 | |
 Chemical structure and packaging | |
| Clinical data | |
|---|---|
| Trade names | Adequan |
| AHFS/Drugs.com | Veterinary Use |
| License data | |
| Routes of administration | UsuallyIM orIA |
| ATCvet code |
|
| Legal status | |
| Legal status | |
| Pharmacokinetic data | |
| Protein binding | 30–40% |
| Metabolism | Renal |
| Onset of action | 48 hours for peak levels in joints (IM) |
| Duration of action | 96 hours (IM) |
| Excretion | Urine |
| Identifiers | |
| UNII | |
| Chemical and physical data | |
| Molar mass | 3,000–15,000Da |
Polysulfated glycosaminoglycan (PSGAG), sold under the brand nameAdequan, is an injectable drug for dogs and horses that is used to alleviate thelimpness, pain, and lowered range of motion caused byarthritis.[2] It is made of repeatdisaccharide units (comprisinghexosamine andhexuronic acid), and is similar toglycosaminoglycans already present in thecartilage; PSGAG thus easily integrates itself there.[3][4]In vitro studies have shown it to inhibit the enzymes that degrade cartilage and bone, as well as suppress inflammation and stimulate the synthesis of replacement cartilage. While it can cause an increased risk of bleeding, it is relatively safe and has a highLD50. PSGAG is one of the most widely prescribed joint treatments for horses.[5]
While it is widely used, some studies still show conflicting results in terms of efficacy, causing some to claim that PSGAG is not solely responsible for the significant mitigation of arthritis seen in success cases.[6]
PSGAG is mostly used in dogs and horses for treating traumatic arthritis anddegenerative joint disease (osteoarthritis).[7] It has shown to be better at treating acute than chronicarthritis, though some studies say that its effectiveness in acute cases is still limited if degenerative enzymes have not played a role.[8] While it is currently only FDA-approved for dogs and horses, PSGAG is also used off-label to treatlameness in swine, as a chondroprotectant ("joint protector") or treatment ofinterstitial cystitis in cats, and to treat arthritis in rabbits.[1][3][9]
PSGAG is first administered as a series of injections over several weeks, and can be continued once or twice a month thereafter.[10] It is normally injectedintramuscularly, though can also be injectedintra-articularily (directly into the joint) in horses orsubcutaneously in off-label uses.[2] Giving PSGAG intra-articularily requires it to be givenaseptically,[8] and is sometimes supplemented by the antibioticamikacin to prevent infection.[1][3][7]
There are nogeneric or human-labeled equivalents of PSGAG in the US.[1][7][10]
Side effects from intra-articular administration can include joint pain, swelling, lameness, and, rarely, infection of the joint. Intramuscular injection can cause dose-dependentinflammation andbleeding, since PSGAG is an analogue of the anticoagulantheparin.[4] In dogs, this may manifest as bleeding from the nose or as bloody stools.[7] The increased risk of bleeding has some advising not to give PSGAG to animals with bleeding disorders, though its onlyabsolute contraindication is hypersensitivity to PSAGs when it is being given intra-articularily.[1][10]
Overdose on PSGAG is quite rare, as theLD50 is over 1000 mg/kg when givenintravenously to dogs. Signs of overdose include exacerbated side effects such as joint pain, swelling, and lameness.[4][7] When dogs received three times the normal dose intramuscularly twice a week for 13 weeks, they had increasedliver andkidney weight, as well as microscopiclesions on the liver, kidneys, andlymph nodes. At 11 times the normal dose, they also had increasedalanine transferase,cholesterol, andprothrombin time (i.e. coagulation via theextrinsic pathway took longer), and fewerplatelets.[11]
Normally, joint cartilages haveproteoglycan complexes, which are proteins with side chains made ofglycosaminoglycans such askeratan sulfate andchondroitin sulfate attached to strands ofhyaluronic acid. The glycosaminoglycan side chains are polyanionic, which causes adjacent side chains to push each other away and create a "bottle brush", where hyaluronic acid is the stem and the side chains are the bristles. When pressure is exerted on the joint, fluids move between thechondrocytes andsynovial fluid, exchanging nutrients.[4]
In degenerative joint disease, the proteoglycan complexes start disappearing, and the hyaluronate becomes poorer in quality and scarcer. This lowers the viscosity of the synovial fluid (which increases friction) and causeswhite blood cells and enzymes to enter and effect cartilage degradation and inflammation.Steroids that are released as a result kill the chondrocytes. The remaining chondrocytes have trouble exchanging nutrients with the synovial fluid, which would allow them to repair some damages.[4]
The mechanism of PSGAGin vivo is based on observations and studiesin vitro. PSGAG inhibits many of the catabolic enzymes that degrade cartilage, proteoglycans, and hyaluronic acid.[6][10] The enzymes that are inhibited includeserine proteases, which play a role in theIL-1 degradation of proteoglycans and collagen;lysosomal enzymes that cause proteoglycans to dissociate from hyaluronic acid; elastase;metalloproteinases such asstromelysin, which degrade cartilage matrix proteins;collagenases such ascathepsin B1; andhyaluronidase.[4][12] PSGAG inhibits the synthesis ofprostaglandin E2, which is released upon joint injury and causes inflammation, increases the loss of proteoglycan, and reduces the threshold ofpain receptors.[3][11][12] Inhibiting thecomplement pathway further reduces inflammation, most likely by alteringC-reactive protein. The inhibition of blood coagulation reduces resultant fibrinolysis, which would cause cell death and increase local inflammation.[2][4]
PSGAG also stimulates the synthesis of glycosaminoglycans, hyaluronic acid, and collagen, which increase synovial viscosity.[3] It cannot, however, completely reverse the disappearance of cartilage, nor can it reverse bone loss caused by arthritis.[12][10]
PSGAG reaches peak blood concentration in 20–40 minutes when injected intramuscularly; 30–40% of it binds toblood proteins. It enters all tissues, reaching cartilage within two hours.[12] When PSGAG reaches the synovial fluid, it is then taken up by the cartilage matrices, with osteoarthritic cartilage showing a stronger preference for taking it up.[3][11] It reaches its peak levels in the joints at 48 hours, and lasts up to 96 hours, before leaving and being excreted by thekidneys.[1][4]
