Intraarticular Hyaluronic Acid Supplementation in the Horse: The Role of Molecular Weight

Osteoarthritis (OA) is a primary cause of lameness and loss of use in the equine industry. Treatment of affected joints is aimed at reducing synovial inflammation, halting the inflammatory cascade within the joint, minimizing articular cartilage breakdown, and reducing pain. Treatments of affected joints commonly used by equine practitioners include intraarticular hyaluronic acid (HA). Consideration of the average molecular weight (MW) and concentration of the HA product may dictate what product is selected. The purpose of this review is to briefly summarize for the practitioner the scientific data available evaluating the significance of hyaluronic acid molecular weight with regard to efficacy and duration of action in horses when administered intraarticularly. In summary, the beneficial effects of HA supplementation are attributable to the anti-inflammatory effects, improvement in viscoelastic properties of the synovial fluid, and interaction with the synovial membrane affecting pain transmission and joint metabolism. As this review shows, the importance of HA molecular weight with regard to efficacy of treating synovial inflammation and osteoarthritis has not been clearly demonstrated, and results are conflicting. Until there is a full understanding of the mechanism of action of HA within the joint, the veterinarian's choice of HA products will continue to be based on clinical preference. Additional studies directly comparing products of different HA average molecular weights and formulations in a controlled in vivo setting are needed to assess the importance of HA molecular weight in treating joint disease.     

Non-steroidal anti-inflammatory drugs in equine orthopaedics

Orthopaedic disorders are commonly encountered in equine veterinary medicine, and non-steroidal anti-inflammatory drugs (NSAIDs) play an important role in the management of many equine orthopaedic disorders. There are multiple NSAIDs available for use in horses, including both non-selective and selective NSAIDS, and the body of literature evaluating the efficacy of these medications, their effects on normal and inflamed musculoskeletal tissues, and their side effects is broad. This review aims to summarise the current literature on the use of NSAIDs for equine orthopaedic disorders and examines new and future avenues for the management of inflammation in equine orthopaedics.     

Intra-articular drug delivery: the challenge to extend drug residence time within the joint

The rationale behind developing sustained release microsphere formulations of non-steroidal anti-inflammatory drugs (NSAIDs) administered via the intra-articular (IA) route is to minimise the systemic bioavailability and attendant side-effects associated with oral drug administration. Overall dose is reduced whilst therapeutic benefit within the joint is maintained. The potential benefits of IA therapy for osteoarthritis (OA) are not achieved using currently available medications and delivery vehicles due to the rapid clearance of therapeutic substances from the synovial space. There is a need for sustained release delivery systems if the potential of IA drug administration is to be realised. Rationally designed microspheres taken up by synovial macrophages offer a strategy to sustain drug delivery within the joint, and to deliver NSAIDs directly to pivotal inflammatory cells. The efficacy of microsphere candidates may be evaluated in large animal models of OA. The principles of IA microsphere drug delivery may also be applicable to other classes of drugs.     

The use of nutraceuticals for osteoarthritis in horses.

In horses, lameness is often attributable to some degree of osteoarthritis (OA), a complex disease process that is highlighted by eventual degradation of articular cartilage. Conventional therapies for OA in horses are designed to relieve pain and discomfort and often include pharmacologic intervention with nonsteroidal anti-inflammatory drugs or intra-articular steroids. Oral administration of nutraceutical products to the horse is common and easy and is perceived to be a benign treatment for OA in horses. The main goal for use of nutraceuticals is to use them in OA cases to attempt to lower the dose of other drugs that are more problematic while potentially preventing further degradation (disease or structure modifying). This article attempts to define a nutraceutical, identifies areas that need to be considered when these products are used, and describes the known scientific effects of the most common compounds contained in currently available equine nutraceuticals.     

Extracorporeal shock wave therapy for treatment of osteoarthritis in the horse: clinical applications.

Veterinarians have begun using extracorporeal shock wave therapy (ESWT) for treatment of osteoarthritis (OA) in horses, although relatively little information has been published about its efficacy or mechanism of action. As a clinician, it can be difficult to know if and when ESWT should be recommended. Case studies in which ESWT is used to treat advanced OA in horses are discussed. ESWTseems to be a valuable adjunct for management of equine OA. It is the purpose of this article to discuss indications and techniques as well as to share clinical experiences using ESWT in the treatment of OA in the horse.     

