Chondroitin sulfates (CS) are glycosaminoglycans (GAGs, previously termed mucopolysaccharides) that are large, heterogeneous biological polymers and are used by the body to maintain proper elastic integrity within tissues.
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.
J Am Geriatr Soc 1968 Jul; 16(7):779-785
TREATMENT OF CORONARY ARTERIOSCLEROTIC HEART
DISEASE WITH CHONDROITIN SULFATE-A: PRELIMINARY REPORT
Lester M. Morrison, M. D.
Los Angeles, California
ABSTRACT: The acid mucopolysaccharide, chondroitin sulfate-A (CSA), which is active in preventing experimentally-induced atherosclerosis in monkeys, rats and rabbits, also has anticoagulant properties in rabbits and in patients with angina pectoris from coronary arteriosclerotic heart disease.
For an average period of one and a half years (range, one to two years), CSA was administered orally (tablet or powder) to 60 patients with clinically manifest coronary arteriosclerotic ban disease, in dosages ranging from 1.5 to 10.0 gm daily. No toxic effects were noted and the medication was well tolerated. These patients were matched with a comparable group of 60 control patients for age, sex, and clinical and laboratory findings.
In the 60 control patients, 13 acute coronary incidents occurred; 7 were myocardial infarctions, of which 2 were fatal and 6 required hospital treatment in coronary-care units for “acute coronary insufficiency” or “acute myocardial ischemia” or impending myocardial infarction.
In the 60 CSA-treated patients there was only 1 coronary incident – a fatal case of myocardial infarction.
This preliminary report suggests that “feasibility” studies are warranted to determine the therapeutic effects of CSA for the prevention of coronary arteriosclerotic heart disease in statistically designed, triple-blind investigations on a larger series of patients over longer periods of time.
Arch Intern Med 1970 Oct; 126(4): 569
Morrison LM
Chondroitin therapy
Administration of chondroitin sulfate appears to be effective in preventing heart attacks, according to Lester Morrison, MD, professor and director of the Institute for Arteriosclerosis Research at Loma Linda University School of Medicine.
Dr. Morrison reported to the recent American College of Angiology meeting in New York on the results of a double-blind study of 120 patients with a history of myocardial infarction and/or coronary artery disease verified by electrocardiography
Half the patients received chondroitin sulfate A (CSA) in addition to conventional therapy. CSA is a mucopolysaccharide compound.
His results were quite dramatic: six “coronary incidents” and five related deaths in the experimental group compared to 36 “coronary incidents” and nine related deaths the 60 matched control patients.
Dr. Morrison added that experimental studies have shown CSA can prevent as well as accelerate regression and healing of coronary aortic atherosclerosis.
The patients had been treated for ischemic coronary artery heart disease for six months to 20 years before the start of the study. All had received various drugs that were continued and in some cases expanded during the study. The experimental group patients were slightly younger (average of 65.5 than the controls (65.9 years) at the start of the study. The control group included 35 women and the experimental group, 44 women.
Patients received 10 gm/day CSA at the start of the study, but dosage was later reduced to 1.5 gm/day. None of the patients have suffered any toxic effects.
Four of the patients in the experimental group died following myocardial infarction. The fifth patient suffered a fatal massive cerebrovascular hemorrhage complicated by terminal coronary insufficiency and congestive heart failure. The sixth “coronary incident” was a case of acute coronary insufficiency, but that patient recovered.
Sixteen control patients suffered a total of 19 myocardial infarctions. Nine of these patients died. Ten patients also underwent 11 episodes of coronary insufficiency, and there were six cases of myocardial ischemia.
Three other patients among the 120 died. One patient in the CSA group suffered a skull injury that induced ventricular fibrillation leading to death. Another died from a malignant cerebral astrocytoma. One of the control patients died of mesenteric thrombosis.
Atherosclerosis, 1972, 16: 105-118
Elsevier Publishing Company, Amsterdam – Printed in The Netherlands
PREVENTION OF VASCULAR LESIONS BY CHONDROITIN SULFATE A IN THE CORONARY ARTERY AND AORTA OF RATS INDUCED BY A HYPERVITAMINOSIS D AND A CHOLESTEROL-CONTAINING DIET
L. M Morrison, G. S. Bajwa, R. B. Alfin-Slater and B. H. Ershoff
Institute for Arteriosclerosis Research, Loma Linda University School of Medicine, Culver City, Calif. 90230 and the University of California School of Public Health, Los Angeles, Calif. 90024 (U.S.A.)
