Chondroitin Sulfate

Comparative study of the effects of chondroitin sulfate isomers on atherosclerotic subjects.

ZFA, 34(2):153-9 1979

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.

Chondroitin sulfates (CS 4&6): practical applications and economic impact

Presse Med 1998 Nov 21;27(36):1866-8

PROVEN CLINICAL BENEFIT: It has been demonstrated that CS 4&6 administered at the dose of 1200 mg/d for several months is more effective than placebo and as effective as nonsteroidal anti- inflammatory drugs (NSAID) in providing pain relief and improving joint function without risk in subjects with osteoarthritis of the hip and the knee. The beneficial effect persists several weeks after the end of treatment. These advantages should thus have an overall cost-lowering effect. EVALUATION OF THE ECONOMIC IMPACT: A medico-economical study was conducted to reevaluate the beneficial effect of CS 4&6 on the quantity of NSAID prescriptions in France and to determine whether the drug was used correctly in accordance with indications at an adequate dose and treatment duration. DATABASES USED: Two databases, IMS a data bank on medical prescriptions in France, and THALES which gives information on prescriptions by 300 general practitioners, allowed a dynamic analysis of the medical files of 11,000 patients with osteoarthritis. ECONOMICAL BENEFIT: The cost of NSAID prescriptions by general practitioners was reduced by an estimated 67% in patients treated with CS 4&6. In terms of the quantity of NSAID used, the reduction in the CS 4&6 treated group was 63% and 85.3% respectively in patients treated by generalists and by specialists. The quantity of NSAIDs prescribed was reduced by two-thirds when CS 4&6 were represcribed. The cost related to CS 4&6 treatment was compensated for by the reduction in physiotherapy costs and by fewer co-prescriptions for gastroprotective drugs. This study confirmed the randomized clinical studies demonstrating that a regimen of CS 4&6 for several weeks at the dose of 1200 mg/d lowers prescriptions of NSAID which can be completely avoided in nearly half the cases.

Biochemical and pharmacokinetic aspects of oral treatment with chondroitin sulfate.

Arzneimittelforschung, 45(8):918-25 1995 Aug

Chondroitin sulfate (Condrosulf) was characterized for structure, physiochemical properties and purity. This glycosaminoglycan has a relative molecular mass of about 14,000, a sulfate-to-carboxyl ratio of 0.95 due to the high percentage of monosulfated disaccharides (38% 6-monosulfate and 55% 4-monosulfate) and a low amount of disulfated disaccharides (1.1%) inside the polysaccharide chains. No other glycosaminoglycans were detected in the preparation. Chondroitin sulfate was labelled by reduction with sodium 3H-borohydride and administered by oral route in the rat and dog. More than 70% of radioactivity was absorbed and found in urine and tissues. The plasma radioactivity was fractionated by size-exclusion chromatography in three fractions: radioactivity associated with high, intermediate and low molecular mass compounds. The peak value of the concentration of high molecular mass radioactivity compounds in plasma was reached after 1.6 and 2.1 h for the rat and dog, respectively. After 36 h the high molecular mass radioactivity compounds were still present in plasma of dog and rat. After 24 h radioactivity was higher in the intestine, liver, kidneys, synovial fluid and cartilage than in other tissues. Condroitin sulfate was orally administered to man (healthy volunteer) in a single daily dose of 0.8 g and in two daily doses of 0.4 g. The results showed that both forms of administration determined a significant increase of plasma concentration of chondroitin sulfate as compared with predose value over a full 24 h period. Elimination constant values and tmax (of the first administration in the case of fractionated dose) were almost the same for the two administrations.

Glycosaminoglycans delay the progression of nephropathy in NIDDM.

