Managing Joint Disease in the Racehorse in the Face of Stricter Drug Restrictions

IN-DEPTH: RACING-RELATED LAMENESS

C. Wayne McIlwraith, BVSc, PhD, Diplomate ACVS, ACVSMR

Author’s address: Gail Holmes Equine Orthopaedic Research Center, Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523; e-mail: [email protected]. © 2013 AAEP.

1. Introduction racing to protect equine health and welfare. Par- Intra-articular use of corticosteroids has become a ticipants included analytical chemists, veterinary recent focus (or re-focus) of attention in the Thor- pharmacologists, veterinary surgeons, racing regu- oughbred racing industry. The clinical use and sci- latory veterinarians, and practicing racetrack veter- entific basis of intra-articular corticosteroid inarians. Among the recommendations was a administration including catastrophic injury, artic- prohibition on intra-articular use of corticosteroids ular cartilage degradation, and the development of within 7 days of a race, taking into consideration the osteoarthritis (OA) as well as the timing of injection concerns expressed by many participants about the relative to racing have been reviewed.1 Most re- proximity of intra-articular injections to race day. cently, there has been very specific examination by The experts also recommended a 72-hour with- the Racing, Medication, and Testing Consortium drawal time for dexamethasone, a commonly used (RMTC). At the time of that press release, the short-acting corticosteroid that can be administered RMTC had approved (1) minimal withdrawal time intravenously, intramuscularly and orally. Other recommendations for corticosteroids on the basis of short-acting corticosteroids would have similar re- both recently completed work funded in part by the strictions. It was also noted that the recommenda- RMTC and conducted at the University of Pennsyl- tions would fundamentally change the use of vania, University of California-Davis, Kenneth L. corticosteroids in veterinary practice in racing in the Maddy Laboratory, and HFL Laboratory-Kentucky United States and therefore recommended a grace and other corticosteroid research conducted both in period to allow veterinarians time to adjust their the United States and abroad and (2) recommenda- veterinary practices and to allow trainers time to tions were developed during an RMTC-hosted Cortico- adjust their training practices to comply with the steroid Experts Conference in Anaheim, California, on new regulations. Further details regarding these November 30, 2012. This meeting brought together recommendations are discussed below (Table 1). qualified individuals with professional expertise in The purpose of this review is to offer possible key areas with the goal of providing a comprehen- modifications and alternatives with the intra-artic- sive plan for regulating corticosteroid use in horse ular and systemic therapy for traumatic joint injury

NOTES

436 2013 ր Vol. 59 ր AAEP PROCEEDINGS IN-DEPTH: RACING-RELATED LAMENESS

Table 1. Corticosteroid Threshold Chart

Withdrawal Time for 95/95 Minimum Experimental Tolerance Interval at Withdrawal Route of Administration Experimental Dose and Medication Threshold Time* Administration† Dosage‡ Route of Administration

Betamethasone 10 pg/mL of 7 Days Intra-articular Total of 9 mg of 7 Days plasma or betamethasone (as a serum mixture of betamethasone sodium phosphate and betamethasone acetate) in one joint Dexamethasone 5 pg/mL of 3 Days Intravenous, 0.05 mg/kg of 3 Days plasma or intramuscular, dexamethasone (as serum and oral dexamethasone sodium phosphate) Isofluprodone TBD TBD Intra-articular 20 mg total dose of Pending isoflupredone (as isoflupredone acetate, Predef 2X) in one joint Methylprednisolone 100 pg/mL of 7 Days Intra-articular Total of 100 mg of 21 Days plasma or methylprednisolone serum (as methylprednisolone acetate) in one joint§ Prednisolone TBD TBD Intravenous and Pending oral Triamcinolone 100 pg/mL of 7 days Intra-articular Total of 9 mg 7 Days acetonide plasma or triamcinolone serum acetonide in one joint

