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® ® § Quality by Design Products for Life ® TECHNICAL MONOGRAPHS OUR FAMILY OF PRODUCTS FOR JOINT HEALTH REFERENCES Mission Statement To provide safe, effective, quality products that improve the quality of life for our customers using: 1. Homandberg GA, Guo D, Ray LM, et al. Mixtures of glucosamine and chondroitin sulfate reverse fibronectin fragment mediated damage to cartilage more effectively than either agent alone. Osteoarthritis Cartilage 2006;14:793-806. 2. Adebowale A, Du J, Liang Z, et al. The bioavailability and pharmacokinetics of glucosamine hydrochloride and low molecular weight chondroitin sulfate after single and multiple doses to beagle dogs. Biopharm Drug Dispos 2002;23:217-225. 3. Chan PS, Caron JP, Orth MW. Effect of glucosamine and chondroitin sulfate on regulation of gene expression of proteolytic enzymes and their inhibitors in interleukin-1-challenged bovine articular cartilage explants. Am J Vet Res 2005;66:1870-1876. 4. Chan PS, Caron JP, Rosa GJM, et al. Glucosamine and chondroitin sulfate regulate gene expression and synthesis of nitric oxide and prostaglandin E(2) in articular cartilage explants. Osteoarthritis Cartilage 2005;13:387-394. 5. Dechant JE, Baxter GM, Frisbie DD, et al. Effects of glucosamine hydrochloride and chondroitin sulphate, alone and in combination, on normal and interleukin-1 conditioned equine articular cartilage explant metabolism. Equine Vet J 2005;37:227-231. 6. Lippiello L, Woodward J, Karpman R, et al. In vivo chondroprotection and metabolic synergy of glucosamine and chondroitin sulfate. Clin Orthop Relat Res 2000;381:229-240. 7. McNamara PS, Barr SC, Erb HN, et al. Hematologic, hemostatic, and biochemical effects in cats receiving an oral chondroprotective agent for thirty days. Vet Therapeutics 2000;1:108-117. 8. McNamara PS, Barr SC, Erb HN. Hematologic, hemostatic, and biochemical effects in dogs receiving an oral chondroprotective agent for thirty days. Am J Vet Res 1996;57:1390-1394. 9. Orth MW, Peters TL, Hawkins JN. Inhibition of articular cartilage degradation by glucosamine-HCl and chondroitin sulphate. Equine Vet J Suppl 2002:224-229. 10. Sauve F, Paradis M, Refsal KR, et al. Effects of oral administration of meloxicam, carprofen, and a nutraceutical on thyroid function in dogs with osteoarthritis. Can Vet J 2003;44:474-479. 11. Chan PS, Caron JP, Orth MW. Effects of glucosamine and chondroitin sulphate on bovine cartilage explants under long-term cartilage conditions. Am J Vet Res 2007;68:709-715. 12. Chan PS, Caron JP, Orth MW. Short-term gene expression changes in cartilage explants stimulated with interleukin 1-beta plus glucosamine and chondroitin sulfate. J Rheumatol 2006;33:1329-1340. 13. Das AK, Hammad TA. Efficacy of a combination of FCHG49® glucosamine hydrochloride, TRH122® low molecular weight sodium chondroitin sulfate and manganese ascorbate in the management of knee osteoarthritis. Osteoarthritis Cartilage 2000;8:343-350. 14. Leffler CT, Philippi AF, Leffler SG, et al. Glucosamine, chondroitin and manganese ascorbate for degenerative joint disease of the knee or low back: a randomized, double-blind, placebo-controlled pilot study. Mil Med 1999;164:85-91. 15. Scroggie DA, Albright A, Harris MD. The effect of glucosamine-chondroitin supplementation on glycosylated hemoglobin levels in patients with type 2 diabetes mellitus. Arch Intern Med 2003;163:1587-1590. 16. van Blitterswijk WJ, van de Nes JCM, Wuisman PIJM. Glucosamine and chondroitin sulfate supplementation to treat symptomatic disc degeneration: biochemical rationale and case report. BMC Complement Altern Med 2003;3:2. 17. Schenck RC, Clare DJ, Gilley JS, et al. Role of a glucosamine/chondroitin sulfate formula in treatment of an osteochondral impaction injury in a collegiate basketball player. Ortho Tech Rev 2000;2:12-15. 