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Wirkungen und Nebenwirkungen der intraartikulären medikamentellen Therapie beim Pferd – eine Literaturübersicht – Teil 1: Konventionelle intraartikuläre medikamentelle Therapie und Risiken der Gelenkinjektion beim Pferd
Abstract
Die unter dem englischen Begriff der Osteoarthritis (OA) zusammengefassten pathologischen Veränderungen von Gelenken sind eine wich- tige Lahmheitsursache beim Pferd. Häufig wird die OA mit der intraartikulären Applikation von verschiedensten Medikamenten behandelt. Eine Vielzahl von wissenschaftlichen Studie beschäftigt sich mit Wirkmechanismus, Effektivität, Dosierung und Nebenwirkungen der intra- artikulären Therapie. Das Ziel dieser Literaturübersicht ist es, die Wirksamkeit der gängigsten Präparate beim Pferd anhand von in vitro- und in vivo-Studien evidenzbasiert zu beschreiben. Die evidenzbasierte Medizin (EbM) ist der gewissenhafte, ausdrückliche und vernünfti- ge Gebrauch der gegenwärtig besten externen, wissenschaftlichen Evidenz für Entscheidungen in der medizinischen Versorgung indivi- dueller Patienten. Die Praxis der EbM bedeutet die Integration individueller klinischer Expertise mit der bestverfügbaren, externen Evidenz aus systematischer Forschung. In diesem ersten Teil der Literaturübersicht werden konventionelle intraartikuläre medikamentelle Therapeu- tika wie Corticosteroide, Hyaluronsäure und Polysulfatiertes Glykosaminoglykan und die zu diesen Medikamenten zur Verfügung stehen- den wissenschaftlichen Erkenntnisse dargestellt und auch allgemeine Nebenwirkungen der intraartikulären Injektion besprochen.
... Bei der Behandlung von Gelenkserkrankungen von Pferden wird die intraartikuläre Medikation gegenüber der systemischen bevorzugt, da eine relativ hohe Konzentration des Wirkstoffes am Wirkort erreicht wird und ein geringeres Risiko für systemische Nebenwirkungen besteht (Caron 2005, Ehrle et al. 2013. Jedoch kann es durch eine intraartikuläre Injektion zu Komplikationen kommen, die entweder durch die Vorgehensweise selbst oder durch das applizierte Arzneimittel verursacht werden (Dooley und Martin 2002). ...
Autologous Conditioned Serum (ACS) is considered to have a high level of safety, which has not yet been statistically volidated in a large number of veterinary patients. The aims of this study were to determine the frequency of complications and potential risk factors for a larger number of horses who received intra-articular injections with ACS. For this purpose medical records of horses that had been treated at least in one joint of the fore- or hindlimb with ACS were evaluated retrospectively. Potential risk factors were diagnostic joint injections up to three days prior to ACS injection, drugs or antibiotics administered systemically or intra-articularly at the same time as ACS, and arthroscopies and joint lavages, respectively, at a time interval of up to 47 days before intra-articular ACS injection. A total number of 1,445 joint injections were carried out on 387 horses. The complication rate after intra-articular ACS injection was determined by the adjusted Wold method and was 4.8 per 1,000 injections (95% CI 1.7-9.3). To ensure this complication rate in a prospective study, at least 5,900 subjects per group should be treated. Serious or life-threatening complications were not observed. The intra-articular administration of ACS is associated with a low complication risk.
Compilation of regenerative therapies and their use in the Horse.
A large torn wound of the dorsal elbow region was observed in a 17-year-old Arabian mare. Surgical reconstruction was performed with the horse in standing sedation, but suture dehiscence occurred 2 days later. Autologous platelet-rich gel (PRG) was then applied to the wound every 3 weeks for a total of 3 administrations to accelerate good-quality healing. The wound had healed rapidly and completely within 5 months of the first PRG treatment, without chronic effects or formation of exuberant tissue granulation and with minimum scarring. This case report suggests that topical treatment with autologous PRG, as additional therapy, might be considered beneficial in the management of large-wound healing in horses, and it can be regarded as safe and inexpensive treatment that can be used in field.
This study was carried out to evaluate the effect of platelet-rich plasma (PRP) on the treatment of tendinopathy induced in the superficial digital flexor tendon (TFDS) of horses, by using histologic evaluation. Six healthy crossbred geldings aged 8 to 15 years (12±3) were used. The TFDS tendinopathy was provoked in both forelimbs, by intratendinous administration of 2.5mg collagenase (2.5mg/mL), and this procedure was considered as the beginning of the experimental phase. At 12 days after induction of the tendinopathy, the animals were subjected to the following treatments: (1) in the lesion caused in the right superficial digital flexor tendon (PRP-treated group), 2.5mL PRP activated with calcium chloride at 0.0125mol/L at concentrations from 320,000 to 500,000 platelets/μL, were injected; (2) in the tendinopathy of the left SDFT (control group), 2.5mL 0.9% saline solution was administrated. Thirty-six days after the treatments, a biopsy of the injured area was performed for histologic evaluation. In both groups, the histologic analysis showed an increase in the fibroblastic density, as well as the presence of neovascularization, lymphocytes, and plasmocytes infiltrate and tissue organization at variable intensity. In the PRP-treated group, the SDFT was more organized, with the collagen fibers and fibroblasts being better arranged on the tendon matrix. The numbers of the fibroblasts and blood vessels did not differ between the groups. Histologic evaluation 36 days after tendinopathy showed that injuries under a single PRP treatment present a more uniform and organized tissue repair when compared with the control group.
