Research points to pentosan polysulfate to treat equine osteoarthritis

Some things are simply better the second time around. We learn more, we know more and we see things differently. Such is the case with pentosan polysulfate (PPS).

This drug has been in use in Australia and parts of Europe for more than 30 years, and it's currently enjoying a surge in interest and use in the United States. Recent research focusing on its effects in horses has finally started to provide previously lacking scientific evidence for its specific beneficial impact as an antiarthritic agent in sport horses.

Initial uses

PPS is a multifaceted drug and was initially used as an antithrombolytic agent to help prevent blood clots in people. It also was found to have antilipidemic properties, which led to its being used to help prevent fat buildup within blood vessels.

The properties of PPS were first investigated in sheep, dogs, rabbits, rats and chickens. Researchers noted a beneficial effect in cases of osteoarthritis in dogs, and sodium PPS was first approved as an injectable canine arthritis treatment in 1986 in Australia. It was next approved for the treatment of canine arthritis in New Zealand, the United Kingdom, Canada and Ireland. Since some of the initial studies also focused on use in people, PPS next gained approval as a human joint treatment throughout most of the European community, Scandinavia, South Africa and Australia.

No studies looking at the effects of PPS in horses had been done at that time, but the drug nonetheless began to be used to treat equine osteoarthritis, and claims both for and against its efficacy have circulated during the years. Good, intuitive reasons to expect PPS to function beneficially in horses have been around, as well as plenty of hard science and research in other species to point to, but the equine veterinary research community has been relatively slow to do the testing required to prove such claims.

Recent research and testing, however, have begun to provide horse owners with a much more complete understanding of the workings of PPS and have led to a renewed interest in this antiarthritic medication for sport horses in the United States.

Properties and adverse effects

Pentosan is a polymer produced from xylan, which is a complex hemicellulose extract from the beechwood plant. It can be formulated as a sodium salt or a calcium derivative. And it can be administered orally, intramuscularly, intravenously or intra-articularly. The calcium derivative is absorbed orally and subcutaneously much more efficiently than the sodium salt, which is primarily used intramuscularly.

Adverse effects of PPS use are related to its primary function as an anticlotting or thrombolytic agent and are dose-dependent. It's not recommended for use in postsurgical cases, for horses with autoimmune problems or prior bleeding issues or in situations in which trauma and possible bleeding could occur.

These concerns bring the two aspects of PPS into conflict, since the typical situation in which osteoarthritis becomes a problem requiring treatment is in performance sport horses, yet it's exactly this use that's most likely to result in possible trauma, injury and bleeding. This was the dilemma that, at least in part, initially prevented more widespread use of PPS in athletic horses.

Attention to dosage and frequency resulted in relatively safe use over time, however, and veterinarians and trainers in Australia and Europe became comfortable with its use. PPS was routinely used in racehorses throughout those regions, with no documented increase in problems associated with exercise-induced pulmonary hemorrhage or other performance-related bleeding problems.

Statistics from Biopharm Australia Pty. Ltd., the company that produces and distributes PPS in that country (where it's sold as Cartrophen Equine Forte), indicate that only 14 adverse drug reactions occurred during a 14-year period ending in August 2007.1 Most adverse responses (13 of 14) were injection-site reactions, and company researchers concluded that the reports represent a low incidence (less than 0.01 percent) of adverse events on an individual dose basis in horses.

In addressing possible bleeding problems, a group of researchers reported that when PPS was administered at the recommended dose of 3 mg/kg, activated partial prothrombin time (PPT)—a standard measure of the clotting mechanism in the body—did not return to baseline until 24 hours after injection.2 Thus, the researchers concluded that it's best to not administer PPS at doses up to 3 mg/kg within 24 hours of high-stress activities or in situations in which physical injury could occur.

Some veterinarians administer higher PPS doses (up to 6 mg/kg) because of a perceived greater antiosteoarthritis effect. At this dosage, the PTT returns to normal within 48 hours of administration, so the timing of PPS treatment becomes very important in sport horses.

The anticoagulant effect of PPS is mild and is between one-sixth and one-tenth that of sodium heparin, which is the most commonly used medical anticoagulant.3 Furthermore, PPS releases tissue plasminogen activator from the endothelium, or the lining of the blood vessels.3 It's this action that brings about the enzymatic breakdown of thrombolytic emboli or blood clots within blood vessels, and PPS doesn't affect the systemic blood-clotting system. This recently explained distinction helps make calculated use of PPS safer for exercising horses and potentially more worthwhile.

Efficacy

PPS affects arthritic joints in several ways. It has no analgesic or primary pain-relieving effects in and of itself, but its ability to influence the overall health of the equine joint has led to its being classified as a structure-modifying osteoarthritic drug. These compounds treat the cause of the arthritis process rather than simply alleviate the pain produced by that process.