*The RMTC has recommended a 7-day regulatory withdrawal time for all intra-articular use of corticosteroids, recognizing that the clearance times for some will be longer than 7 days. Furthermore, this regulation is not in conﬂict with the withdrawal time for dexamethasone listed here; the use of dexamethasone intra-articularly is inappropriate because it would be considered off-label and a violation of the provisions of the Animal Medicinal Drug Use and Clariﬁcation Act (AMDUCA). †Route of administration: Administration of these corticosteroids by other routes of administration may affect the length of time it takes before the medication is below the regulatory threshold (eg, betamethasone injected intramuscularly takes approximately 33 days for its plasma concentration to fall below the regulatory threshold). The withdrawal times for betamethasone, methylprednisolone, and triamcinolone acetonide apply to the intra-articular route of administration only and should not be interpreted as guidance for withdrawal of these substances after other routes of administration. ‡Administration dosage and related 95/95 withdrawal times: This is provided as guidance and does not constitute a guarantee. It does not account for repeat dosage, multiple articular site dosage, the effects of combining other medications with these corticosteroids, or different dosages from those listed here. A risk assessment must be done by the veterinarian and trainer to determine protocol that complies with the prohibition against administration of an intra-articular dose within 7 days of racing. §Please note that for this dose of methylprednisolone acetate, a 21-day period from administration to racing is recommended to ensure that the medication is below the regulatory threshold. The minimum withdrawal time in this case anticipates the possibility of lower doses being used and assumes that these lower doses may decrease the length of time required for the concentration of the medication to fall below the regulatory threshold.

and OA in the horse. Other countries have trav- regarding a series of experimental studies with in- eled down this pathway some time ago. More clear tra-articular therapy. restrictions on the use of medication should be con- After review of the data and addition of a toler- sidered in the positive light that at the same time, ance interval for safety, the RMTC was able to cal- there has been validation of non-corticosteroid treat- culate a recommended withdrawal time with the ments even in the acute stage of joint inﬂammation experimental dose of 100 mg of intra-articular meth- and newer biological therapies have emerged that ylprednisolone acetate (MPA) in one articular space, have no side effects and offer positive advances. on the basis of a 95/95 tolerance interval, requiring approximately 16.6 days for the concentration of 2. Intra-Articular Corticosteroids: What Has MPA in plasma or serum to fall below the 100 pg/mL Changed? threshold. This was rounded out to 21 days. In As discussed above, the RMTC issued a 7-day limi- February 2012, Mid-Atlantic regulators, horsemen, tation for long-acting corticosteroids so that they and industry representatives met to discuss the im- would fall below their respective threshold levels plementation of numerous medication guidelines,

