Polysulfated Glycosaminoglycans (Adequan)
Polysulfated glycosaminoglycan (PSGAG) is currently the only member of a group of polysulfated glycosaminoglycans that include, in addition to Adequan, pentosan polysulfate (CartrophenR) and glycosaminoglycan peptide complex (RumalonR). PSGAG has been traditionally used where articular cartilage damage is considered to be present rather than in the treatment of acute synovitis. It has also been used prophylactically to prevent day to day loss of cartilage components.
There have been numerous studies of PSGAG. The structure of PSGAG is very close to heparin. PSGAG has been shown to inhibit the effects of various enzymes associated with cartilage degeneration, including both collagenase and stromelysin, serine proteinases and others. PSGAG also has been shown to have a direct inhibitory effect on PGE2 synthesis and it is suggested that there is an anti-IL-1 effect. PSGAG also stimulates the synthesis of hyaluronic acid in the horse.
The protective effects of PSGAG on equine cartilage are not accepted by everybody. Although it was initially reported that PSGAG causes increased collagen and glycosaminoglycan synthesis in cartilage cultures from normal and osteoarthritic horses, more recent work by another investigator showed little effect on PG degradation. We need more research on the precise mechanisms of action of PSGAG and its interactions with cytokines involved in joint disease.
In live animal studies, the chondroprotective effect of PSGAG was first shown in dogs in which osteoarthritis was experimentally induced with meniscal removal. Work with an arthritis model in rabbits showed that there was a lower neutral metalloproteinase activity, increased chondrocyte counts, and maintenance of proteoglycan content. Both a prophylactic (preventing) and therapeutic (treatment) effect have been shown in experimental models with dogs.
Studies in the horse – We investigated the effects of intra-articular PSGAG on an experimental model of osteoarthritis in horses some years ago. Briefly, we showed that if we had chemically-induced degeneration developing in the cartilage, Adequan could greatly prevent it. However, if we made a defect in the cartilage, Adequan did not heal the defect. From this we concluded that the presence of Adequan could reduce ongoing degradation in the articular cartilage but could not heal a defect that was already there. We have seen good responses to PSGAG after surgery when there is significant cartilage degeneration. Although we know it does not heal defects left in the joint (discussed in more detail later), we hope (and presume) that it does decrease the rate of further cartilage degradation that probably ensues in most joints.
Potential complications of intra-articular injection – After intra-articular Adequan had been used for a few years, some veterinarians felt there was an increased risk of infection after intra-articular therapy. Based on research done here at CSU, we did demonstrate that PSGAG could have a greater potential in this regard. There were two important findings that came out of this research. The first was that we only need 100 organisms to infect a joint (compared to 1,000,000 to infect a skin laceration). This confirmed the observations of many that aseptic technique when injecting a joint was critical. The next stage of our research was with a subinfective dose simulating chance contamination. When Adequan was given at the same time, it potentiated this risk of infection. In a second study, we showed that conjunctive administration of a small dose of antibiotic prevented any infections.
In the meantime, the concomitant development of intramuscular Adequan led to it being used more frequently than intra-articular therapy. I still like to use intra-articular Adequan in a horse with severe cartilage damage, at least for the first injection after surgery. On the other hand, intramuscular use is far more frequent. However, aspects of how much intramuscular drug reaches the joint and its over-efficacy compared to intra-articular Adequan is still controversial. The dose rate for intramuscular Adequan is 500 mg. Although the manufacturers state it should be given every four days, we tend to use it weekly. The dose rate for intra-articular Adequan is 250 mg.
There have been a number of oral glycosaminoglycan products that have become available for horses recently and we are frequently asked questions with regard to their efficacy. Current products available include a purified chondroitin sulfate product from bovine trachea (Flex-FreeR) and a complex of glycosaminoglycans and other nutrients from the sea mussel, Perna canaliculus (Syno-FlexR). More recently, a combination of glucosamine hydrochloride, chondroitin sulfate and what is described as a mixture of other PSGAGs has been marketed as a «nutriceutical» (CosequinR). Individual veterinarians and owners have commented on what they consider to be positive results. Cosequin has been evaluated using the Freund’s adjuvant model of inflammatory joint disease and no benefit was demonstrated on clinical signs (lameness, stride length, carpal circumference, carpal flexion) in synovial fluid protein parameters.
On the other hand, the oral administration of glucosamine sulfate has been associated with decreased pain and improved range of motion compared to placebo in a controlled clinical trial in humans. In another trial, glucosamine sulfate was as effective as Ibuprofen at relieving symptoms of osteoarthritis in people. In vitro studies using glucosamine sulfate have demonstrated increased glycosaminoglycan and proteoglycan synthesis and in vivo studies have demonstrated an anti-inflammatory activity through inhibition of enzyme activity and free radical production.
The other question frequently asked is, is the oral product absorbed sufficiently? In studies done, there has been some absorption of an intact molecule but we still await demonstration of this in the horse.