corticosteroids had only caused a 13% success rate of such cases. Also, half of the patients that did not respond to indomethacin treatment responded to subsequent CS treatment. Over 212 traumatic sports injuries to knee joints that involved cartilage damage were treated with semi-synthetic CS by intra-articular injections. Pain, flexibility and effusion decreases were noted for 65-73% of patients. No side effects were noticed in any of these studies. Although injectable CS and not oral CS was used in these studies, this indicates that if enough CS is delivered to an injury site, healing can be hastened. Only 100-1000 mg per day of CS was used.

A chiropractic study utilizing lower back pain patients analyzed for pain, flexibility and strength by a computerized mechanical testing machine also found significant improvements after CS supplementation when compared to manganese sulfate. This study used commercially available products available to chiropractors. Lower back strength increased 66% for patients supplemented with CS, and only 7% for manganese sulfate. Importantly, supplementation with CS and a wide range of nutrients tailored to musculoskeletal system health including vitamins, minerals, proteolytic enzymes, amino acids and neonatal glandulars improved lower back strength by 258%. This suggests that while CS by itself may be very useful for repair of mesenchymal matrix tissue, accessory nutrients may further enhance progression of healing. Also, lack of nutrients (such as iron) known to antagonize these key nutrients may render such a combination more effective.

Guidelines for Use

Since there is very little information on doses of CS and therapeutic benefits, no hard and fast guidelines are available. Fortunately, there is enough data to suggest clinical dosages of CS for connective tissue healing. For products containing purified CS, 1-2 grams per day per mouth seems sufficient to produce clinically noticeable improvements in healing. Less pure forms need higher doses, ranging up to 10 grams per day for trachea powder. Fortunately, higher doses of purified CS or trachea powder seem to be well tolerated and well absorbed, but it is not known if the healing process can be further accelerated by such doses.

Summary

The use of CS for repair of connective tissue (mesenchymal matrix) has actually shown more benefit in clinical situations than antiinflarnmatory drug treatments. Documentation of benefits in human trials after topical, injected or oral use of products containing CS as their primary ingredient have usually been successful. Improvements in acceleration of healing averaged about 20%, with improvements of 40-50% being common. In addition, mechanically stronger repair of tissues was almost universally achieved (again, approximately 20% stronger than controls). Adjunctive nutrients may further enhance accelerate or improve healing by CS. Finally, the importance of connective tissue in the healing process has repeatedly been ignored by the medical research establishment because of the complexity and technical difficulties inherent to connective tissue research methods. One glaring exception is the field of chiropractic, which has of necessity explored connective tissue health and repair in a common-sense, results-oriented manner. It is equally logical that the nutrition of connective tissue should be of paramount importance to the practice of physical medicine and chiropractic.

CHONDROITIN SULFATES AND
CARDIOVASCULAR HEALTH

Cardiovascular disease (CVD) is still the leading cause of death in the United States, claiming over one-half of all deaths. Since one in four Americans (over 63 million) presently suffer from diagnosed CVD, health of our hearts and arteries should be our primary health concern. Fortunately, consumers, major food suppliers and the medical community are becoming more aware of the wholesale dietary changes necessary for reducing CVD death rates. Smoking less and eating less calories, less cholesterol, less saturated fats, less refined carbohydrates and less salt are steps in the right direction. Exercising more and eating more fresh vegetables (without the rich sauces), more fresh fruit, more whole grains and legumes, more fish and leaner cuts of meat should also help. However, not everyone will follow these dietary guidelines, and for those that do, beneficial reductions of CVD prevalence can still take many years to first appear. Besides, what can be done in the meantime for those diagnosed with CVD?

Chondroitin Sulfates Roles and
Cardiovascular Disease

We will focus on the cardiovascular effects that one nutrient -- chondroitin sulfates (CS) -- can have. CS have roles quite different from those usually described. One role is being a structural component of vascular intima (blood vessel walls). Unfortunately, during aging, CS is slowly replaced by keratan sulfates, which are shorter polymers. This replacement gives a stiffer, less permeable arterial lining, which adversely influences transmission of nutrients and speeds damage from free radicals, both steps which are known to accelerate atherogenesis.

Another role of even more importance has been repeatedly overlooked. Lipoprotein lipase, which has attracted much research attention lately, is the enzyme that digests fats (triglycerides) in LDL and VLDL particles. This enzyme is attached to one end of a stalk of modified CS, with the other and anchored to the cell membrane of blood vessel cells. Remember that all our tissues and organs receive nutrients and expel wastes through these blood vessel cells endothelial cells). When a VLDL or LDL particle attaches to an endothelial cell, lipoprotein lipase enzymes, riding on their CS stalks, migrate to the particle and begin digestion. Thus, lipoprotein lipase appears to be "activated." If CS synthesis is less than normal, or breakdown faster than normal, there will be less stalks and less lipase activity. This will result in an accumulation of fats (and cholesterol) in blood vessel cells, also known as one of the first steps in atherogenesis.