Severe lesions in the coronary arteries and aortas occurring primarily in the media and consisting of degeneration, calcification, plaque formation, metachromasia and the prD” Cce of intracellular and extracellular stainable lipid material present mainly in the areas of the damaged media were induced within 6 weeks in young adult rats fed a purified diet supplemented with 1.5% cholesterol, 0.5% cholic acid and 1.25 million U.S. P. units of vitamin D2 per kg of ration. Such lesions were noted in the aortas of 17 of 18 male rats as well as 16 of 16 female rats and the coronary arteries of all rats fed the above diet.
Lesions of the aorta were completely prevented in 18 of 18 male rats and were present in only 5 of 18 female rats fed a similar ration supplemented with chondroitin sulfate A at a I% level in the diet. Lipid-containing coronary lesions were present in only 3 of 18 male rats and 3 of 18 female rats fed the latter diet. The protective effects of chondroitin sulfate A administration indicated above were not accompanied by a reduction in plasma and liver cholesterol or liver total lipids compared to that of rats fed a similar diet without the chondroitin sulfate A supplement.
ZFA 1979;34(2):153-9
Comparative study of the effects of chondroitin sulfate isomers on atherosclerotic subjects
Nakazawa K, Murata K
Effects of isomers of chondroitin sulfate on atherosclerosis were clinically compared, based on sulfate linkage and the amount of sulfate, by using chondroitin 4-sulfate, chondroitin 6-sulfate and chondroitin polysulfate. Fourty eight age-matched atherosclerotic subjects were selected from a home for the elderly in order to the treatment with the agents. The isomers of chondroitin sulfate were given a daily dose of 4.5 g perorally. During the experimental period for 64 months, mortality, serum cholesterol, thrombus-formation time and thrombus weight were examined. The result obtained was as follows: mortality in the groups treated with the isomers of chondroitin sulfate was less than the age-matched untreated control group. Serum cholesterol value in the group treated by the isomers of chondroitin sulfate, chondroitin polysulfate group in particular, fell lower than the pre-treatment value. Thrombus formation time prolonged 150% in the group treated with chondroitin polysulfate over the untreated control group and the resultant thrombus weight was reduced in the treated group. Thus, these data indicated that the isomers of chondroitin sulfate are clinically effective on the treatment of atherosclerosis in the order of chondroitin polysulfate, chondroitin 4-sulfate and/or chondroitin 6-sulfate.
Artery 1987;14(6):316-37
Suppression of atherogenesis in hypercholesterolemic rabbits by chondroitin-6-sulfate
Matsushima T, Nakashima Y, Sugano M, Tasaki H, Kuroiwa A, Koide O
2nd Department of Internal Medicine, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan.
The effect of chondroitin-6-sulfate, obtained from shark cartilage, on atherogenesis in rabbits fed a high cholesterol diet was studied. Male Japanese white rabbits were housed for 10 weeks in three groups, one group was fed ordinary pellets and was injected intraperitoneally with saline (standard-diet group), one was fed pellets containing 1% cholesterol and was injected intraperitoneally with saline (cholesterol-diet group), and the third group was fed pellets containing 1% cholesterol, and was injected intraperitoneally with 10 mg of chondroitin-6-sulfate (C-6-S group). Injections were done daily. The plasma total cholesterol, and cholesterol from very low-density lipoprotein in the C-6-S group after 5 weeks in the test period, and low-density lipoprotein cholesterol in the C-6-S group at the end of the test period were lower than those of the cholesterol-diet group. Significantly fewer atherosclerotic lesions of the aortic surface were found macroscopically in the C-6-S group than in the cholesterol-diet group. The cholesterol, esterified cholesterol and calcium concentrations of the aortic intima-media in the C-6-S group were significantly lower than in the cholesterol-diet group. Hydroxyproline levels in these three groups were not different. The uronic acid concentration of the intima-media in the cholesterol-diet group was significantly higher than in the C-6-S group (P less than 0.02). Though the percentage of heparan sulfate on total glycosaminoglycans (GAGs) of the C-6-S group was lower than in the cholesterol-diet group, there were no significant differences in the percentages of dermatan sulfate and chondroitin-4/6-sulfate in total GAGs between the cholesterol-diet and C-6-S groups. These results suggest that chondroitin-6-sulfate suppresses cholesterol deposition in the aorta of rabbits fed a 1% cholesterol diet, probably partly due to a decrease in the plasma low-density lipoprotein cholesterol, and partly due to a change in arterial metabolism.
Exp Med Surg. 25, 61-71, 1967
Treatment of Atherosclerosis with Acid Mucopolysaccharides
By LESTER M. MORRISON, J. JOSEPH QUILLIGAN, Jr.,
KATSUMI MURATA, 0. ARNE SCHJEIDE, LEON FREEMAN,
and BENJAMIN H. ERSHOFF
From the Institute for Arteriosclerosis Research, Loma Linda University School of Medicine, Los Angeles, California; and the Laboratory of Nuclear Medicine’ and Radiation Biology, and Department of Biophysics and Nuclear Medicine,
University of California School of Medicine, Los Angeles.