AAEP PROCEEDINGS ր Vol. 59 ր 2013 437 IN-DEPTH: RACING-RELATED LAMENESS including the corticosteroid recommendations, on a signs were seen with HA compared with that in regional uniformed basis. Numerous regulators control horses, but, histologically at day 70, there and horsemen expressed concerns regarding the dis- was significantly less fibrillation with HA treatment parity between the 7-day ban on intra-articular use compared with that in controls. The place for HA of MPA and the 21-day recommendation for the ex- in combination therapy is therefore not as an acute perimental dose to comply with the proposed regu- anti-inflammatory but as a long-term disease-modi- latory threshold. There was a feeling from fying osteoarthritis drug (DMOAD). veterinarians as well that compliance with the recommendations would be difficult and could place 5. Polysulfated Glycosaminoglycan horsemen and veterinarians attempting to comply Work examining the effect of intra-articular polysul- with the recommendations in good faith in “harm’s g way” and that the better approach may be to ban the fated glycosaminoglycan (PSGAG) suggests that drug and recommended use of alternative therapies. this product has significant effects on acute synovitis and can be used in lieu of intra-articular cortico- To continue the principal goal of the RMTC in hav- 4 ing regulatory thresholds adopted and uniformity steroids. In a controlled study with the use of the attained, a decision was made to remove methyl- equine osteochondral fragment–OA model, eight prednisolone from the list of approved therapeutics. horses received PSGAG (250 mg) and amikacin sulfate (125 mg) intra-articularly at 14, 21, and 28 days 3. Working Within the 7-Day Rule after induction of OA, and eight control horses re- As discussed in an earlier review,1 controlled studies ceived 2 mL of saline (0.9% NaCl) solution and ami- have been performed in the horse to clarify thera- kacin sulfate (125 mg) intra-articularly on study peutic response as well as deleterious effects for days 14, 21, and 28. The degree of synovial mem- betamethasone esters,a MPA,b and triamcinolone brane vascularity and subintimal fibrosis was sig- acetonidec (TA). In a survey of AAEP members, a nificantly reduced with PSGAG treatment, and lower number of respondents were using MPA in there was a trend for reduced fibrillation at day 70. high-motion joints (25.7%), with most (77.3%) opting This indicated significant symptom-modifying OA for TA instead.2 A higher percentage (72.7%) were effects as well as potential DMOAD effects. In still using MPA in low-motion joints. In contrast to other unpublished work, however, it was shown that the published works documenting the negative ef- the combination of triamcinolone acetonide and PS- fects of MPA, most respondents indicated that sci- GAG was inferior to either triamcinolone acetonide entific papers and data determined their choice of alone or PSGAG alone and so current indications corticosteroid use. The use of Depo-Medrolb has are that PSGAG, if used intra-articularly, should decreased since demonstration of negative effects on be used alone and not in combination with the cartilage, but there is still considerable use. corticosteroids. It is expected that the pragmatics of prolonged withdrawal time will further decrease the use of the 6. Extracorporeal Shock Wave Therapy drug. In addition to the options of betamethasone esters and TA as well as isoflupredone acetate,d Evaluation of extracorporeal shock wave therapy there are other medication options that are also (ESWT) in the osteochondral fragment model of OA presented below. A window into the future can eas- also showed symptom-modifying effects in the carpal joint.5 Extracorporeal shock wave therapy has ily be examined by looking at racetrack practitio- 6,7 ners’ use in other countries. In the author’s native also been used to treat horses with OA. Horses country of New Zealand, there is currently a 48-day were randomly allocated to receive local application withholding period for Depo-Medrol; personal com- of ESWT at days 14 and 28, a positive control ther- munications indicate that there is no use of that apy (intramuscular PSGAG), or sham ESWT (pla- drug in racehorses and that it is not missed.e Race- cebo). The degree of lameness in horses treated track practice has emerged with considerable TA with ESWT improved significantly compared with use (withdrawal period is 4 to 5 days) and an in- the degree of lameness in placebo-treated or creasing use of interleukin-1 receptor antagonist PSGAG-treated horses. No disease-modifying ef- protein therapy in carpal, fetlock, and distal tarsal fects were evident in the results for synovial fluid, joints. synovial membrane, or cartilage from the ESWT- treated or PSGAG-treated horses. There were no 4. Hyaluronan significant effects of ESWT on any bone variable, but Combination therapy of corticosteroids and hyaluro- serum osteocalcin concentration was significantly nan (HA) is quite common and can be defended greater than in horses that received ESWT com- scientifically. In an experimental study of equine pared with placebo-treated control horses. The in- osteoarthritis induced by osteochondral fragmenta- crease of serum biomarkers was indicative of bone tion in the middle carpal joint, eight horses received remodeling, but there were no negative effects re- 20 mg of HAf intra-articularly 14, 21, and 28 days vealed. It could be concluded that ESWT is a viable after induction of OA.3 No adverse treatment-re- non-pharmaceutical treatment for acute inflamma- lated events were detected. No changes in clinical tion in equine joints.

