Chondroprotective agents: Do they work? (Proceedings)


Chondroprotective agents: Do they work? (Proceedings)

Nov 01, 2010

Regulation: Chondroprotective agents are available as injectable and oral formulations. The injectable formulations are classified as drugs and are regulated by the FDA. The present discussion will focus on the more nebulous branch of chondroprotective agents, the nutraceuticals. Oral formulations are considered to be nutraceuticals, a somewhat poorly-defined term used to describe compounds supplied exogenously to facilitate normal body functions and structures. Human and veterinary nutraceuticals are considered somewhat differently, as human compounds are classified as dietary supplements under the 1994 Dietary Supplement Health and Education Act (DSHEA), whereas veterinary formulations are excluded from DSHEA. As DSHEA clarified the regulation of human nutraceuticals, the lack of DSHEA coverage of veterinary products has left the regulatory status of veterinary nutraceuticals in limbo. State feed laws may govern the majority of products, but most products do not appear on Association of American Feed Control Officials (AAFCO) list of products that are "generally recognized as safe" (GRAS). As unregulated products, nutraceuticals are not required to meet U.S. Food and Drug Administration (FDA) guidelines for efficacy, purity, and potency. Similarly, supplement manufacturers are not required to follow Good Manufacturing Procedures (GMP), resulting in the sale of products that may differ from their stated ingredients are dose. Irregardless, both human and veterinary nutraceuticals are prohibited from making claims that would represent the supplement as a drug. Under The Food, Drug, and Cosmetic Act, a drug is "intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease". Thus, under DSHEA, nutraceutical products can claim on their labels that they support normal body structure and function but cannot make statements regarding mitigation or prevention of disease. This labeling requirement is somewhat at odds with how nutraceutical chondroprotective agents are most often used, where veterinary patients may receive these agents in an attempt to slow the progression of osteoarthritis and reduce pain.

Actions of Chondroprotective Agents: There are several different types and classes of nutraceutical agents purported to have actions in cartilage and joints. Chondroprotective agents are sometimes referred to as slow-acting, disease-modifying, osteoarthritis agents (SADMOAs). Numerous other agents, such as green-lipped muscle, avocado/soybean unsaponifiables, pentosan polysulphate, special milk protein concentrate, and elk velvet antler, have also been advanced as potential chondroprotective agents. However, due to limitations in space, the present discussion will be confined to the most commonly used agents, glucosamine and chondrotin sulfate. . The SADMOA agents are thought to act by promoting the synthesis of hyaline cartilage, which is a mixture of collagens, proteoglycans, and water. The water in the cartilage is an essential component of shock absorption during loading of the joint, and is attracted to cartilage by the proteoglycan macromolecules. The proteoglycan is actually a complex mixture of smaller constituents, such as multiple glycosaminoglycans, chondroitin sulfate, and keratin sulfate, attached to a protein and hyaluronic acid core. Glucosamine and chondroitin sulfate are two of the building blocks incorporated into the articular proteoglycans, and so are supplemented in hope that excess amounts of circulating precursors will encourage the net formation of hyaline cartilage. Other oral nutraceutical agents, such as manganese and ascorbate, are administered as cofactors for the synthesis of proteoglycans and collagen. As catabolism of hyaline cartilage has been implicated in the pathogenesis of osteoarthritis, a shift from catabolic to anabolic effects would be expected to improve joint function and decrease the pain associated with osteoarthritis. Although this line of reasoning provides a rational explanation for efficacy of oral chondroprotective agents, in vitro studies suggest that other mechanisms, such as scavenging of free radicals and direct anti-inflammatory effects, may also be involved in chrondroprotection. Numerous in vitro studies have detected positive anabolic and anti-inflammatory effects of glucosamine and chondroitin disaccharides on explants or cell cultures of chondrocytes. Anti-inflammatory effects include blockade of interleukins, decreased production of prostaglandins, inhibition of metalloproteinases, and a reduction in reactive oxygen species, perhaps moderated through inhibition of NF-kappa B nuclear translocation1 . These in vitro studies are largely impressive and demonstrate a rational mechanism of action of the SADMOAs in modulating osteoarthritis. However, most of the in vitro work has used much higher concentrations of glucosamine and chondroitin disaccharides than are found in the plasma after oral administration, complicating the direct applicability of these studies to clinical efficacy.

Oral Absorption of Chondroprotective Agents: Pharmacokinetic and efficacy studies have been reported in both the human and veterinary peer-reviewed literature for several of these agents, demonstrating absorption and activity. The SADMOAs generally have limited oral absorption as an intact molecule as a consequence of their structure. For example, chondroitin sulfate and proteoglycans are large, charged macromolecules, so they are not absorbed intact. However, chondroitin sulfate is readily cleaved to distinct disaccharides that can be found at elevated concentrations in the plasma after oral administration in dogs. The elimination of chondroitin disaccharides appears to be slower than that of glucosamine, with accumulation occurring with the administration of multiple doses. Although the slow accumulation of chondroitin may partially explain the delayed onset of action of the SADMOAs, the proposed mechanism of cartilage synthesis suggested by in vitro studies would also support a slow onset of action. Indeed, significant improvements in dogs with osteoarthritis that were administered glucosamine and chondroitin were reported at 70 days after beginning supplementation.2 Additional studies with radiolabeled compounds have revealed that fragments of chondroitin are absorbed from the gastrointestinal tract and can be found in synovial fluid and hyaline cartilage, demonstrating both absorption and a tropism for joints. Glucosamine is a much smaller molecule than is chondroitin and is better absorbed intact from the gastrointestinal tract in the species that have been studied, including in dogs. In one formulation of glucosamine HCl administered orally to dogs, the bioavailability was low (12%), but the glucosamine was rapidly absorbed, with a maximum plasma concentration achieved in 1.5 hours. Although glucosamine is rapidly metabolized to simple sugars, exongenously administered glucosamine also exhibits a tropism for articular cartilage, which may offset its rapid metabolism.

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