18. Williams A, Gillis A, McKenzie C, et al.Glycosaminoglycan distribution in cartilage as determined by delayed gadolinium-enhanced MRI of cartilage (dGEMRIC): potential clinical applications. AJR 2004;182:167-172. 19. Lippiello L, Saiz P. Glucosamine and chondroitin sulfate: biological response modifiers of chondrocytes under simulated conditions of joint stress. Osteoarthritis Cartilage 2003;11:335-342. 20. Clegg DO, Reda DJ, Harris CL, et al. Glucosamine, chondroitin sulfate and the two in combination for painful knee osteoarthritis. N Engl J Med 2006;354:795-808. 21. Leeb BF, Schweitzer H, Montag K, Smolen JS. A metaanalysis of chondroitin sulfate in the treatment of osteoarthritis. J Rheum 2000;27:205-211. 22. Richy F, Bruyere O, et al. Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis: a comprehensive meta-analysis. Arch Intern Med 2003;163:1514-1522. 23. McAlindon TE, LaValley MP, Gulin JP, et al. Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis. JAMA 2000;283:1469-1475. 24. Kahan A, Uebelhart D, De Vathaire F, et al. Long term effects of chondroitins 4 and 6 sulfate on knee osteoarthritis: The study on osteoarthritis progression prevention, a two-year, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2009;60(2):524-533. 25. Muniyappa R, Karne RJ, Hall G, et al. Oral glucosamine for 6 weeks at standard doses does not cause or worsen insulin resistance or endothelial dysfunction in lean or obese subjects. Diabetes 2006;55:3142-3150. 26. Barnhill JG, Fye CL, Williams DW, et al. Chondroitin product selection for the glucosamine/chondroitin arthritis intervention trial. J Am Pharm Assoc 2006;46:14-24. 27. Data on file, Nutramax Laboratories, Inc. 28. Lippiello L, Nardo J, Harlan R, and Chiou T. Metabolic effects of avocado/soy unsaponifiables on articular chondrocytes. Evid Based Complement Alternat Med 2008;5:191-197. 29. Au R, Al-Talib TK, Au AY, et al. Avocado soybean unsaponifiables (ASU) suppress TNF- ␣, IL-1 ‚ COX-2, iNOS gene expression, and prostaglandin E2 and nitric oxide production in articular chondrocytes and monocyte/macrophages. Osteoarthritis Cartilage 2007;15:1249-1255. 30. Au RY, Au AY, Frondoza CF. Suppression of TNF- ␣ , IL-1, iNOS, and P38 expression by the combination of avocado soy unsaponifiables, glucosamine, and chondroitin sulfate in human macrophage-like THP-1 cells. [abstract] In Proceedings of the Osteoarthritis Research Society International. 11th World Congress on Osteoarthritis. Prague, Czech Republic.; Dec 7-10, 2006. P304. 31. Au RY, Au AY, Rashmir-Raven AM, et al. Inhibition of pro-inflammatory gene expression in chondrocytes, monocytes, and fibroblasts by the combination of avocado soybean unsaponifiables, glucosamine, and chondroitin sulfate. Faseb J 2007;21(7):A702.7. 32. Au RY, Au AY, Cade M, et al. Down-regulation of pro-inflammatory markers in equine chondrocytes and osteoblasts by avocado soybean unsaponifiables, glucosamine, and chondroitin sulfate. In Proceedings of the 2007 ACVS Veterinary Symposium. Chicago, IL; October 18-21, 2007. 33. Jomphe C, Gabriac M, Hale TM, et al. Chondroitin sulfate inhibits the nuclear translocation of nuclear factor-K  in interleukin-1 -stimulated chondrocytes. Basic Clin Pharmacol Toxicol 2008;102:59-65. 34. Punke JP, Au AY, Au RY, et al. Modulation of prostaglandin E2 production in feline articular chondrocytes propagated in monolayer and dynamic microcarrier culture. In Proceedings of the 2007 ACVS Veterinary Symposium.Chicago, IL; October 18-21, 2007. 35. Demko JL, Phan PV, Kramer EA, et al. Modulation of prostaglandin E-2 production in IL-1 activated chondrocytes propagated on microcarrier spinner culture. Proceedings of the 53rd Annual Meeting of the Orthopaedic Research Society. San Diego, CA; February 11-14, 2007. A:507. 