438 2013 ր Vol. 59 ր AAEP PROCEEDINGS IN-DEPTH: RACING-RELATED LAMENESS 7. Underwater Treadmilling also a significant reduction in synovial membrane Aquatic therapy has become increasingly popular in hyperplasia in treated compared with placebo OA its use for rehabilitation of equine musculoskeletal joints at day 70 and a trend for improvement (P Ͻ injuries. The mechanism of action of aquatic ther- 0.10) in cartilage gross score and cartilage histo- apy and its potential use in the clinical management chemistry noted in ACS-treated OA joints compared of equine OA has been recently reviewed.8 Recent with placebo-treated OA joints. The hypothesis human research has increased our understanding of that the main effect of this new therapy was signif- neuromuscular responses to joint pain.9 Joint icant increases in interleukin (IL)-1 receptor antag- mechanoreceptors are characterized as sensory re- onist protein (IL-1ra) was confirmed, with increases ceptors within periarticular tissues that respond to seen at days 35 and 71. changes in joint position and motion and are also A newer product, IRAP II,l with a modified tech- important in regulating neuromuscular control as- nique including a newly designed device with dual sociated with joint stability.10 Pain, inflammation, ports, has since been produced, and a comparative and joint effusion alter the normal sensory input study was performed on the cytokine profiles of from articular mechanoreceptors, which may cause IRAP and IRAP II with the use of equine blood.18 motor neuron excitability and reduced muscle acti- Specifically, the level of IL-1ra in IRAP II was vation.11 Experimentally induced knee effusion significantly increased compared with IRAP, and produced significant quadriceps muscle inhibi- the ratio of IL-1ra to IL-1␤ also significantly in- tion.12–14 Joint instability alters the distribution of creased in IRAP II compared with IRAP. On the weight-bearing forces across articular surfaces and other hand, there was a significantly increased level induces an increase in the recruitment of adjacent of tumor necrosis factor-␣ in IRAP compared with muscles to help aid in joint stability.15 The result- IRAP II but no significant difference in IL-1␤ levels. ing functional imbalance and paired agonist-antag- Production of insulin-like growth factor (IGF)-1 and onist muscle groups contributed to increased joint transforming growth factor-␤ was both significantly instability and altered limb biomechanics, which increased over serum alone, and no significant dif- leads to further progression of OA and chronic mal- ference between the two products was seen. On the adaptive compensatory mechanisms.16 There is an basis of the extrapolation of doses used in this study, increasing perception among veterinarians that the recommendation for IRAP after arthroscopic joint injuries may recur or be exacerbated as the surgery is 6 mL in knees, fetlocks, distal interpha- result of muscle weakness, reduced joint range of langeal joints, and tendon sheaths but 10 to 12 mL motion, and poor proprioception, as exemplified by in femoropatellar or femorotibial joints. Treatment immobilization of the equine metacarpophalangeal in the latter joints would therefore require two prep- joint. The entire musculoskeletal system must be arations (two preparations of IRAP or IRAP II to rehabilitated to return the horse to optimal perfor- give three injections at this dose rate). mance.8 Recently, the use of underwater tread- The use of the IRAP products has considerably milling has been assessed in the equine OA model, increased in racing jurisdictions outside the United and both decrease in osteoarthritis as well as im- States. They represent a specific biological therapy proved proprioception were demonstrated.h without negative side effects and have been well This is a clear demonstration that underwater accepted by racing jurisdictions other than in Scan- treadmilling can be used as an adjunctive device for dinavia, where there have been attempts to ban the treatment of traumatic joint inflammation, and their use. There is no scientific validity to exclud- there is no indication that it could not be used with ing such products from use in the competing athlete. a racehorse in full training. In the 2009 joint therapy usage survey, sport horse practitioners were significantly more likely than 8. Autologous Conditioned Serum (IRAP or IRAP II) racehorse or show horse veterinarians to use IRAP Autologous conditioned serum (ACS) was initially products (P ϭ 0.0035 and P ϭ 0.04, respectively), developed for the treatment of human OA as a prod- but this was in the United States. The author sug- uct called Orthokinei and was initially tested in gests that the use of IRAP in racehorses is used horses in Europe and shown to be particularly ben- more often by racetrack practitioners outside of the eficial in OA (of the distal interphalangeal joint) not United States. responding to triamcinolone and HA.j Orthokine was subsequently distributed in the United States 9. Platelet-Rich Plasma as IRAPk and in an experimental study17 was shown Platelet-rich plasma (PRP) has been advocated as a to provide benefit in osteochondral fragment–in- way to introduce increased concentrations of growth duced equine OA. Horses received 6 mL of ACS at factors and other bioactive molecules to injured tis- 14, 21, 28, and 38 days after treatment (control sues in an attempt to optimize the local environ- horses received 6 mL of saline intra-articularly at ment. There are various definitions of PRP, but the the same time). Horses treated with ACS were ob- consensus now is that the product should have an served to have significantly reduced lameness in the increase in platelet content over the level in blood. OA limbs even 5 weeks after the last treatment The initial enthusiasm for PRP was based on growth compared with placebo-treated horses. There was factors within the ␣-granules including transform-