Evaluation of the inflammatory response to two intra-articular hyaluronic acid formulations in normal equine joints

Intra-articular (IA) hyaluronic acid (HA) is commonly used to treat equine arthritis. Inflammatory response or “joint flare” is a recognized potential side effect. However, the incidence and severity of inflammation following IA HA injection in horses is not well documented. This study compared the effects of two IA HA formulations of different molecular weight (MW) and a saline control on clinical signs and synovial fluid markers of inflammation in normal equine joints. Eight adult horses each had three healthy fetlock joints randomly assigned to treatment with either 1.4 mega Dalton HA, 0.8 mega Dalton HA or saline control once weekly for three weeks. Clinical evaluation and synovial fluid analysis were performed by blinded assessors. Outcomes of interest were lameness score, joint effusion score and synovial fluid white cell count and differential, total protein, viscosity and serum amyloid A. Joints injected with HA developed significant mild-to-moderate inflammatory responses often associated with lameness and joint effusion compared with saline control joints. The higher MW HA formulation elicited a significantly greater inflammatory response than the lower MW HA after the first injection. In HA injected joints, viscosity remained poor for the entire study. Both IA HA formulations in this study induced an inflammatory response in healthy equine joints. This may have implications for the use of HA in equine joints. The findings in this study are limited to the two HA formulations used. Further investigation of different HA formulations and the use of HA in normal and arthritic equine joints is warranted.     

Sparing the gut: COX-2 inhibitors herald a new era for treatment of horses with surgical colic

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to manage a wide variety of conditions in horses, including management of colic. Flunixin meglumine is by far the most commonly used drug in the control of colic pain and inflammation and has become a go-to for not only veterinarians but also horse-owners and nonmedical equine professionals. NSAID use, however, has always been controversial in critical cases due to a high risk of adverse effects associated with their potent cyclo-oxygenase (COX) inhibition. There are two important COX isoenzymes: COX-1 is generally beneficial for normal renal and gastrointestinal functions and COX-2 is associated with the pain and inflammation of disease. Newer selective NSAIDs can target COX-2-driven pathology while sparing important COX-1-driven physiology, which is of critical importance in horses with severe gastrointestinal disease. Emerging research suggests that firocoxib, a COX-2-selective NSAID labelled for use in horses, may be preferable for use in colic cases in spite of the decades-long dogma that flunixin saves lives.     

Nonsteroidal anti-inflammatory drugs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are substances other than steroids that inhibit a component of the inflammatory cascade. This article is dedicated to those substances which specifically inhibit cyclooxygenase. NSAIDs are used extensively in the veterinary field. This article discusses their pharmacologic mechanism of action, indications, and toxicity. The two isoforms of cyclooxygenase (COX-1 and COX-2) are reviewed along with the newer NSAID which are more effective and less toxic due to more specific COX-2 inhibition. Specific effects on soft tissue, bone, cartilage, and synovium are summarized. Pain modulation is extensively reviewed as well as the antiendotoxic and antithrombotic uses.     

Analgesia.

Critical to reducing patient morbidity as well as heightened ethical awareness, alleviation of pain in animals has become integral to medical case management and surgical procedures. Pharmacotherapy is directed at peripheral nociceptors, primary and secondary spinal neurons, and pain-processing areas in the CNS. Accordingly, three primary pharmacologic strategies have evolved: drugs that bind to and activate opioid receptors, drugs that bind to and activate alpha 2 receptors, and drugs that reduce de novo prostaglandin synthesis. In horses, the two predominant types of pain encountered are musculoskeletal and visceral pain. Several factors must be considered when devising a therapeutic strategy, including the etiology of the painful event, desired duration of therapy (acute vs chronic), desire for sedation, and potential side effects and toxicity. Opioids and alpha 2 agonists are particularly effective for visceral pain associated with colic. Butorphanol remains the only commercially available opioid and provides superior visceral analgesia compared with pentazocine or flunixin meglumine but not compared with the alpha 2 agonists. The behavioral changes such the sedative effects of alpha 2 agonists and the increased locomotion and CNS excitability seen with some opioids are important considerations when these agents are used as analgesics. NSAIDs may be considered for visceral pain therapy also, especially pain associated with an inflammatory component or endotoxemia. In particular, flunixin meglumine and ketoprofen provide prolonged analgesia and suppress the effects of endotoxin. Long-term therapy of musculoskeletal diseases usually necessitates chronic NSAID use. Although many NSAIDs are now available in approved equine formulations, there remain some important differences among NSAIDs for the practitioner to consider when choosing an analgesic. NSAIDs differ in their ability to ameliorate pyrexia, affect platelet function, alleviate pain, and reduce inflammation. For ease of administration, those available for oral use include phenylbutazone, meclofenamic acid, flunixin meglumine, and naproxen. All are potentially ulcerogenic, and poor tolerance to one may necessitate switching to another with a better toleration profile or to drug from a different analgesic class.     

Osteoarthritis in the cat: 2. how should it be managed and treated?