Molecular Therapy (2006) 13, S191|[ndash]|S191; doi: 10.1016/j.ymthe.2006.08.563
493. High Efficiency Gene Targeting to Mammalian Joint Tissue Using Self- Complementary Adeno-Associated Viral Vector Serotypes
Laurie R. Goodrich1, Vivian W. Choi2, Beth C. DudaCarbone1, C. Wayne McIlwraith1 and Richard J. Samulski21Clinical Sciences and Orthopedic Research Center, Colorado State University, Fort Collins, CO2Gene Therapy Center, University of North Carolina, Chapel Hill, NC
To assess the safety and symptomatic changes of IA injections of platelet-rich plasma (PRP) in patients with OA of the hip.
Forty patients affected by monolateral severe hip OA were included in the study. Each joint received three IA injections of PRP, which were administered once a week. The primary end point was meaningful pain relief, which was described as a reduction in pain intensity of at least 30% from baseline levels as evaluated by the WOMAC subscale at 6-months post-treatment. The visual analogue scale (VAS) and Harris hip score subscale for pain were used to verify the results. Secondary end points included changes in the level of disability of at least 30% and the percentage of positive responders, i.e. the number of patients that achieved a >30% reduction in pain and disability.
Statistically significant reductions in VAS, WOMAC and Harris hip subscores for pain and function were reported at 7 weeks and 6 months (P < 0.05). Twenty-three (57.5%) patients reported a clinically relevant reduction of pain (45%, range 30-71%) as assessed by the WOMAC subscale. Sixteen (40%) of these patients were classified as excellent responders who showed an early pain reduction at 6-7 weeks, which was sustained at 6 months, and a parallel reduction of disability. Side effects were negligible and were limited to a sensation of heaviness in the injection site.
This preliminary non-controlled prospective study supported the safety, tolerability and efficacy of PRP injections for pain relief and improved function in a limited number of patients with OA of the hip.
Previous studies of bioactive molecules in platelet-rich plasma (PRP) have documented growth factor concentrations that promote tissue healing. However, the effects of leukocytes and inflammatory molecules in PRP have not been defined.
The hypothesis for this study was that the concentration of growth factors and catabolic cytokines would be dependent on the cellular composition of PRP.
Controlled laboratory study.
Platelet-rich plasma was made from 11 human volunteers using 2 commercial systems: Arthrex ACP (Autologous Conditioned Plasma) Double Syringe System (PRP-1), which concentrates platelets and minimizes leukocytes, and Biomet GPS III Mini Platelet Concentrate System (PRP-2), which concentrates both platelets and leukocytes. Transforming growth factor-β1 (TGF-β1), platelet-derived growth factor-AB (PDGF-AB), matrix metalloproteinase-9 (MMP-9), and interleukin-1β (IL-1β) were measured with enzyme-linked immunosorbent assay (ELISA).
The PRP-1 system consisted of concentrated platelets (1.99×) and diminished leukocytes (0.13×) compared with blood, while PRP-2 contained concentrated platelets (4.69×) and leukocytes (4.26×) compared with blood. Growth factors were significantly increased in PRP-2 compared with PRP-1 (TGF-β1: PRP-2 = 89 ng/mL, PRP-1 = 20 ng/mL, P < .05; PDGF-AB: PRP-2 = 22 ng/mL, PRP-1 = 6.4 ng/mL, P < .05). The PRP-1 system did not have a higher concentration of PDGF-AB compared with whole blood. Catabolic cytokines were significantly increased in PRP-2 compared with PRP-1 (MMP-9: PRP-2 = 222 ng/mL, PRP-1 = 40 ng/mL, P < .05; IL-1β: PRP-2 = 3.67 pg/mL, PRP-1 = 0.31 pg/mL, P < .05). Significant, positive correlations were found between TGF-β1 and platelets (r(2) = .75, P < .001), PDGF-AB and platelets (r(2) = .60, P < .001), MMP-9 and neutrophils (r(2) = .37, P < .001), IL-1β and neutrophils (r(2) = .73, P < .001), and IL-1β and monocytes (r(2) = .75, P < .001).
Growth factor and catabolic cytokine concentrations were influenced by the cellular composition of PRP. Platelets increased anabolic signaling and, in contrast, leukocytes increased catabolic signaling molecules. Platelet-rich plasma products should be analyzed for content of platelets and leukocytes as both can influence the biologic effects of PRP.
Depending on the clinical application, preparations of PRP should be considered based on their ability to concentrate platelets and leukocytes with sensitivity to pathologic conditions that will benefit most from increased platelet or reduced leukocyte concentration.
Equine mesenchymal stem cells (MSC) are of particular interest both for basic research and for the therapeutic approach to musculoskeletal diseases in the horse. Their multilineage differentiation potential gives them the capability to contribute to the repair of tendon, ligament and bone damage. MSCs are also considered a promising therapeutic aid in allogeneic cell transplantation, since they show low immunogenicity and immunomodulating functions.
Adipose tissue-derived adult equine stem cells (AdMSC) can be isolated, expanded in vitro and then inoculated into the damaged tissue, eventually in the presence of a biological scaffold. Here we report our preliminary experience with adipose-derived mesenchymal stem cells in allogeneic cell-therapy of tendonitis in the horse. MSCs, derived from visceral adipose tissue, were grown in the presence of autologous platelet lysate and characterized for their differentiation and growth potential. Expanded AdMSC were inoculated into the damaged tendon after their dispersion in activated platelet-rich plasma (PRP), a biological scaffold that plays an important role in maintaining cells in defect sites and contributes to tissue healing. Fourteen out of sixteen treated horses showed a functional recovery and were able to return to their normal activity.