AAEP PROCEEDINGS ր Vol. 59 ր 2013 439 IN-DEPTH: RACING-RELATED LAMENESS ing growth factor-␤, platelet-derived growth fac- differentiate to lineages of mesenchymal tissue in- tor-1, and IGF-2, fibroblast growth factor, epidermal cluding bone, cartilage, muscle, ligament, tendon, growth factor, as well as endothelial growth factor. adipose, and stroma.25 Multiple different path- There are a number of other bioactive factors in PRP ways of multipotent MSCs and the proteins involved contained in dense granules of platelets,19 and there in their transcriptional control have been described is an emerging paradigm that more than just plate- in a review of MSC therapy in equine musculoskel- lets are playing a role in PRP.20 etal disease.26 The clinical use of MSCs in horses, The use of PRP to treat joint disease is currently justification for their use, and issues surrounding increasing in the horse. Up until this time, the their use have been reviewed.27 Early work with author has tended to recommend IRAP rather than labeled MSCs has shown that they have an affinity PRP for treatment of joints. However, good clinical for damaged joint tissue, and more recent work has results with the use of PRP to treat OA in people confirmed their ability to localize and participate in have been reported,21 and recent in vitro work the repair of damaged joint structures including cru- showed beneficial effects on cartilage metabolism.22 ciate ligaments, menisci, and cartilage lesions.28 More recently, a comparison between HA and PRP Most in vivo studies performed in animals other intra-articularly in the treatment of OA in the knee than horses are focused on meniscal repair. A par- showed that local injection of a low-platelet-count ticularly significant study involved direct intra-ar- PRP productm had a significant effect shortly after ticular injection with beneficial effects to meniscus the final infiltration and a continuously improved and secondary OA.29 This led to the initiation of a sustained effect up to 24 weeks Western Ontario and clinical study with intra-articular bone marrow–de- McMaster Universities Arthritis Index (WOMAC rived mesenchymal stem cells (BMSCs) plus HA scores 65.1 and 36.5 in the HA and PRP groups, therapy in clinical cases of femorotibial joint respectively, P Ͻ 0.001), in which the clinical out- trauma. Meniscal injury (and other soft-tissue in- comes were better as compared with HA-treated jury) with secondary OA is a common problem in our horses.23 Also in the HA group, the worst results population of horses.30 It has also recently been were obtained for grade III gonarthrosis, whereas demonstrated that experimental equine meniscal the clinical results obtained in the PRP group did lacerations can be healed with equine BMSCs in not show a statistically significant difference with fibrin glue and show increased vascularization, de- regard to the grade of gonarthrosis. The mean creased thickness in repair, and increased total WOMAC scores for grade III gonarthrosis were bonding.31 We also examined the use of BMSCs in 74.85 in the HA group and 41.20 in the PRP group the equine osteochondral fragment model.32 In a (P Ͻ 0.001). comparative study, it was shown that there was Along with this study, recent work has suggested significant improvement in synovial fluid prosta- that whereas higher numbers of platelets are seen in glandin E (PGE)2 levels with BMSC treatment and some PRP products, this brings higher white cell nominal improvement in symptom- and disease- count levels and higher catabolic cytokine levels.24 modifying effects. On the other hand, there was an In another study looking at the anabolic and cata- interesting negative response with adipose-derived bolic activities of cartilage and meniscal explants in stromal vascular fraction cells in that there was an vitro and the effect of a single-spin PRPm compared increase in synovial fluid tumor necrosis factor-␣ with a double-spin product,n ADAMTS-4 gene ex- levels and no significant change in PGE2 levels. pression was lowest for the single-spin PRP (AD- The anti-inflammatory effect was another good ex- AMTS-4 or aggrecanase 1 is considered a major ample of trophic effects with MSCs. The term factor in articular cartilage degradation). Also, ra- “trophic effects” applies to the observation that in diolabel incorporation with 35-sulfate (an index of addition to adult marrow-derived MSCs being capa- glycosaminoglycan synthesis) and 3H-proline incor- ble of dividing and their progeny further differenti- poration (as an indication of collagen synthesis) ating into one of several mesenchymal phenotypes were significantly enhanced with the single-spin such as osteoblasts and chondrocytes, these MSCs system. Therefore, there is growing scientific sup- also secrete a variety of cytokines and growth factors port for the possible use of PRP after surgery, but we that have both paracrine and autocrine activities.33 still need good clinical evidence in the horse. These secreted bioactive factors suppress the local At this stage, the use of PRP as a treatment for immune response, inhibit fibrosis (scar formation) acute synovitis and capsulitis or early OA cannot be and apoptosis, enhance angiogenesis, and stimulate recommended. mitosis and differentiation of tissue-intrinsic repar- ative or stem cells. 10. Mesenchymal Stem Cells The trophic effects of BMSCs have been further The use of mesenchymal stem cells (MSCs) or mes- demonstrated by a recent study in the horse in enchymal stromal cells has become popular as an which an intra-articular injection of 20 million BM- adjunctive therapy in equine orthopedics. Most SCs in 20 mg of HAf was compared with HA alone in work has concentrated on the multipotent cells pres- the repair of full-thickness microfractured defects on ent in adult bone marrow that can replicate an un- the medial femoral condyle.34 There was enhance- differentiated cell and have the potential to ment of the firmness of the repair tissue at 6 and 12