36. Ameye LG, Chee WS. Osteoarthritis and nutrition. From nutraceuticals to functional foods: a systematic review of the scientific evidence. Arthritis Res Ther 2006;8:R127. 37. Usha PR, Naidu MUR. Randomised, double-blind, parallel, placebo-controlled study of oral glucosamine, methylsulfonylmethane and their combination in osteoarthritis. Clin Drug Invest 2004;24:353-363. 38. Kim LS, Axelrod LJ, Howard P, et al. Efficacy of methylsulfonyl-methane (MSM) in osteoarthritis pain of the knee: a pilot clinical trial. Osteoarthritis Cartilage 2006;14:286-294. High quality ingredients Researched ingredients Routine audits of active ingredient suppliers Manufacturing standards practiced by the pharmaceutical industry 2208 Lakeside Boulevard • Edgewood, Maryland 21040 nutramaxlabs.com 1-800-925-5187 Patient samples and informative brochures are available and easy to request. Your choice: • Call Customer Service 1-877-COSAMIN • Visit cosaminsamples.com These statements have not been evaluated by the Food & Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease. 13-1015-00 Printed on recycled paper. Exclusive Formula Published randomized, double-blinded, placebo-controlled clinical trials have concluded that the combination of glucosamine hydrochloride and pharmaceutical-grade chondroitin sulfate that constitutes Cosamin DS is effective in improving joint function and reducing joint pain.13,14,20 Several meta-analyses of published randomized clinical trials (RCTs) have reported the effectiveness of pharmaceutical-grade chondroitin sulfate when compared to placebo.21-23 A two year RCT published February 2009 in Arthritis and Rheumatism, The Study on Osteoarthritis Progression Prevention (STOPP), demonstrated that long-term administration of CS (800 mg/daily) can slow knee joint structure degradation. The minimum joint space width loss was significantly reduced in the CS group as compared with the placebo group. In addition, pain improved significantly faster in the CS group (P< 0.01) than in the placebo group. The researchers concluded that CS has combined structure-modifying and symptom-modifying effects.24 Experimental in vitro and in vivo trials have demonstrated that the combination of glucosamine and chondroitin sulfate was more effective than either substance alone in inhibiting progression of cartilage lesions and in maintaining cartilage health.1,5,6 ▲ Source: SLACK Incorporated Market Research Survey, June 2005 and February 2006. Surveys conducted of orthopedic surgeons and rheumatologists relating to glucosamine/chondroitin sulfate brands. In published, controlled clinical trials, reported adverse effects were similar in type and frequency among participants receiving a placebo and those receiving glucosamine and/or sodium chondroitin sulfate as used in Cosamin DS. Additional clinical studies have demonstrated that Cosamin DS, and glucosamine as a single agent, have no effect on blood glucose concentrations, hemoglobin A1c or insulin resistance among those studied.15,25 There are no known drug or dietary supplement interactions, or serious side effects with Cosamin DS. ASU is a potent compound derived from avocados and soybeans. NMX1000® ASU is standardized to contain a minimum of 30% avocado/soybean unsaponifiables. In vitro studies support the effects of ASU for the promotion of joint health by: . Stimulating production of collagen and proteoglycans, major constituents of cartilage. . Decreasing the expression of cyclooxygenase-2, the enzyme that controls the production of prostaglandin E (PGE ). . Decreasing expression of inducible nitric oxide synthase (iNOS) which regulates the production of nitric oxide. . Inhibiting the expression of tumor necrosis factor- (TNF- ) 28 29† 2 2 10.5 10 p=0.04 9.5 ISK 9 8.5 8 7.5 7 Baseline 2 4 6 Months Cosamin DS Placebo Fig. A WITH COSAMIN DS Statistically significant