Diabetes Care 1997 May;20(5):819-23

OBJECTIVE: To determine the effect of oral administration of glycosaminoglycans on metabolic control and albumin excretion rate (AER) in NIDDM patients with increased urinary albumin excretion. RESEARCH DESIGN AND METHODS: Twelve NIDDM hypertensive patients (age 52 +/- 3 years, HbA1c 7.7 +/- 0.2%) on antihypertensive treatment were enrolled in a double-blind placebo-controlled study, assuming either placebo or sulodexide (100 mg/day) for 4 months; at the end of this period, a crossover was performed. We have evaluated routine biochemical parameters plus AER and coagulative function every 2 months. RESULTS: Both plasma fibrinogen (from 4.15 +/- 0.32 to 2.77 +/- 0.47 mmol/l) and AER (from 128.3 +/- 40.6 to 39.6 +/- 11.9 micrograms/min) decreased significantly after treatment with glycosaminoglycans in respect to placebo; moreover, blood pressure control ameliorated, also in the absence of any variation of therapy. CONCLUSIONS: Glycosaminoglycan therapy, likely in association with a satisfactory control of blood pressure values, seems to prevent the progression of diabetic nephropathy in NIDDM.

Comparison of the antiinflammatory efficacy of chondroitin sulfate and diclofenac sodium in patients with knee osteoarthritis.

J Rheumatol, 23(8):1385-91 1996 Aug

OBJECTIVE: To assess the clinical efficacy of chondroitin sulfate (CS) in comparison with the nonsteroidal antiinflammatory drug (NSAID) diclofenac sodium (DS) in a medium/longterm clinical study in patients with knee osteoarthritis (OA). METHODS: This was a randomized, multicenter, double blind, double dummy study. 146 patients with knee OA were recruited into 2 groups. During the first month, patients in the NSAID group were treated with 3 x 50 mg DS tablets/day and 3 x 400 mg placebo (for CS) sachets; from Month 2 to Month 3, patients were given placebo sachets alone. In the CS group, patients were treated with 3 x 50 mg placebo (for diclofenac) tablets/day and 3 x 400 mg CS sachets/day during the first month; from Month 2 to Month 3, these patients received only CS sachets. Both groups were treated with 3 x 400 mg placebo sachets from Month 4 to Month 6. Clinical efficacy was evaluated by assessing the Lequesne Index, spontaneous pain (using the Huskisson visual analog scale), pain on load (using a 4 point ordinal scale), and paracetamol consumption. RESULTS: Patients treated with the NSAID showed prompt and plain reduction of clinical symptoms, which, however, reappeared after the end of treatment; in the CS group, the therapeutic response appeared later in time but lasted for up to 3 months after the end of treatment. CONCLUSION: CS seems to have slow but gradually increasing clinical activity in OA; these benefits last for a long period after the end of treatment.

Anti-arthrosis treatments: efficacy and tolerance of chondroitin

Presse Med 1998 Nov 21;27(36):1862-5

CHONDROPROTECTIVE DRUGS: Long-acting chondroprotective drugs have a symptomatic effect. They are only effective in subjects with osteoarthritis and have no pure pain relieving effect. They act within several weeks, improve functional manifestations and have a remnant effect. CHONDROITIN SULFATES 4&6: CS 4&6 are glycosaminoglycans which participate in the matrix structure of cartilage. They are well absorbed after oral intake. They have a dose-dependent inhibitor effect in vitro on proteoglycan and collagen catabolism and have been shown to stimulate matrix synthesis. Several clinical studies have demonstrated the chondroprotective efficacy of CS 4&6 in osteoarthritis involving the hip, knee and finger joints. OSTEOARTHRITIS OF THE KNEE: A controlled randomized double-blind study versus placebo was conducted in 104 patients with femorotibial osteoarthritis. The objective was to demonstrate that CS 4&6 given orally in a sequential regimen at the dose of 800 mg/d has a beneficial effect both in terms of clinical manifestations and in terms of the anatomic progression in patients with osteoarthritis of the knee. The main efficacy criteria was the Lequesne functional score. After 1 year of treatment with CS 4&6, the functional impairment was reduced by approximately 50%, a significant improvement over placebo for all clinical criteria. Tolerance was excellent or good in more than 90% of the cases. A STRUCTURE MODULATOR: This study suggests that chondroitin sulfates act as structure modulators as shown by the improvement in the interarticular space visualized on the x-rays of patients treated with CS 4&6.