PPS stimulates the synthesis of proteoglycans and increases the amount of these substances incorporated into the extracellular matrix; this is the supporting structure of the cartilage that makes up the joint's weight-bearing surface. Athletic use over time tends to cause progressive osteoarthritis or joint wear and tear, and it's the slow loss of proteoglycans from the cartilage matrix that weakens the joint's structure and causes lameness and loss of athletic use. The drug's ability to replace these components within the matrix is instrumental to its capacity to halt the progression of arthritis.

PPS also stimulates synovial fibroblasts (cells that make up the joint capsule) to produce increased amounts of high-molecular-weight hyaluronic acid. These actions improve the viscosity and volume of the joint fluid that lubricates and stabilizes the joint and helps limit further degradation of joint cartilage. Additionally, PPS inhibits and modulates inflammatory mediators including histamine, serotonin, superoxide free radicals and proteins of the complement system, which have all been implicated in the degradation of cartilage matrix.

Initial interest in PPS stemmed from its ability to break up fibrin, a major component of blood clots. Since cartilage has no intrinsic blood supply, it depends on underlying bone for the vessels needed to bring necessary nutrients. The osteoarthritis process erodes some joint surfaces and thickens other areas, which can cause a great reduction in blood flow and, thus, in nutritional support of cartilage. The deposition of fats and fibrin into the underlying joint-related vessels of stressed equine athletes can cause them to become clogged, which further reduces blood flow and contributes to cartilage degeneration. PPS has specific activities that remove fibrin clots and lipids (fats) from blood vessels, and that translates into better blood flow, reduced degeneration within the joint and eventual reduction in joint pain.

Mechanism of action

The known properties of PPS have for years provided a reasonable assurance of what was happening on a physiologic basis within the sport horse, but only recently have researchers begun to investigate and prove that the suspected mechanisms are in fact true.

Researchers in the Department of Anatomy at the University of Bristol in Langford, England, were the first to demonstrate that intramuscular injections of PPS showed sufficient concentration of the drug in synovial or joint fluid.4 This proved that injecting PPS into a horse's muscles eventually got the drug into the joints, and "the concentration was sufficient to elicit a potential therapeutic effect on synovial metabolism, and possibly also to stimulate proteoglycan synthesis and reduce matrix metalloproteinase (one of the major cartilage degeneration agents) activities in articular or joint cartilage."4

More recently, researchers at the Orthopaedic Research Center at the College of Veterinary Medicine at Colorado State University looked at the drug's actions on 18 horses that underwent surgically induced osteoarthritis.5 This study was one of the first to investigate PPS use in a clinical setting, and various parameters were used to evaluate the drug's efficiency, including blinded lameness and range of motion examinations (research evaluators didn't know which horses received drug vs. placebo), blood and joint fluid analysis and serial radiographs.

The study's authors concluded that PPS use produced trends that were not highly significant but showed more positive recordable differences between the treatment and placebo groups histologically rather than clinically. They concluded that PPS does have a beneficial therapeutic effect but that further study is indicated.5

They also found that PPS may not be sufficiently potent to demonstrate a clinical effect at the current dose of 3 mg/kg, which may be the reason many practitioners are recommending a higher dose of 6 mg/kg. Caution always should be used and attention to timing and dosage is important.

Conclusion

PPS is not currently available in the United States, although some laboratories are compounding it for extralabel use. Caution should be exercised with any such preparation. PPS is generally given intramuscularly once weekly for four to five weeks and monthly thereafter. Clinical response is usually seen after the first two or three doses. It's too early to tell if PPS is going to be the next big thing or merely a product whose time has come and gone. Further testing will determine how PPS—the wonder from down under—fits into what's currently available for arthritis in horses, and whether the second time around is truly better.

Dr. Marcella is an equine practitioner in Canton, Ga.

References

1. Biopharm Australia Pty Ltd. Cartrophen Equine Forte: a disease modifying osteoarthritis drug. Available at: www.arthritis.au.com/content/CEF_technical_brochure.pdf.

2. Dart A, Perkins N, Dowling, et al. The effect of three different doses of sodium pentosan polysulphate on haematological and haemostatic variables in adult horses. Aust Vet J 2001;79(9):624-627.

3. Maffrand JP, Herbert JM, Bernat A, et al. Experimental and clinical pharmacology of pentosan polysulfate. Semin Thromb Hemost 1991;17(Suppl. 2):186-198.

4. Fuller CJ, Ghosh P, Barr AR. Plasma and synovial fluid concentrations of calcium pentosan polysulphate achieved in the horse following intramuscular injection. Equine Vet J 2002;34(1):61-64.

5. McIlwraith CW, Frisbie DD, Kawcak CE. Evaluation of intramuscularly administered sodium pentosan polysulfate for treatment of experimentally induced osteoarthritis in horses. Am J Vet Res 2012;73(5):628-633.