Cell transplantation for the treatment of joint disease is an important clinical tool. Genetic modification of cells before transplantation has shown enhanced healing. Ex vivo genetic modification of joint tissue cells with various adeno-associated virus (AAV) serotypes has not been investigated. The transduction efficiencies of self-complementary AAV serotypes (1-6 and 8) were determined in joint tissue containing chondrocytes and synoviocytes isolated from equine models. When comparing scAAV serotypes for efficient transduction ex vivo, in chondrocytes versus synoviocytes, serotypes 6 and 2, and serotypes 3 and 2, respectively, appeared superior for gene expression. Unlike adenoviral vectors, no upregulation of inflammatory markers, such as matrix metalloproteinases and aggrecanase, was seen on treatment of joint tissue with AAV vectors ex vivo. Our findings also corroborate that ex vivo transduction of joint tissue can result in high transgene protein levels over time, and transplantation modalities might be feasible using AAV vectors in the treatment of joint-related diseases.
The success of tissue engineering applications can potentially be dramatically improved with the addition of adjuncts that increase the proliferation and differentiation of progenitor or stem cells. Platelet-rich plasma (PRP) has recently emerged as a potential biologic tool to treat acute and chronic tendon disorders. The regenerative potential of PRP is based on the release of growth factors that occurs with platelet rupture. Its autologous nature gives it a significant advantage in tissue engineering applications. To test whether PRP may be useful specifically for cartilage regeneration, a cell culture experiment was devised in which mesenchymal stem cells (MSCs) were grown in control media or media enhanced with inactivated, buffered PRP. Proliferation 7 days after PRP treatment was increased: 1.041 versus 0.199 for the control media cells ( p<0.001). The messenger RNA (mRNA) level of the osteogenic marker RUNX2 was 52.84 versus 26.88 for the control group ( p<0.005). Likewise the mRNA level of the chondrogenic markers Sox-9 and aggrecan was 29.74 versus 2.29 for the control group ( p<0.001) and 21.04 versus 1.93 ( p<0.001), respectively. These results confirm that PRP enhances MSC proliferation and suggest that PRP causes chondrogenic differentiation of MSC in vitro.
Mesenchymal stem cells are pluripotent cells found in multiple human tissues including bone marrow, synovial tissues, and adipose tissues. They have been shown to differentiate into bone, cartilage, muscle, and adipose tissue and represent a possible promising new therapy in regenerative medicine. Because of their multi-potent capabilities, mesenchymal stem cell (MSC) lineages have been used successfully in animal models to regenerate articular cartilage and in human models to regenerate bone. The regeneration of articular cartilage via percutaneous introduction of mesenchymal stem cells (MSC's) is a topic of significant scientific and therapeutic interest. Current treatment for cartilage damage in osteoarthritis focuses on surgical interventions such as arthroscopic debridement, microfracture, and cartilage grafting/transplant. These procedures have proven to be less effective than hoped, are invasive, and often entail a prolonged recovery time. We hypothesize that autologous mesenchymal stem cells can be harvested from the iliac crest, expanded using the patient's own growth factors from platelet lysate, then successfully implanted to increase cartilage volume in an adult human knee. We present a review highlighting the developments in cellular and regenerative medicine in the arena mesenchymal stem cell therapy, as well as a case of successful harvest, expansion, and transplant of autologous mesenchymal stem cells into an adult human knee that resulted in an increase in meniscal cartilage volume.
Osteoarthritis (OA) is prevalent and difficult to treat. Autologous conditioned serum (ACS), marketed under the trade name Orthokine, is a novel, injectable antiarthritic derived from the patient's own blood. The present study is the first time ACS has undergone a controlled clinical trial.
We investigated 376 patients with knee OA in a prospective, randomized, patient- and observer-blinded, placebo-controlled trial using an intention-to-treat analysis (ITT). The clinical effects of ACS were compared to hyaluronan (HA) and saline (placebo) as assessed by patient-administered outcome instruments (Western Ontario and McMaster Universities osteoarthritis index, global patient assessment, visual analog scale, Short-Form 8) after 7, 13 and 26 weeks. After 104 weeks an observer-blinded follow-up was carried out. Frequency and severity of adverse events were used as safety parameters.
In all treatment groups, intra-articular injections produced a reduction in symptoms as well as an improvement in quality of life. However, the effects of ACS were significantly superior to those of HA and saline for all outcome measures and time points, and improvements were clinically relevant; there were no differences between the effects of HA and saline. The frequency of adverse events was comparable in the ACS and saline groups, but higher in the HA group.
The data demonstrate that ACS injection considerably improves clinical signs and symptoms of OA. It remains to be determined whether ACS is disease-modifying, chondroprotective, or chondroregenerative.
Human mesenchymal stem cells are thought to be multipotent cells, which are present in adult marrow, that can replicate as
undifferentiated cells and that have the potential to differentiate to lineages of mesenchymal tissues, including bone, cartilage,
fat, tendon, muscle, and marrow stroma. Cells that have the characteristics of human mesenchymal stem cells were isolated
from marrow aspirates of volunteer donors. These cells displayed a stable phenotype and remained as a monolayer in vitro.
These adult stem cells could be induced to differentiate exclusively into the adipocytic, chondrocytic, or osteocytic lineages.
Individual stem cells were identified that, when expanded to colonies, retained their multilineage potential.
BACKGROUND Polyacrylamide hydrogel (PAAG) is a nondegradable water-based polymer with high viscoelasticity. The gel is used as a tissue filler, the only risk being prolonged infection with anaerobic, contaminating microorganisms if not treated early with broad-spectrum antibiotics.OBJECTIVE With silicone gel as reference, PAAG tissue integration and migration was studied in a longitudinal study of the pig.MATERIALS AND METHODS Forty-one pigs were used. PAAG and silicone gel were injected into mammary tissue, and PAAG was injected into urethral or bladder wall or the anal canal. Tissues and regional lymph nodes were examined at 1, 1 1/2, 3, 3 1/2, 6, 12, and 14 months, and other lymph nodes and organs were examined at 1, 6, 12, and 14 months.RESULTS PAAG was invaded by macrophages and giant cells that were gradually replaced by a network of fibrous tissue. Silicone gel was seen inside these cells or as large vacuoles, surrounded by a fibrous capsule. Regional lymph nodes contained PAAG only at 1 1/2 months and silicone gel at 12 months.CONCLUSION PAAG is a stable, viscoelastic bulking agent, which unlike silicone gel is slowly integrated within its host tissue via a thin fibrous network. Long-term risk of fibrosis and migration is minimal.