Another link between CVD and CS is in prevention of thrombus (clot) formation. Platelets and leukocytes (white blood cells) actually secrete CS and other similar glycosaminoglycans during the early stages of clot formation to prevent excess thrombus formation. This is why large doses of heparin can prevent blood from clotting. Again, if CS synthesis is lessened by age or nutrient deficiencies, then clot formation may become poorly controlled, resulting in strokes or infarcts.

Also, CS can sequester considerable amounts of calcium by virtue of its sulfate groups. If levels of CS in arterial tissues decrease, then calcium ions may precipitate out, and hardening of the arteries results.

Finally, levels of CS and its turnover may be natural signals to arterial cells for genetic activity relating to life, death and metabolism of these cells. Obviously, CS are important cellular components that must have normal metabolic status preserved, or else insidious adverse cardiovascular consequences may ensue.

Chondroitin Sulfates - Clinical
Experience With CVD

During the year that chondroitin sulfates were first isolated (1861), Rudolph Virchow proposed that arteriosclerosis might be due to defects or deficiencies of the ground substance in connective tissue of blood vessel walls, now known to contain CS and other GAGs. Finally, almost 100 years after Virchow's prophetic remarks, Dr. Lester Morrison in California pioneered tile use of CS preparations for CVD in 1955. Thereafter, Dr. Morrison and his Japanese collaborators embarked on a series of clinical studies that culminated in a book in 1974.

Ultimately, a control group of 60 patients with CVD was given conventional treatment for 6 years. Another 60 patients with CVD were given the same conventional treatment and also given oral CS (at least 750 mg per day). The results were dramatic. The bottom line: survival was clearly superior in the CS-treated group. Only 7% (4/60) of the CS-treated group died from CVD causes, while 23% (14/60) of the control group died of CVD Nonfatal abnormal cardiac events were similarly decreased in the CS-treated group (6 vs. 42). These remarkable results were explained by a combination of reduc?? of serum cholesterol (10-20%), reduction of serum triglycerides (27%) prolongation of clotting times (up to 50%) and activation of lipoprotein lipase, seen in this and other studies. Doubtlessly, facilitation of arterial healing and prevention of arterial aging changes also played important roles. Concurrently, spontaneous CVD in monkeys was reversed by oral CS treatment.

How To Use CS Products In CVD

In Morrison's study, continuous dosing with 1 to 3 grams of purified CS daily was given. No other supplements were routinely taken. Since we already know that purified CS is absorbed readily by humans, it appears logical to consume daily CS supplements in divided portions. Meals should slow down, but not inhibit, absorption of CS. Thus, it is ideal to take CS supplements on a empty stomach, but taken with meals is also acceptable. No adverse side effects have been reported after millions of doses over years of use for purified CS. Like other nutrients, results from CS may only be measurable after weeks or months of consistent intake. Patience and perseverance are necessary for optimum results.

Chondroitin Sulfates and Arteries -
The Future

With well-known and important roles in arterial health and promising clinical studies, why has use of CS for CVD been virtually ignored? The answer is too long to include in this installment, but involves difficulties in isolation, characterization, and patent laws that make approving CS as a drug for CVD to be financial suicide for pharmaceutical companies. Other avenues of marketing cannot legally make drug claims; therefore doctors and consumers remain unaware of the therapeutic values that CS exhibits. Other nutrients are also in this legal limbo, which would make a suitable topic for another installment.

Needless to say, a single substance is not a panacea. Some potential drawbacks to use of CS in CVD include cost and the need for continual ingestion of rather large numbers of capsules or tablets daily (anywhere from 2-10). Perhaps dosage could be lowered if accessory nutrients (such as Vitamin C and l-Lysine, etc.) are also consumed, but there is scant research on this notion. There are no adequate food sources that can provide similar levels of absorbed CS obtainable from supplements. Thus, the consumer and doctor must weigh the potential benefits of CS supplementation (increased survival and less cardiovascular incidents) against the moderate cost and longevity of use.

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REDUCTION OF ISCHEMIC CORONARY HEART DISEASE BY CHONDROITIN SULFATE A
Lester M. Morrison, M.D., F.A.C.A.

Presented in part before the Annual Conventions of the American College of Angiology, June 27,1970, New York City and the International College of Angiology, Dublin, Ireland July 3, 1970.

From the Institute For Arteriosclerosis Research, Loma Linda University School of Medicine and the University of California Center For Health Sciences, Los Angeles.