functional improvement in the Cosamin DS group versus placebo. A double-blind, placebo-controlled study recruited 93 patients with knee pain and mild or moderate radiographic changes of the knee from a single center. Patients were evaluated initially and then every two months for six months. The authors reported that patients in the Cosamin DS group showed significant improvement in knee pain scores as measured by Lequesne index of severity of osteoarthritis of the knee (ISK) at four and six months compared to the placebo group.13 Lower ISK values correlate with decreased knee pain. Articular Cartilage NIH Study: Moderate-Severe Pain Group 100 Fig. B WITHOUT COSAMIN DS 90 79.2% 80 69% 70 p=0.002 p=0.06 60 50 Placebo Celecoxib Glu CS Glu/CS Response rates in the subset of patients with moderate to severe pain as measured by WOMAC. Articular Cartilage Fig. A and B Shown above are photomicrographs of representative safranin 0-stained histological sections from femoral condyles harvested following a four-month placebo-controlled study which measured the influence of the orally administered ingredients of Cosamin DS on progression of cartilage breakdown in an animal model of joint destabilization. Proteoglycan is stained red by this process, enabling the cartilage to be clearly visualized. Figure (A) demonstrates the protective effect provided by the specific ingredients of Cosamin DS, which was typical of the subject cartilage in this group. Figure (B) is representative of the state of cartilage breakdown observed in the placebo-administered group.6 For even greater control of inflammatory markers than the combination of glucosamine and chondroitin sulfate Cosamin®ASU is an advanced proprietary formulation that combines NMX1000® avocado/soybean unsaponifiables (ASU) with Cosamin’s FCHG49® glucosamine and pharmaceutical-grade TRH122® sodium chondroitin sulfate. This advanced formulation was developed to provide an increased level of joint health support, with an even greater effect on inflammatory markers than the combination of glucosamine and chondroitin sulfate. Six-month follow up of patients given Cosamin DS (Lequesne index data) % Responders The combined benefits of FCHG49® glucosamine and pharmaceutical grade TRH122® sodium chondroitin sulfate have been well documented through published in vitro, in vivo, and human clinical studies.1-19 These specific trademarked ingredients have been shown in laboratory in vitro research to inhibit expression of degradative enzymes and mediators involved in the process of cartilage breakdown. They also stimulate production of the cartilage matrix components which are comprised primarily of proteoglycans and type II collagen. EFFICACY WITHOUT WORRY Additional in vitro studies have elucidated potential mechanisms by which the ingredients in Cosamin ASU may inhibit expression of the mediators of cartilage breakdown. The combination of ingredients in Cosamin ASU decrease expression of transcription factor nuclear factor KB and signal transduction gene, mitogen activated protein kinase-14 (MAPK-14 also known as p38).30,33 The signal transduction genes are key in the pathway of cartilage breakdown. Inhibition of their expression may intervene in the process of cartilage breakdown. The beneficial effects of inhibiting the expression of mediators which contribute to the destruction of cartilage by the ingredients in Cosamin ASU have been shown in vitro to extend across multiple cell types in the joint.30-32,34,35 The combination of ingredients found in Cosamin ASU does not, however, completely block the expression of inflammatory mediators. This is beneficial as low levels of the mediators are necessary for normal cell, organ and tissue function. In the NIH-sponsored Glucosamine/chondroitin Arthritis Intervention Trial (GAIT), efficacy in the reduction