To assess clinical, radiographic, histologic, and biochemical effects of sodium pentosan polysulfate (NaPPS) administered IM for treatment of experimentally induced osteoarthritis in horses.
18 horses.
Osteoarthritis was induced arthroscopically in 1 middle carpal joint of all horses. Nine horses received NaPPS (3 mg/kg, IM) on study days 15, 22, 29, and 36. Nine control horses received the same volume of saline (0.9% NaCl) solution IM on study days 15, 22, 29, and 36. Clinical, radiographic, gross, histologic, histochemical, and biochemical findings as well as findings of synovial fluid analysis were evaluated.
No adverse treatment-related events were detected. Induced osteoarthritis caused a substantial increase in lameness, response to flexion, joint effusion, radiographic findings, synovial membrane inflammation, and articular cartilage fibrillation. Articular cartilage fibrillation was substantially reduced by NaPPS treatment, and concentrations of chondroitin sulfate 846 epitope were significantly increased in the synovial fluid of osteoarthritic and non-osteoarthritic joints of treated horses.
Results indicated that NaPPS has some beneficial disease-modifying effects and may be a therapeutic option for osteoarthritis in horses.
This study aimed to find a simple, cost-effective, and time-efficient method for the preparation of platelet-rich plasma (PRP), so the acquired benefits will be readily available for multiple procedures in smaller outpatient clinics and to explore the safety and efficacy of the application of PRP in the treatment of degenerative lesions of articular cartilage of the knee.
The study was designed as a prospective, cohort study with a control group. A total of 120 patients with Grade 1, 2, or 3 osteoarthritis according to the Kellgren and Lawrence grading scale were enrolled in the study. One group of patients was treated using three intra-articular applications of PRP, and the second group of patients was given three injections of hyaluronic acid. Outcome measures included the Western Ontario and McMaster Universities Osteoarthritis Index and the 11-point pain intensity Numeric Rating Scale.
On average, a 4.5-fold increase in platelet concentration was obtained in the PRP group. No severe adverse events were observed. Statistically significantly better results in the Western Ontario and McMaster Universities Osteoarthritis Index and Numeric Rating Scale scores were recorded in a group of patients who received PRP injections after a 3- and 6-mo follow-up.
Our preliminary findings support the application of autologous PRP as an effective and safe method in the treatment of the initial stages of knee osteoarthritis. Further studies are needed to confirm these results and to investigate the persistence of the beneficial effects observed.
Three-dimensional scaffolds like hydrogels can be used for cell and drug delivery and have become a major research focus in tissue engineering. Presently, we investigated the regenerative potency of platelet-rich plasma (PRP) combined with a chondrocyte/hydrogel composite scaffold in the repair of articular cartilage defects using a rabbit model. Primary isolated joint chondrocytes from the trachlear groove of rabbit were cultured in hydrogels as follows; hydrogel (2900 Pa or 5900 Pa)+chondrocytes and hydrogel+chondrocytes+PRP for in vitro analysis and in vivo implantation. The 5900 Pa hydrogel markedly increased cellular viability and development in a time-dependent manner. Furthermore, the hydrogels attenuated the expression of SOX-9, aggrecan, and type II collagen. PRP-containing hydrogels produced an immediate increase in mRNA levels of cannabinoid receptor (CB)1 and CB2, compared with control and PRP-free hydrogels. Osteochondral defects were enhanced recovery with formation of cartilage and perichondrium in the 5900 Pa hydrogel+chondrocytes+PRP. Hydrogel may provide a suitable environment for proliferation and maturation of joint chondrocytes in relation to the gelation density and bioactive sources like PRP resulting in improvement for cartilage regeneration.
The refinement of the use of platelet-derived growth factors that has occurred over the last decade has led to a broadening of the fields of use, in particular for new treatments in orthopaedics aimed at improving tissue regeneration.
Twenty-seven patients, aged between 18 and 81 years, with a diagnosis of degenerative joint disease lasting for more than 1 year were treated. The patients were divided into two groups, one with arthritis of the knee, the other with degenerative cartilage disease of the knee. Both groups were treated with a therapeutic protocol consisting of a cycle of three infiltrations of platelet-rich plasma at weekly intervals.The extemporaneous preparation was made from a sample of about 8 mL of venous whole blood collected into a specific Fibrin Polymer 2 test-tube from RegenLab(®) and centrifuged before addition of calcium gluconate.During the initial pre-treatment evaluation, specific questionnaires were administered, the Numerical Rating Scale (NRS) for subjective measurement of pain and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC); these assessments were repeated 7 days after the end of the treatment and at 6 months during the follow-up.
The parameters evaluated improved in both groups after treatment and there was a further improvement after 6 months of follow-up; furthermore, there was a substantial decrease in pain right after the first infiltration.
The patients were treated on an out-patient basis by a specifically created multidisciplinary team comprising a transfusion specialist, an orthopaedist and a radiologist, who collaborate in a symbiotic manner. The out-patient protocol exploits the regenerative properties of platelet-rich plasma, which is a low cost treatment; in practice, a diagnostic-therapeutic programme of lower intensity, but of high technical and professional quality is created. The strategy also reduces both the number of hospital services and the pharmacological support required, thereby optimising the use of health care resources.