440 2013 ր Vol. 59 ր AAEP PROCEEDINGS IN-DEPTH: RACING-RELATED LAMENESS months as well as a significant increase in aggrecan control group given 4 mL of saline intravenously at content in the repair tissue. those same times.36 As a potential alternative for the use of acute traumatic synovitis and capsulitis, MSCs would not Oral HA appear to be an option. There are good indications A number of oral nutraceuticals are used after ar- that MSCs have long-term effects for soft tissue throscopic surgery. All these products are unli- inflammation within the joint as well as articular censed, and, with the exception of oral HA,p no cartilage repair. The amount of DMOAD effects is scientific evidence has been produced to support less certain; their use is important in long-term their use. However, one oral HA productp has been regenerative therapies but not in the acute shown to benefit postoperative effusion after ar- situation. throscopic surgery for tarsocrural osteochondritis dissecans (OCD).37 Oral HA (100 mg) was given 11. Systemic (Parenteral) Medications daily for 30 days after surgery in 24 yearlings (with 27 joints operated), and another 24 yearlings (30 Polysulfated Glycosaminoglycan joints operated) were treated with placebo daily for Polysulfated glycosaminoglycan administered intra- 30 days. An examiner blinded to the treatment muscularly is still very popular, but evidence is lim- groups scored the effusion at 30 days on a scale of 0 ited to anecdotal opinion. Intramuscular injections to 5. The mean 30-day effusion score in the treated of 500 mg after surgery were commonly recom- group was 0.67 as compared with 2.05 in the placebo mended by the author until a controlled study in group (P Ͻ 0.0001). experimentally induced equine OA showed no significant difference in the administration of intra- References and Footnotes muscular PSGAG (every 4 days for 28 days) as a 1. McIlwraith CW. The use of intra-articular corticosteroids in positive control treatment in an evaluation of ESWT the horse: what is known on a scientific basis? Equine Vet on experimentally induced osteoarthritis in the mid- J 2010;42:563–571. 5 2. Ferris DJ, Frisbie DD, McIlwraith CW, et al. Current joint dle carpal joints of horses. Consequently, it is therapy usage in equine practice: a survey of veterinarians thought that the use of intramuscular PSGAG is 2009. Equine Vet J 2011;43:530–535. very limited as a treatment. Any prophylactic 3. Frisbie DD, Kawcak CE, McIlwraith CW, et al. Evaluation value is still unproven. of polysulfated glycosaminoglycan or sodium hyaluronan administered intra-articularly for treatment of horses with experimentally induced osteoarthritis. Am J Vet Res 2009;70: Pentosan Polysulfate 203–209. Intramuscularly administered sodium pentosan 4. Kawcak CE, Frisbie DD, McIlwraith CW. Effects of extracorporeal shockwave therapy and polysulfated glycosamino- polysulfate (NaPPS) has been commonly used out- glycan therapy on subchondral bone and serum and synovial side the United States for the treatment of osteoar- fluid biomarkers in an equine osteoarthritis model. Am J thritis as well as after surgery. Recently, NaPPS Vet Res 2011;72:772–779. at a dose of 3 mg/kg intramuscularly at 15, 22, 29, 5. Frisbie DD, Kawcak CE, McIlwraith CW. Evaluation of the and 36 days after induction of experimental carpal effect of extracorporeal shockwave treatment on experimentally induced osteoarthritis in middle carpal joints of horses. osteoarthritis caused a significant reduction in ar- Am J Vet Res 2009;70:449–454. ticular cartilage fibrillation and an increase in chon- 6. McClure SR, Weinberger T. Extracorporeal shockwave droitin sulfate 846 epitope (a synthetic biomarker) therapy: clinical applications and regulation. Clin Tech in the synovial fluid of both osteoarthritic and non- Equine Pract 2003;2:358–367. osteoarthritic joints. This indicated that NaPPS 7. Revenaugh MS. Extracorporeal shockwave therapy for 35 treatment of osteoarthritis in the horse: clinical application. has some beneficial disease-modifying effects. Vet Clin North Am Equine Pract 2005;21:609–625. The product is available in a 12-mL vialo (which is 8. King MR, Haussler KK, Kawcak CE, et al. Mechanisms of the approximate dose for a 1000-lb horse), but cau- aquatic therapy and its potential use in managing equine tion must be exercised in the United States because osteoarthritis. Equine Vet Edu 2013;25:204–209. 9. Templeton MS, Booth DL, O’Kelly WD. Effects of aquatic the product is not licensed and is only available as therapy on joint flexibility and functional ability in subjects an intra-articular lavage. with rheumatic disease. J Orthop Sports Phys Ther 1996; 23:376–381. Intravenous HA 10. Hurley MV. The effects of joint damage on muscle function, proprioception and rehabilitation. Man Ther 1997;2:11–17. The use of intravenous HA (40 mg IV) after surgery 11. Johansson H, Sjolander P, Sojka P. A sensory role for the is used by some clinicians, and there is scientific cruciate ligaments. Clin Orthop 1991;268:161–178. evidence that would support its use. With a study 12. Iles J, Stokes M, Young A. Reflex actions of knee joint afferents during contraction of the human quadriceps. Clin in the equine osteochondral fragment–OA model, Physiol 1990;10:489–500. three treatments of 40 mg were given intravenously 13. Hopkins J, Ingersoll C, Drause B, et al. Effect of knee joint 13, 20, and 27 days after osteochondral fragment effusion on quadriceps and soleus motoneuron pool excitabil- creation. There was a significant decrease in lame- ity. Med Sports Sci Sports Exerc 2001;33:123–126. 14. Palmieri R, Tom J, Edwards J, et al. Arthrogenic muscle ness, synovial fluid protein and PGE2 levels, syno- response induced by an experimental knee joint effusion is vial membrane vascularity, and synovial membrane mediated by pre- and post-synaptic spinal mechanism. J cellular infiltration at day 72 compared with the Electromyogr Kinesiol 2004;14:631–640.