Efficacy and tolerability of chondroitin sulfate 1200 mg/day vs chondroitin sulfate 3 x 400 mg/day vs placebo.

Osteoarthritis Cartilage 1998 May;6 Suppl A:25-30

This multicenter randomized, double-blind, controlled study was performed to compare the efficacy and tolerability of chondroitin sulfate (CS, Condrosulf, IBSA, Lugano, CH) 1200 mg/day oral gel vs CS 3 x 400 mg/day capsules vs placebo, in patients with mono or bilateral knee osteoarthritis (Kellgren and Lawrence radiographic score grade I to III). A total of 127 patients, 40 of whom were treated with CS 1200 mg/day, 43 with CS 3 x 400 mg/day and 44 with placebo, were included in the statistical analysis of this 3-month treatment study. In the CS groups, Lequesne's Index and spontaneous joint pain (VAS) showed a significant reduction of clinical symptoms (P < 0.01 for both parameters), while only a slight reduction was observed in the placebo group (P = ns for Lequesne's Index and P < 0.05 for VAS). The physician's and patient's overall efficacy assessments were significantly in favour of the CS groups (P < 0.01). The treatment carried out with the three formulations was very well tolerated. In conclusion, these results indicate that CS favours the improvement of the subjective symptoms, improving the joint mobility. An additional consideration is that the efficacy of 1200 mg CS as a single daily dose does not differ from that of 3 x 400 mg daily doses of CS for all the clinical parameters taken into consideration.

Chondroitin sulfate: S/DMOAD (structure/disease modifying anti- osteoarthritis drug) in the treatment of finger joint OA.

Osteoarthritis Cartilage 1998 May;6 Suppl A:37-8

A total of 119 patients were included in a randomized, double-blind, placebo-controlled trial in order to assess the S/DMOAD properties in OA of chondroitin sulfate (CS 4&6, 3 x 400 mg/day, Condrosulf IBSA, Lugano, CH). Posteranterior roentgenographies of the interphalangeal (IP) joints were carried out at the start of the study and at yearly intervals. This enabled the investigators to document the radiological progression of the anatomical lesions in the pathological finger joints over a 3-year period. It was shown that the progression of OA in the IP finger joints in an individual can be determined by the evolution of his finger joints through previously described anatomical phases: 'N' (not affected), 'S' (classical OA), 'J' (loss of joint space), 'E' (erosive OA) and 'R' (remodeled joint). Structure/disease-modifying anti-OA drug (S/DMOAD) properties were searched for by assaying the number of patients developing OA in previously normal IP joints ('N' > 'S'), or progressing through the described anatomical phases of the disease ('S' > 'J', 'S' > 'E', 'J' > 'E', 'S' > 'R', 'J' > 'R', 'E' > 'R'). In the CS 4&6 group we observed a significant decrease in the number of patients with new 'erosive' OA finger joints. This result is particularly important since OA of the finger joints becomes a clinical problem (pain, functional loss) when 'S' joints progress to 'J' and especially 'E' phases. During and after these 'E' phases, joints will remodel and show the nodular deformities characteristic of Heberden's and Bouchard's nodes. Treated patients were protected against erosive evolution.

Anti-inflammatory activity of chondroitin sulfate.