Several cell-based therapeutic options to treat musculoskeletal injuries in horses are commercially available. The current literature supports the use of cell-based therapies to treat equine musculoskeletal injuries. Researchers continue to search for more effective cell-based therapies to provide practitioners with optimal treatment tools for musculoskeletal injuries in horses. Cell-based therapies require specialized facilities and technical competencies that might not be available or economically justifiable in many private practices. This review provides a summary of current commercially available cell-based therapeutic products for equine applications, their similarities and differences, and current objective data relating to their clinical efficacy.
Autologous biologic therapies such as platelet-rich plasma and autologous conditioned serum are in widespread clinical use to treat musculoskeletal pathology in horses. These substances exert a therapeutic effect through the provision of either anabolic or anti-catabolic factors, or a combination of both. This article discusses the history, experimental and clinical literature, and currently accepted preparation and usage strategies for both platelet-rich plasma and autologous conditioned serum.
The aim of our study is to compare the efficacy of platelet-rich plasma (PRP) and viscosupplementation (hyaluronic acid [HA]) intra-articular injections for the treatment of knee cartilage degenerative lesions and osteoarthritis (OA).
The study involved 150 patients affected by cartilage degenerative lesions and early and severe OA. Fifty symptomatic patients were treated with 3 autologous PRP intra-articular injections and were evaluated prospectively at enrollment and at 2- and 6-month follow-up. The results obtained were compared with 2 homogeneous groups of patients treated with HA injections. One group was treated with injections of high-molecular weight HA; the other group was treated with low-molecular weight (LW) HA. International Knee Documentation Committee and EQ VAS scores were used for clinical evaluation; adverse events and patient satisfaction were also recorded.
At 2 months' follow-up, the PRP and LW HA groups showed a similar improvement, with higher results compared with the high-molecular weight HA group (P < .005). At 6 months' follow-up, better results were observed in the PRP group (P < .005). PRP and LW HA treatments offered similar results in patients aged over 50 years and in the treatment of advanced OA. PRP showed a better performance compared with HA in younger patients affected by cartilage lesions or early OA.
Autologous PRP injections showed more and longer efficacy than HA injections in reducing pain and symptoms and recovering articular function. Better results were achieved in younger and more active patients with a low degree of cartilage degeneration, whereas a worse outcome was obtained in more degenerated joints and in older patients, in whom results similar to those of viscosupplementation have been observed.
Level II, prospective comparative study.
Medications are frequently employed to treat intra-articular (IA) problems in the performance horse. Actual usage of the different IA medications in horses is not available.
To determine the most common usage of these medications, members of the American Association of Equine Practitioners (AAEP) were surveyed.
An email link to an online survey was electronically sent to 6305 AAEP members and the responses tabulated and analysed with a logistic regression model.
A total of 831 survey responses were submitted and tabulated. Eighty per cent of the respondents indicated that they see 100% equine cases in their practice. The majority of respondents (77%) use triamcinolone acetonide (TA) to treat high motion joints and 73% use methylprednisolone acetate (MPA) to treat low motion joints. Veterinarians treating the Western performance and Sport horse were significantly more likely to use TA in high motion joints compared to MPA (P = 0.0201 and P<0.0001, respectively). Triamcinolone acetonide use compared to MPA in high motion joints by racehorse veterinarians was significantly lower compared to other veterinarians (P<0.0001). Polysulphated glycosaminoglycan (Adequan) and hyaluronate sodium (Legend) were the most commonly used disease modifying products (63 and 57% of respondents, respectively). Sport horse practitioners were significantly more likely than race or show horse veterinarians to utilise IRAP products (P = 0.0035 and P = 0.04, respectively). Respondents who had been in practice for more than 10 years were significantly less likely to use antimicrobials in their joint injections compared to those in practice for less than 10 years (P<0.0001).
Significant differences existed in usage of medications related to primary discipline treated and years practicing.
The results of this study aid in defining the current usage of different joint therapy medications within equine practice. This knowledge can guide further research as well as education.
Osteoarthritis (OA) is one of the most prevalent and debilitating conditions affecting the horse. Autologous conditioned serum (ACS), commercially available as IRAP and IRAP II, is a recently developed treatment for OA in which plasma is prepared from venous blood by incubation with glass beads for 24 h. This product has been shown to increase anti-inflammatory cytokines and growth factors in human blood. However, data for equine ACS preparations are lacking.
To characterise the protein profiles produced by commercially available ACS systems in equine blood.
Blood was drawn from 5 horses into 6 groups: red top vacutainer (control), IRAP and IRAP II, with and without heparin. Samples were collected 1 or 24 h post draw and analysed for IL-1ra, IL-10, IGF-1, TGF-β, TNF-α and IL-1β using ELISAs.
Twenty-four hour IRAP and IRAP II samples contained significantly higher levels of all cytokines relative to 1 h serum controls. At 24 h, IRAP II contained significantly higher levels of IL-1ra and IRAP contained significantly higher levels of TNF-α, compared to 24 h controls. In addition, TGF-β, IL-10 and IL-1β in IRAP and IRAP II sera were similar to 24 h serum controls. The addition of heparin significantly reduced levels of IGF-1, TNF-α and TGF-β, and significantly elevated levels of IL-1ra.
The cytokine profile that IRAP II produced is modestly better than IRAP. Incubation of whole blood in glass tubes stimulated cytokine synthesis, although not as efficiently as IRAP II.
Although high levels of IL-1ra were found in ACS, elevation of other factors suggests these cytokines play a previously understated role in clinical improvements. Because ACS has been shown to alleviate clinical symptoms of OA, the present study suggests that factors other than IL-1ra alone might be involved in its clinical efficacy. Species-dependent elevations of cytokines warrant further investigation and optimisation of the systems appears to be necessary based on the differences between human and equine blood.
