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José Vergés MD, MSc, PhD Clinical Pharmacologist Scientific Director BIOIBERICA S.A. Barcelona, Spain

CHONDROITIN SULFATE: CLINICAL REVIEW IN OSTEOARTHRITIS. José Vergés MD, MSc, PhD Clinical Pharmacologist Scientific Director BIOIBERICA S.A. Barcelona, Spain. J.

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José Vergés MD, MSc, PhD Clinical Pharmacologist Scientific Director BIOIBERICA S.A. Barcelona, Spain

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  1. CHONDROITIN SULFATE: CLINICAL REVIEW IN OSTEOARTHRITIS José Vergés MD, MSc, PhD Clinical Pharmacologist Scientific Director BIOIBERICA S.A. Barcelona, Spain J

  2. Chondroitin sulfate (CS) belongs to the group of glycosaminoglycans, important constituents of cartilage extracellular matrix1. Chondroitin sulfate (Condrosan® / Condrosulf®) is a symptomatic slow acting drug for osteoarthritis (SYSADOA) in Europe2, where it has been approved as a drug for more than ten years in several countries. DESCRIPTION (1).Hardingham T. Osteoarthritis Cart (1998) 6, (Supplement A), 3-5. (2)Lequesne M. G. Rev Rhum (Eng/Ed) 1994; 61: 69-73.

  3. CHONDROITIN SULFATE ACTION MECHANISMS3-4 STIMULATES:  proteoglycans  HA INHIBITS:  cartilage degradative enzymes (collagenase,elastase, proteoglycanase, fosfolipase A2, N-acetylglucosaminidase, etc.)  cartilage damaging substances (free radicals)  apoptosis  NO Stromelysin (MMP-3)  NF-kB • EFFECT: • anti-inflammatory activity • Membrane stabilising action (3)Ronca F et.al. Osteoarthritis Cart (1998) 6, (Supplement A), 14-21. (4) Blanco FJ. et. al. Rev. Esp. Reumatol 2001; 28, 1: 12-17.

  4. 9 randomized, controlled, clinical trials have been conducted in Europe with Condrosan® / Condrosulf®, comparing its effect against placebo (PBO) and sodium diclofenac (SD) (150 mg) in 1163 patients with knee and hand osteoarthritis (OA)5-13. The results from these clinical trials conclude that CS is as effective as SD and around 50% more effective than PBO (p < 0.05) in the reduction of OA symptoms5,14,15. Besides, its efficacy lasts for at least 3 months after treatment suppression (carry-over effect). CLINICAL EVIDENCE (5) Morreale, et al. J. Rheumatol. 1996, 23: 1385-1391. (6) Kissling R. et al. Osteoarthritis Cart 1997, 5 (Supplement A), 9: 70. (7) Bucsi L, et.al. Osteoarthritis Cart 1998, 6 (supplement A):31-36. (8). Pavelka K, et al. Litera Rheumatologica 1998, 24:21-30. (9). Uebelhart D, et.al. Osteoarthritis Cart 1998, 6, (Supplement A), 39-46. (10). Uebelhart D, et al. Osteoarthritis Cart 2004, 12:269-276. (11) Michel B, et al.. Osteoarthritis Cart 2001, 9 (supplement B), LA2. (12) Verbruggen G, et al. Osteoarthritis Cart (1998) 6, (Supplement A), 37-38.(13) Vebruggen G. et al. Clinical Rheumatology 2002, 21: 231-241.(14) Leeb F, et al. J. Rheumatol. 2000; 27: 1: 205 211. (15) du Souich P, Vergés J. Clin. Pharm. Ther. 2001; 70: 5-9.

  5. CS may act as a structure disease modifying OA drug (S/DMOAD), that is, it may slow down disease progression16. S/DMOAD • 3 clinical trials in knee OA have evidenced a stabilization of joint space width with CS treatment as opposed to a narrowing of joint space with PBO9-11. • 2 clinical trials in hand OA concluded that disease progression was lower in CS-treated patients and less patients from this group developed erosive OA12-13. (9). Uebelhart D, et.al. Osteoarthritis Cart 1998, 6, (Supplement A), 39-46. (10). Uebelhart D, et al. Osteoarthritis Cart 2004, 12:269-276. (11) Michel B, et al.. Osteoarthritis Cart 2001, 9 (supplement B), LA2. (12) Verbruggen G, et al. Osteoarthritis Cart (1998) 6, (Supplement A), 37-38.(13) Vebruggen G. et al. Clinical Rheumatology 2002, 21: 231-241. (16). Jordan KM, et al.Ann Rheum Dis 2003; 62:1145-1155

  6. The tolerance of the product is very well documented; equivalent to PBO and much higher than that of SD14. It isnot metabolized by enzymes from cytochrome P450. It can not present drug interactions at this level. Pharmacosurveillance data from Europe, where no serious adverse events have been reported for more than 10 years, support the safety of the product. SAFETY PROFILE (14) Leeb F, et al. J. Rheumatol. 2000; 27: 1: 205 211.

  7. EULAR RECOMMENDATIONS 200416 Evidence based medicine (16). Jordan KM, et al.Ann Rheum Dis 2003; 62:1145-1155.

  8. Clinical efficacy on symptom reduction and improvement of functional capacity Persistent clinical effect after treatment suppression (evidenced for at least 3 months) Greater safety than conventional therapy (analgesics, NSAIDs). It does not cause drug interactions. CS ADVANTAGES

  9. There is only one CS approved as a drug in several European countries, which is therefore considered as the reference product17. This CS is manufactured by BIOIBERICA (CSdBio-Active) and marketed in Europe by IBSA and BIOIBERICA; and in the the U.S.A. by Nutramax Laboratories, Inc. (under the trademark Cosamin®). This CS is being used by the NIH for its Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT). [Its IND number is: 59,181]. CLINICAL BIOEQUIVALENCE I (17). Vergés J., et al. Proceeding of the Western Pharmacology Society 2004 (submitted for publication). Poster Presentation, 47th Annual Meeting of the Western Pharmacology Society, Hawaii, 25-29 January (poster N. W-20).

  10. A study analysing the contents of glucosamine and CS of several US products, concluded that the amounts found were significantly different from label claim in some products, with deviations from 0 to 115%18. It also evidenced that characteristics such as: molecular weight, flexibility of structure, sulfation and method of manufacture may influence oral absorption. Among all products compared, the one from Bioibérica evidenced the highest permeability rate. CLINICAL BIOEQUIVALENCE II 1mol Wt = 16,900 dalton (95% Bioiberica) (18)Adebowale A, et al. JANA 2000, 3 (1): 37-44.

  11. In order to ensure equivalent clinical results in terms of efficacy and safety, other CS products must show their bioequivalence to the reference formulation17. For this purpose, we propose the following method to determine the bioequivalence of two CS formulations: Only the CS (product b) presenting an equivalent clinical effect to the reference CS (product a) within a variation range of 0.8 to 1.2 in the a/b ratio for the Emax, T50 and values for the 3 following parameters: Lequesne Index, Visual Analogue Scale (VAS) and pain on load, can be considered bioequivalent. CONCLUSION (17). Vergés J., et al. Proceeding of the Western Pharmacology Society 2004 (submitted for publication). Poster Presentation, 47th Annual Meeting of the Western Pharmacology Society, Hawaii, 25-29 January (poster N. W-20).

  12. THANK YOU FOR YOUR ATTENTION!

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