Osteoarthritis Cartilage 1998 May;6 Suppl A:14-21

The pharmacokinetics of chondroitin sulfate (CS, Condrosulf, IBSA, Lugano, Switzerland) were investigated in rats and in healthy volunteers using CS tritiated at the reducing end and CS labeled with 131I or 99mTc respectively. A rapid absorption of orally administered CS is observed in rats and in humans when the drug is dissolved in water. Lower and delayed absorption is observed when CS is administered in gastroresistant capsules. The absolute bio-availability is 15 and 12% for rats and humans respectively. The CS shows a tropism for cartilagineous tissues in rats and for knee tissues in humans as demonstrated by scintigraphic analysis with 99mTc-CS. Monomers, oligo and polysaccharides produced by enzymatic hydrolysis of CS appear in the blood and tissues together with native CS. The effects of partially depolymerized (m.m. 3 to 15 kD) and desulfated fractions on human leukocytes were investigated. CS and its fractions inhibit the directional chemotaxis induced by zymosan-activated serum, are able to decrease the phagocytosis and the release of lysozyme induced by zymosan and to protect the plasma membrane from oxygen reactive species. In rats the oral administration of CS significantly decreases granuloma formation due to sponge implants and cell migration and lysosomal enzyme release in carrageenan pleurisy. Compared with nonsteroidal anti-inflammatory drugs (indomethacin, ibuprofen), CS appears to be more effective on cellular events of inflammation than on edema formation. It is noteworthy that CS is devoid of dangerous effects on the stomach, platelets and kidneys. In synovial fluid of patients requiring joint aspiration, treated orally for 10 days with CS (800 mg/day) the hyaluronate concentration and the intrinsic viscosity significantly increased, while collagenolytic activity, phospholipase A2 and N-acetylglucosaminidase (NAG) decreased. These results give an insight into the mechanism of the anti-inflammatory and chondroprotective actions demonstrated by this drug in a number of clinical trials in patients with osteoarthritis.

Death of articular chondrocytes. Mechanisms and protection.

Presse Med 1998 Nov 21; 27(36):1859-61

APOPTOSIS IN JOINT CARTILAGE: Apoptosis is the physiologically programmed death of cells to be distinguished from necrosis which caused non-programmed cell death. In joint cartilage, more than 50% of the chondrocytes show signs of apoptosis compared with 10% in normal cartilage. ROLE OF NITRIC OXIDE: In osteoarthritis the production of nitric oxide (NO) appears to be increased, inducing apoptosis of articular chondrocytes stimulated by interleukin 1. NO inhibitors can limit the progression of experimentally induced joint lesions in animal models. IN VITRO RESULTS: The protective effect of the chondroitin sulfates CS4 and CS6 against death of chondrocytes exposed to NO has been demonstrated in vitro. Chondrocytes for New Zealand white rabbits were cultivated in the presence of an NO donor for exposure durations from 12 to 72 hours, with or without adding CS 4&6 to the culture medium. After 3 days of culture, NO induced a significant rise in the number of apoptotic chondrocytes. In 70% of the cases, preventive treatment with 100 micrograms/ml CS 4&6 lowered the number of dead cells. This cytoprotective effect reached a mean 28% and was inversely dependent on the duration of exposure to the NO donor.

Effects of oral chondroitin sulfate on the progression of knee osteoarthritis: a pilot study

Osteoarthritis Cartilage 1998 May;6 Suppl A:39-46

The aim of this study was to assess the clinical, radiological and biological efficacy and tolerability of the SYSADOA, chondroitin 4- and 6-sulfate (CS, Condrosulf, IBSA, Lugano, Switzerland), in patients suffering from knee osteoarthritis. This was a 1-year, randomized, double-blind, controlled pilot study which included 42 patients of both sexes, aged 35-78 years with symptomatic knee OA. Patients were treated orally with 800 mg chondroitin sulfate (CS) per day or with a placebo (PBO) administered in identical sachets. The main outcome criteria were the degree of spontaneous joint pain and the overall mobility capacity. Secondary outcome criteria included the actual joint space measurement and the levels of biochemical markers of bone and joint metabolism. This limited study confirmed that chondroitin sulfate was well- tolerated and both significantly reduced pain and increased overall mobility capacity. Treatment with CS was also associated in a limited group of patients with a stabilization of the medial femoro-tibial joint width, measured with a digitized automatic image analyzer, whereas joint space narrowing did occur in placebo-treated patients. In addition, the metabolism of bone and joint assessed by various biochemical markers also stabilized in the CS patients whereas it was still abnormal in the PBO patients. These results confirm that oral chondroitin 4- and 6-sulfate is an effective and safe symptomatic slow- acting drug for the treatment of knee OA. In addition, CS might be able to stabilize the joint space width and to modulate bone and joint metabolism. This is the first preliminary demonstration that a SYSADOA might influence the natural course of OA in humans.