This article aims to provide a comprehensive review of the current literature that pertains to the therapeutic use of autologous platelet-rich plasma (PRP). The basic science literature regarding the role of growth factors in mediating the healing process and the laboratory data from in vitro and in vivo studies that evaluated PRP are reviewed. Subsequently, the current evidence regarding PRP efficacy from animal models, human surgical studies, and human clinical studies is presented. A critical analysis of the literature follows, and the article concludes with the authors' perspectives on the state of PRP as a potentially efficacious bioregenerative treatment option for musculoskeletal and sports medicine applications. The relevant articles in this review were obtained via PubMed literature searches for PRP publications that pertain to musculoskeletal and sports medicine conditions. This article is not intended to be a formal meta-analysis.
The permanent filler polyacrylamide hydrogel (Aquamid) has been used for soft-tissue augmentation for more than 16 years. To evaluate the safety and efficacy of the material, the manufacturer initiated in 2001 a prospective clinical trial with a follow-up of 5 years. This represents one of the longest running studies on currently used fillers.
Two hundred fifty-one patients were enrolled in a noncomparative, prospective study and followed at 15 sites in Europe. The follow-up rates were 228 (90.8 percent), 101 (40.2 percent), 81 (32.3 percent), and 116 (46.2 percent) for the 12-, 24-, 36/48-, and 60-month follow-up periods. Patients received an average of 4.3 ml of Aquamid during an average of 2.4 injection sessions. Preferred areas were the nasolabial folds (37 percent) and the lips (28 percent). Study parameters were cosmetic outcome, blood analysis, and recording of local or generalized symptoms, including adverse reactions.
Aesthetic outcome was rated as "very good" or "good" by 96.5 percent of patients and by 96.0 percent of investigators at final available follow-up. During the entire study period, a total of 53 adverse events and two serious adverse events were classified as treatment related. Thirteen adverse events were gel indurations and four cases of infection were seen. All had been resolved within the study period.
The study showed a very good aesthetic outcome and few adverse events after injection of polyacrylamide gel for soft-tissue augmentation. Correct application was essential to ensure a favorable result. For patients who desire facial soft-tissue augmentation, Aquamid is an excellent alternative to surgery.
The repair process of tendon injuries, which are common in both human and equine athletes, is slow and the quality of the repair tissue is often inferior to the original tendon tissue, which frequently leads to re-injury. The relatively poor vascularization of tendons is considered to be one of the reasons for their limited healing potential. Recently, platelet-rich plasma (PRP), an autologous concentrate of platelets, rich in growth factors, has been shown to enhance the repair process of injured tendons. This effect has been ascribed to the high levels of growth factors in PRP, several of which are known to be involved in tendon repair. Among many other growth factors, the vascular endothelial growth factor, a powerful stimulator of angiogenesis, is abundantly present in PRP, suggesting that enhancement of neovascularization might be one of the working mechanisms. In this study, the effect of PRP on neovascularization was studied in experimentally induced tendon injuries using color Doppler ultrasonography and immunological staining of Factor VIII. PRP induced significantly more neovascularization than the placebo treatment until at least 23 weeks after treatment, as detected by both Doppler ultrasonography and Factor VIII staining. Neovascularization might be one of the explanations for the long-lasting effect of a single intratendinous treatment with PRP.
To evaluate the effect of autologous platelet rich plasma (PRP) combined with microfractures on the treatment of chondral defects. The hypothesis of the study was that PRP can enhance cartilage repair after microfractures.
A chronic full-thickness chondral lesion of the medial femoral condyle was performed in 15 sheep. Animals were divided into three groups, according to treatment: group 1: microfractures; group 2: microfractures+PRP and fibrin glue gel; group 3: microfractures+liquid-PRP injection. Animals were sacrificed at 6 months after treatment. Macroscopic appearance was evaluated according to International Cartilage Repair Society (ICRS) score; cartilage stiffness was analyzed with an electromechanical indenter (Artscan 200); histological appearance was scored according to a modified O'Driscoll score. Comparison between groups for each outcome was performed with Kruskal-Wallis test, and Tukey's test for pairwise comparisons.
Macroscopic ICRS score of group 2 was significantly better than those of the other groups, and score of group 1 was significantly lower than those of the other groups. Scores of group 1 and 3 were significantly lower than that of normal cartilage. Mean cartilage stiffness of groups 1 and 3 was significantly lower than that of normal cartilage. Histological total scores of group 2 and 3 were significantly better than that of group 1.
PRP showed a positive effect on cartilage repair and restoration after microfractures. The procedure was more effective when PRP was used as a gel in comparison with liquid intra-articular injection. Histological analysis revealed that none of experimental treatments produced hyaline cartilage.
Stem cells have received much attention in recent times because of their potential to improve healing of othropaedic problems. This manuscript presents the genesis, issues and current state of stem cell treatment in equine medicine. Current literature supports the use of mesenchymal stem cells (MSCs) for treatment of orthopaedic problems.
Osteoarthritis (OA) is a disease of the entire joint. Different treatment strategies for OA have been proposed and tested clinically without the desired efficacy. One reason for the scarcity of current chondroprotective agents may be the insufficient understanding of the patho-physiology of the joint and whether the joint damage is reversible or irreversible. In this review, we compile emerging data on cellular and pathological aspects of OA, and ask whether these data could give clue to when cartilage degradation is reversible and whether a point-of-no-return exists. We highlight different stages of OA, and speculate whether different intervention strategies (e.g. DMOAD vs. SMOADs) may only be efficacious at distinct stages of OA.