of knee pain was assessed on both glucosamine hydrochloride and chondroitin sulfate individually as well as in combination. In the double-blind study conducted at 16 U.S. rheumatology centers, 1583 patients with knee pain persisting at least 6 months and with radiographic evidence of cartilage breakdown were each randomized to receive one of five agents: a placebo, celecoxib, glucosamine hydrochloride, chondroitin sulfate, or the combination of glucosamine hydrochloride and chondroitin sulfate. The study concluded that the combination of glucosamine hydrochloride and chondroitin sulfate is effective in managing moderate to severe knee pain.20 In the U.S. and Canada, the pharmaceutical-grade, 95% chondroitin sulfate used in this clinical trial is exclusively found in Cosamin DS.26,27 ASU, Glucosamine, and Chondroitin Sulfate Inhibits TNF- ␣ Expression in THP-1 Macrophage-Like Cells 120 Percent of Activated Control (%) Cosamin®DS is the #1 orthopedic surgeon and rheumatologist recommended brand ▲ of glucosamine/chondroitin sulfate. As a joint health supplement, Cosamin DS helps reduce joint pain by using ingredients that are safe, effective, easily absorbed, and proven effective in controlled published U.S. clinical studies. Proven effective for joint pain reduction in U.S. published clinical trials 100 80 60 p < 0.001 40 20 0 Control Control+LPS CS+GLU+LPS ASU+CS+GLU+LPS © 2008 Nutramax Laboratories, Inc. Inhibition of TNF- ␣ gene expression in THP-1 macrophage-like cells ASU, Glucosamine, and Chondroitin Sulfate Inhibits IL-1 Expression in THP-1 Macrophage-Like Cells 120 Percent of Activated Control (%) THE ORTHOPEDIC SURGEON AND RHEUMATOLOGIST #1 RECOMMENDED BRAND 100 80 p = 0.004 60 40 20 0 Control Control+LPS CS+GLU+LPS ASU+CS+GLU+LPS 28,29 † ␣ ␣ © 2008 Nutramax Laboratories, Inc. Inhibition of IL-1 expression in THP-1 macrophage-like cells †Mediators involved in cartilage breakdown and interleukin-1  (IL-1 ).29† In vitro studies indicate that glucosamine and pharmaceuticalgrade sodium chondroitin sulfate when combined with avocado/soybean unsaponifiables (ASU) are even more effective at suppressing expression of inflammatory mediators than the combination of glucosamine and chondroitin sulfate alone.30-32 Examples of these findings are illustrated in the graphs at right. The cells used in these studies were stimulated with Lipopolysaccharide (LPS). The untreated controls indicate the normal level of TNF- ␣ and IL-1 gene expression by the cells in these studies.31 In vitro research has shown that the combination of avocado/soybean unsaponifiables (ASU), glucosamine and chondroitin sulfate decreases the levels of inflammatory markers associated with joint discomfort and cartilage breakdown better than the combination of glucosamine and chondroitin sulfate. The benefits of Cosamin and MSM combined Perfect for athletes and active people Cosamin®MSM is an innovative once-a-day formulation that combines Cosamin’s proprietary FCHG49 glucosamine and pharmaceutical-grade TRH122 sodium chondroitin sulfate with methylsulfonylmethane (MSM) in a natural and artificial orange flavored dietary supplement–just add to water. Cosamin MSM was developed to offer a convenient, delicious way to support joint health while providing an option for those who have difficulty swallowing capsules and tablets. MSM is a di-methylated sulfone molecule [(CH3)2SO2]. This sulfur-containing organic compound is naturally present in low amounts in fruits, corn, tomatoes, coffee and milk.36 Research supports the inclusion of MSM into a Cosamin formulation as published clinical studies have reported that study participants who were administered at least 1,500 mg of MSM demonstrated improved pain scores and quality of life.36-38 Many other products contain sub-optimal levels of MSM. Convenient once-a-day serving