Although atherosclerosis and its complications now account for the majority of deaths in the United States, no satisfactory measure or specific treatment for this “endemic” disease has as yet been found. Atherosclerosis is now believed to be not only a preventable disease, but actually a reversible process as shown by Katz, Pick and their coworkers, Page et al, Anitschkou, Bevans, Davidson, and Kendall , Wilens and others and not necessarily the inevitable end result of “wear and tear”, aging or stress, as pointed out earlier by Morrison et al. The following report deals with the treatment of atherosclerosis of the coronary arteries and the aorta by acid mucopolysaccharides (AMPS) and in particular with chondroitin sulfate A (CSA). Studies were conducted with three species of animals: squirrel monkeys (Salmiri sclurea) which develop naturally occurring atherosclerotic lesions similar in a number of respects to those observed in man, rats and rabbits.
In view of the physiologic effects of CSA which we have noted upon RNA and DNA metabolism at the cellular level, we have considered the possibility that CSA may act therapeutically upon the connective tissue of the artery wall, to account for its anti- atherogenic properties in experimental atherosclerosis. It has been repeatedly observed that the atherosclerotic process in the intima and media of the artery wall is associated with or related to local AMPS accumulation. Many investigators believe that AMPS deposition in the atherosclerotic lesions of the arterial wall are part of the complications of the atherosclerotic process, becoming the basis for calcification and leading to irreversability of the lesions. However, other investigators regard this phenomenon as possibly a defense or reactive mobilization in the connective tissue of the arterial wall. Various investigators have also noted a decrease in CSA and/or CSC with concomitant increase in CSB content of the arterial wall with the advancing atherosclerotic and aging process. If this latter is true, it is suggested that CSA may possibly act as “replacement” therapy in experimental atherosclerosis. Further studies could clarify the mechanism of action.
The effect of CSA on serum cholesterol and total lipids was found to be variable in our experience. In monkeys we found that parenteral CSA gave a significant reduction in total serum lipids after nine months of treatment. The effects of CSA on serum cholesterol were variable.
In rats and rabbits we have found no significant changes of serum cholesterol or total lipids in cholesterol-fed animals treated with CSA compared to cholesterol-fed animals not administered CSA. These findings are not unusual since it its common knowledge that the atheroscerotic process is not necessarily related to serum hype rchole sterolemia or hyperlipernia as pointed out by Morrison ,DeBakey et al. and many others. On the other hand, the case for an etiologic role of serum lipids in experimental atherosclerosis is very good and it appears to be reasonably well established in man.
Oshima et al and Kurita have also tested the effect of chondroitin sulfates (presumably combinations of CSA and CSC with other AMPS obtained from shark or whale cartilage) on blood cholesterol levels in human subjects with hypercholesterolemia and in hype rc holesterolemic rabbits. The CSA used in our studies was extracted from nasal and tracheal bovine cartilage obtained from commercial sources.
CSA in therapeutic dosages has proved to be systemically non-toxic, without discernible side-effects or abnormal vital organ tissue abnormalities in animals and man to date (local nodules, however, were often noted in both rats and rabbits at the higher dosage levels at the site of injection).
Atherosclerosis is no longer the unique accompaniment of the “human predicament”, since it has been recognized as a naturally occurring disease of sub-human, mammals, birds, and fishes. A direct approach to events occurring in cells in the artery wall is the most critical one necessary for therapeutic studies and should not be precluded by concentrating on indirect or secondary concerns over associated factors such as those found in the circulating blood plasma (e.g. cholesterol or triglycerides).
Further studies are now in progress to explore the potential of the acid mucopolysaccharides as agents which may be effective in the prevention and possibly treatment of atherosclerosis.
Summary
The acid mucopolysaccharide chondroitin sulfate A (CSA) was found to have anti-atherogenic properties in sub-human primates, rats and rabbits. Squirrel monkeys, a species which develops spontaneous atherosclerosis similar to that observed in man, were fed cholesterol to accelerate the growth of naturally occurring atherosclerotic lesions. Subcutaneous administration of CSA markedly reduced the incidence and severity of aortic atherosclerosis in these animals. CSA was also active when administered orally in inhibiting the incidence and severity of coronary atherosclerosis in x-irradiated, cholesterol-fed rats. Subcutaneous injections of CSA, however, in contrast to orally administered CSA were without protective effect in the rat. Subcutaneous administration of chondroitin sulfate C, an isomer of CSA, as well as CSA was active in inhibiting aortic atherosclerosis in cholesterol-fed rabbits.
The above findings suggest that certain chondroitin sulfates may have value in the treatment and/or prevention of atherosclerosis in man.