The purpose of this study was the assessment of clinical, biochemical, and histologic effects of intraarticular administered adipose-derived stromal vascular fraction or bone marrow-derived mesenchymal stem cells for treatment of osteoarthritis. Osteoarthritis was induced arthroscopically in the middle carpal joint of all horses, the contralateral joint being sham-operated. All horses received treatment on Day 14. Eight horses received placebo treatment and eight horses received adipose-derived stromal vascular fraction in their osteoarthritis-affected joint. The final eight horses were treated the in osteoarthritis-affected joint with bone marrow-derived mesenchymal stem cells. Evaluations included clinical, radiographic, synovial fluid analysis, gross, histologic, histochemical, and biochemical evaluations. No adverse treatment-related events were observed. The model induced a significant change in all but two parameters, no significant treatment effects were demonstrated, with the exception of improvement in synovial fluid effusion PGE2 levels with bone marrow-derived mesenchymal stem cells when compared to placebo. A greater improvement was seen with bone marrow-derived mesenchymal stem cells when compared to adipose-derived stromal vascular fraction and placebo treatment. Overall, the findings of this study were not significant enough to recommend the use of stem cells for the treatment of osteoarthritis represented in this model.
alpha-Granules are essential to normal platelet activity. These unusual secretory granules derive their cargo from both regulated secretory and endocytotic pathways in megakaryocytes. Rare, inheritable defects of alpha-granule formation in mice and man have enabled identification of proteins that mediate cargo trafficking and alpha-granule formation. In platelets, alpha-granules fuse with the plasma membrane upon activation, releasing their cargo and increasing platelet surface area. The mechanisms that control alpha-granule membrane fusion have begun to be elucidated at the molecular level. SNAREs and SNARE accessory proteins that control alpha-granule secretion have been identified. Proteomic studies demonstrate that hundreds of bioactive proteins are released from alpha-granules. This breadth of proteins implies a versatile functionality. While initially known primarily for their participation in thrombosis and hemostasis, the role of alpha-granules in inflammation, atherosclerosis, antimicrobial host defense, wound healing, angiogenesis, and malignancy has become increasingly appreciated as the function of platelets in the pathophysiology of these processes has been defined. This review will consider the formation, release, and physiologic roles of alpha-granules with special emphasis on work performed over the last decade.
Platelet-rich plasma (PRP) has generated substantial interest for tendon and ligament regeneration because of the high concentrations of growth factors in platelet alpha-granules. This study compared the temporal release of growth factors from bone marrow aspirate (BMA), PRP, and lyophilized platelet product (PP), and measured their effects on tendon and ligament gene expression. Blood and BMA were collected and processed to yield PRP and plasma. Flexor digitorum superficialis tendon (FDS) and suspensory ligament (SL) explants were cultured in 10% plasma in DMEM (control), BMA, PRP, or PP. TGF-beta1 and PDGF-BB concentrations were determined at 0, 24, and 96 h of culture using ELISA. Quantitative RT-PCR for collagen types I and III (COL1A1, COL3A1), cartilage oligomeric matrix protein (COMP), decorin, and matrix metalloproteinases-3 and 13 (MMP-3, MMP-13) was performed. TGF-beta1 and PDGF-BB concentrations were highest in PRP and PP. Growth factor quantity was unchanged in BMA, increased in PRP, and decreased in PP over 4 days. TGF-beta1 and platelet concentrations were positively correlated. Lyophilized PP and PRP resulted in increased COL1A1:COL3A1 ratio, increased COMP, and decreased MMP-13 expression. BMA resulted in decreased COMP and increased MMP-3 and MMP-13 gene expression. Platelet concentration was positively correlated with COL1A1, ratio of COL1A1:COL3A1, and COMP, and negatively correlated with COL3A1, MMP-13, and MMP-3. White blood cell concentration was positively correlated with COL3A1, MMP3, and MMP13, and negatively correlated with a ratio of COL1A1:COL3A1, COMP, and decorin. These findings support further in vivo investigation of PRP and PP for treatment of tendonitis and desmitis.
An in vitro model is described that allows evaluation of the activity of polysulphated polysaccharides on proteoglycan biosynthesis by articular chondrocytes in culture. Proteoglycan biosynthesis is monitored after brief exposure of the cells to sodium iodoacetate, which induces a substantial decrease in overall proteoglycan biosynthesis, leading to a general reduction of proteoglycan content in the culture medium and in the cartilage-like extracellular matrix. Using this in vitro model, pentosan polysulphate (SP 54) and a high molecular weight analogous (SR 24751) were shown to improve proteoglycan incorporation into the extracellular matrix. In contrast, Arteparon and a low molecular weight fraction of SP 54 (SR 25491) were inactive.
Medial meniscectomy was undertaken in adult merino sheep and after 16 weeks exercise each group was administered five weekly intra-articular injections of saline, pentosan polysulphate (PPS), hyaluronic acid (HA) or a combination of PPS + HA. Gait analysis and x-rays were undertaken before and after drug treatment. At sacrifice (26 weeks), joints were examined for gross pathological and histochemical changes. Only the PPS-treated group showed an improvement in gait, with low radiological and histology scores. The HA-treated group showed similar but less significant changes to these parameters.
Joint disease in horses and in humans is a significant social and economic problem and continued research and improvements in therapeutics are needed. Because horses have naturally occurring osteoarthritis that is similar to that of humans, the horse was chosen as a species to investigate gene transfer as a potential therapeutic modality for the treatment of osteoarthritis. Using an established model of equine osteoarthritis, the therapeutic effects resulting from overexpression the equine interleukin-1 receptor antagonist gene sequence through adenoviral mediated gene transfer was investigated. The results of the current study showed intraarticular expression of interleukin-1 receptor antagonist to have favorable effects such as an approximately 28 day upregulation of interleukin-1 receptor antagonist protein expression, significant improvement in clinical parameters of pain and disease activity, and beneficial effects in histologic parameters measured from synovial membrane and articular cartilage when compared with nontransduced joints. Based on the significant improvements seen in this work gene transfer of interleukin-1 receptor antagonist is a practical treatment modality for the equine patient and also offers future promise for human patients.