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15. Shultz SJ, Carcia CR, Perrin DH. Knee joint laxity affects 30. Ferris DJ, Frisbie DD, Kisiday JD, et al. Clinical follow-up muscle activation patterns in the healthy knee. J Electro- of thirty three horses treated for stifle injury with bone mar- myogr Kinesiol 2004;14:475–483. row derived mesenchymal stem cells intra-articularly. Vet 16. Wu S-H, Chu N-K, Liu Y-C, et al. Relationship between the Surg 2013 (in press). EMG ratio of muscle activation and bony structure in osteo- 31. Ferris DJ, Frisbie DD, Kisiday JD, et al. In vivo healing of arthritis knee patients with and without patellar malalign- meniscal lacerations using bone marrow derived mesenchy- ment. J Rehabil Med 2008;40:381–386. mal stem cells and fibrin glue. Stem Cell Int 2012;2012:691– 17. Frisbie DD, Kawcak CE, Werpy NM, et al. Clinical, bio- 605. chemical and histologic effects of intra-articular administra- 32. Frisbie DD, Kisiday JD, Kawcak CE, et al. Evaluation of tion of autologous conditioned serum in horses with adipose-derived stromal vascular fraction or bone marrow- experimentally induced osteoarthritis. Am J Vet Res 2007; derived mesenchymal stem cells for treatment of osteoarthri- 68:290–296. tis. J Orthop Res 2009;27:1675–1680. 18. Hraha TH, Doremus KM, McIlwraith CW, et al. Autologous 33. Caplan AI, Dennis JE. Mesenchymal stem cells as trophic conditioned serum: the comparative cytokine profiles of two mediators. J Cell Biochem 2006;98:1076–1084. commercial methods (IRAP and IRAP II) using equine blood. 34. McIlwraith CW, Frisbie DD, Rodkey WG, et al. Evaluation Equine Vet J 2011;43:516–521. of intra-articular mesenchymal stem cells to augment healing 19. Foster TE, Puskas BL, Mandelbaum BR, et al. Platelet-rich of microfractured chondral defects. Arthroscopy 2011;27: plasma: from basic science to clinical applications. Am J 1552–1561. Sports Med 2009;37:2259–2272. 35. McIlwraith CW, Frisbie DD, Kawcak CE. 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442 2013 ր Vol. 59 ր AAEP PROCEEDINGS