Supported by grants from the John A. Hartford Foundation, the Heart Institute of the National Institutes of Health (NIH), J. David Gladstone, M.D., the Aaron and Rachel Meyer Memorial Foundation, William and Violet Hanna, George and Lucy Carlson and the Crenshaw Research Foundation.

Although the chemical nature of Chondroitin Sulfate has been established since 1861, and that of its isomer chondroitin sulfate A (CSA) since 1956 their biological properties have not been established until recently.

These acid mucopolysaccharides, derived from the ground substance of connective tissue, present in mammals, fish and fowl, as well as in humans, have now been demonstrated to possess physiologic and therapeutic properties significant value in the prevention and treatment of hu tisdisease.

Certain of these biologic properties are now under investigation. They include effects such as anti-inflammatory, anti-allergic, growth- stimulation, repair, regeneration and healing, and in particular, anti-atherogenic (anti-atherosclerotic) and anti-thrombogenic effects related to the prevention and treatment of human ischemic, coronary heart disease (ICD).

CSA has been shown to exert its biologic properties by acting as a hormone-like agent." It is a normal constituent of mammalian blood as well as normal mammalian arterial and aortic tissue, decreasing in quantity and ratio to other acid mucopolysaccharides in atherosclerosis and with age.

The striking reduction of mortality rate and morbidity rate by the oral administration of CSA in human patients with ischemic coronary heart disease and the prevention as well as acceleration of regression or healing of coronary and aortic atherosclerosis in experimental animals may be explained in part by the following ten recently established biologic properties of this particular acid mucopolysaccharide:

1. Lipid clearing effects of CSA were demonstrated in tissue and organ cultures of mammalian (including human) and fowl coronary artery and aortic arterial tissues.

2. Stimulation of cellular metabolism demonstrated in various species of human, mammal and fowl cells in tissue cultures.

3. Increased fatty acid turnover at the cellular level as shown by radioactive isotope labeling studies.

4. Increase in RNA and DNA synthesis of cells in tissue culture systems.

5. Increase in cellular growth, cellular size and cellular quantity of HeLa cells, human amnion and placental cells as well as cells from other mammalian and fowl species.

6. Anti-atherosclerosis or anti-atherogenic activities demonstrated in squirrel monkeys (with naturally occurring atherosclerosis), rats with dietary and x-irradiation produced coronary and aortic atherosclerosis and rats with cholesterol-vitamin D induced coronary and aortic atherosclerosis as well as in rabbits with dietary cholesterol induced atherosclerosis.

7. Anti-inflammatory effects observed in the connective tissue of rat myocardium, aorta and coronary arteries, with particular reference to periarteritis, myocarditis, myocardial necrosis and degeneration.

8. Anti-thrombogenic or anticoagulant activity observed in rabbits, dogs and human subjects as determined by the Chandler rotating loop procedure, histologic studies of stained vasculature and measurements of the electro-negative forces exerted upon blood platelets and cells.

9. Increase in the number of coronary artery branches or collateral circulation noted in experimentally induced coronary atherosclerosis of the rat.

10. Acceleration of healing, regeneration and repair of rat myocardial necrosis and degeneration sequelae to experimentally induced coronary artery thrombosis and sclerosis of the rat.

SUMMARY AND CONCLUSIONS

1. The acid mucopolysaccharide, chondroitin sulfate A (CSA), which inhibited experimentally induced atherosclerosis in squirrel monkeys, rabbits, rats, and thromboses in monkeys, dogs, rabbits, rats and humans, was administered orally in tablet form to 60 patients with demonstrable ischemic coronary artery heart, disease (ICD). Dosage ranged from an initial 10 gm. to 1.5 gm. daily for a period of four years. No toxic effects were noted and the medication was well tolerated.

2. These 60 CSA-treated patients were compared with a similar group of 60 control patients with demonstrable ICD.

3. At the end of four years in the CSA-treated group of 60 patients, 6 coronary incidents occurred. The surviving patients of this group have not required treatment or hospital admission for acute cardiac symptoms or recurrent illness.

4. After four years, 36 coronary incidents occurred in the 60 patient control group. Present ratio of coronary incidents in CSA-treated patients vs. non-CSA-treated patient controls is 6:36 or a ratio of 1: 6.

5. A summation is presented of ten biological properties demonstrated for CSA, which may in part account, for the reduction of mortality and morbidity rates in patients with ischemic coronary disease of the heart treated with CSA over a four-year period.

6. Long term statistically designed studies of CSA treatment for the prevention and treatment of coronary heart disease in a large group of patients are suggested as a result of current findings in experimental and human ischemic coronary heart disease.