Osteoarthritis in horses and in humans is a significant social and economic problem and continued research and improvements in therapy are needed. Because horses have naturally occurring osteoarthritis, which is similar to that of humans, the horse was chosen as a species with which to investigate gene transfer as a potential therapeutic modality for the clinical treatment of osteoarthritis. Using an established model of equine osteoarthritis that mimics clinical osteoarthritis, the therapeutic effects resulting from intra-articular overexpression of the equine interleukin-1 receptor antagonist gene through adenoviral-mediated gene transfer were investigated. In vivo delivery of the equine IL-IRa gene led to elevated intra-articular expression of interleukin-1 receptor antagonist for approximately 28 days, resulting in significant improvement in clinical parameters of pain and disease activity, preservation of articular cartilage, and beneficial effects on the histologic parameters of synovial membrane and articular cartilage. Based on these findings, gene transfer of interleukin-1 receptor antagonist is an attractive treatment modality for the equine patient and also offers future promise for human patients with osteoarthritis.
Effects of anti-arthritic drugs on proteoglycan synthesis by equine cartilage. J. vet. Pharmacol. Therap.25, 289–298.
The concentration–effect relationships of phenylbutazone, indomethacin, betamethasone, pentosan polysulphate (PPS) and polysulphated glycosaminoglycan (PSGAG), on proteoglycan synthesis by equine cultured chondrocytes grown in monolayers, and articular cartilage explants were measured. The effect of PSGAG on interleukin-1β induced suppression of proteogycan synthesis was also investigated. Proteoglycan synthesis was measured by scintillation assay of radiolabelled sulphate (35SO4) incorporation. Polysulphated glycosaminoglycan and PPS stimulated proteoglycan synthesis in chondrocyte monolayers in a concentration-related manner with maximal effects being achieved at a concentration of 10 μg/mL. Polysulphated glycosaminoglycan reversed the concentration-related suppression of proteoglycan synthesis induced by interleukin-1β. Neither PSGAG nor PPS exerted significant effects on radiolabel incorporation in cartilage explants. Betamethasone suppressed proteoglycan synthesis by both chondrocytes and explants at high concentrations (0.1–100 μg/mL), but the effect was not concentration-related. At low concentrations (0.001–0.05 μg/mL) betamethasone neither increased nor decreased proteoglycan synthesis. Phenylbutazone and indomethacin increased radiolabel incorporation in chondrocyte cultures but not in cartilage explants at low (0.1, 1 and 10 μg/mL), but not at high (20 and 100 μg/mL) concentrations. These findings may be relevant to the clinical use of these drugs in the treatment of equine disease.
Autologous platelet-rich plasma is a source of platelet-derived growth factor (PDGF) and transforming growth factor beta (TGF-beta), both important in accelerating hard and soft tissue maturation. This article describes a two-step centrifugation method to sequester and concentrate platelets to a level four to eight times baseline whole blood values. The technique produces concentrations of PDGF-AB above 500% and TGF-beta1 greater than 800%. Flow cytometry measuring p-selectin expression shows that the platelets remain quiescent throughout the procedure, maintaining their integrity and viability, with no inadvertent activation.
Nonhealing wounds of the lower equine limb represent a challenging model. The platelet is a natural source of a myriad of growth factors and cytokines that promote wound healing. This study evaluates the potential of platelet derived factors to enhance wound healing in the lower equine limb. Platelets were isolated from horse blood and activated with thrombin, a process known to induce growth factor release. This produced a platelet gel composed of platelet-rich plasma (PRP). To test this all-natural wound healant, 2.5-cm(2) full thickness cutaneous wounds were created below the knee and hock of a thoroughbred horse. Wounds were treated with PRP gel or left untreated. Sequential wound biopsies collected at Days 7, 36, and 79 postwounding permitted comparison of the temporal expression of differentiation markers and wound repair. To test the hypothesis that wounds treated with PRP gel exhibit more rapid epithelial differentiation and enhanced organization of dermal collagen compared to controls, tissues were stained for cytokeratin 10, a suprabasal differentiation marker, and the reestablishment of collagen was evaluated by trichrome staining. PRP gel-treated wounds at Day 7 expressed intense cytokeratin 10 staining near the wound junction in suprabasal epidermal layers, while staining in control tissues was less intense and restricted to apical epidermal layers distal to the wound junction. By Day 79, the staining was equal in both groups. However, PRP gel-treated wounds at Day 79 contained abundant, dense collagen bundles oriented parallel to each other and to the overlying epithelium, whereas control tissues contained fewer collagen fibers that were oriented randomly. Thus, treatment of wounds with PRP gel induced accelerated epithelial differentiation and produced tissue with organized, interlocking collagen bundles. This study reveals that this novel all-natural wound healant induced wound repair in injuries previously deemed untreatable.
There is little published information available describing clinical signs, arthroscopic findings and prognosis of meniscal injuries in horses.
To evaluate the effect on the outcome not only of the arthroscopic findings and treatment, but also of the clinical and radiographic signs in these horses.
The following were recorded for each case: the meniscal injury, graded according to severity; clinical and radiographic findings prior to surgery; any concurrent injury in the joint seen at arthroscopy. The effect of these factors and the grade of injury on the outcome were analysed using Fisher's exact test or Chi-square analysis. Only horses whose meniscal injury was judged to be the primary cause of lameness were included in the series.
A series of 80 meniscal injuries were diagnosed and treated arthroscopically by the authors at the Liphook Equine Hospital and 47% of horses returned to full use. Statistically, poor prognosis was associated with increasing severity of the meniscal injury, the presence of concurrent articular cartilage lesions and radiographic abnormalities in the joint. Arthroscopic treatment of many lesions was limited by the inaccessibility of parts of the femorotibial joint.
Further work is required to improve and evaluate arthroscopic techniques for the treatment of these injuries.