PRACTICAL RELEVANCE: Osteoarthritis (OA) is very common in the cat and in many cases is associated with significant long-term pain, which limits mobility and activity, and severely compromises the animal's quality of life. CLINICAL CHALLENGES: The treatment of chronic arthritic pain is a major challenge and many analgesic drugs used in other species are not licensed, not available or not tested for use in the cat. Many older cats with painful OA have some degree of chronic kidney disease (CKD) and many clinicians are reluctant to use non-steroidal anti-inflammatory drugs (NSAIDs) in these animals because of the potential for nephrotoxicity. EVIDENCE BASE: There are several publications that show that meloxicam is an effective NSAID for the cat and can be used long-term. It is easy to administer and there is published evidence that meloxicam can actually slow the progression of CKD in this species. Many other drugs are used to treat chronic pain in the cat but there is no documented evidence of their efficacy in OA. Unlike the dog, there is limited evidence for the effectiveness of omega-3 fatty acid-rich diets in managing feline OA and further work is required. There is no published data as yet for the usefulness or otherwise of nutraceuticals (glucosamine and chondroitin) in managing feline OA; studies in the authors' clinic suggest some pain-relieving effect. Research into environmental enrichment as a way of improving quality of life in cats with painful OA is lacking, but it is an approach worth using where possible. Modifications to the environment (eg, provision of comfortable bedding and ramps) are also important.     

Clinical pharmacology and therapeutic uses of non-steroidal anti-inflammatory drugs in the horse

Weak organic acids possessing anti-inflammatory, analgesic and antipyretic properties--commonly known as aspirin-like drugs--have been used in equine medicine for almost 100 years. These non-steroidal anti-inflammatory drugs (NSAIDs) may be classified chemically into two groups; the enolic acids such as phenylbutazone and carboxylic acids like flunixin, meclofenamate and naproxen. All NSAIDs have similar and possibly identical modes of action accounting for both their therapeutic and their toxic effects. They block some part of the cyclo-oxygenase enzyme pathway and thereby suppress the synthesis of several chemical mediators of inflammation, collectively known as eicosanoids. The available evidence indicates that some of the newer NSAIDs have a reasonable safety margin but further studies are required. The toxicity of phenylbutazone in the horse has been investigated very thoroughly in recent years and it has been shown to cause renotoxicity and, most significantly, ulceration of the gastrointestinal tract when relatively high doses are administered. Several factors may predispose towards phenylbutazone toxicity in the horse, including breed and age, but high dosage is considered to be particularly important. The absorption into, and fate within, the body of NSAIDs are considered and particular attention is drawn to the ways in which these pharmacokinetic properties relate to the drugs' toxicity and clinical efficacy. In reviewing current knowledge of the clinical pharmacology of this important group of drugs, it is hoped to provide the clinician with a rational, scientific basis for their safe and effective use in equine practice.     

Applications of equine models of acute inflammation. The Ciba-Geigy Prize for Research in Animal Health

The development of reproducible models of acute inflammation in which inflammatory heat is easily quantified and from which inflammatory exudate is readily harvested has facilitated studies in the horse of the actions of steroids and non-steroidal anti-inflammatory drugs (NSAIDS). Blockade of the synthesis of eicosanoids and suppression of inflammatory heat by clinical dose rates of NSAIDS suggests a causal link between the two events and provides further evidence for a role of these compounds in acute equine inflammation. The tendency for enolic and carboxylic acids NSAIDS to accumulate in inflammatory exudate may account for the duration of action of these compounds in inhibiting exudate eicosanoid synthesis and the data confirm clinical experiences with these drugs. A novel NSAID which inhibits both cyclo-oxygenase and lipoxygenase pathways of arachidonic acid metabolism, BW540C, and two anti-inflammatory steroids, betamethasone and dexamethasone, have been evaluated in the models of equine inflammation with some interesting and unexpected findings. This paper emphasises the interrelationships between the inflammatory process and the actions and fate of anti-inflammatory drugs.     

Application and indications of magnetic resonance imaging and computed tomography of the equine head

The equine head is an anatomically highly complex area affected by a range of disorders, making the diagnosis of head conditions challenging. Imaging techniques play a crucial role in the diagnostic work-up of head disorders. Tomographic imaging methods, such as computed tomography (CT) and magnetic resonance imaging (MRI) are particularly useful in avoiding problems associated with superimposition of multiple structures in this highly complex region. Both techniques are becoming more widely available in equine medicine. However, the choice between CT and MRI for imaging the equine head is not always straightforward. Each modality has advantages and disadvantages in terms of practicality, costs and diagnostic value for particular problems. The aim of this review is to describe the application of CT and MRI for imaging the equine head and to provide a practical guide for their use in different anatomical structures and clinical indications. This should allow the equine practitioner to make an informed decision on which modality to choose.     

Antibacterial drug resistance and equine practice

The equine practitioner is in a position to make day‐to‐day decisions regarding antimicrobial drug (AMD) use for their patients as well as to educate their clients regarding judicious use. General guidelines regarding judicious use of AMDs in equine patients have been developed by the American Association of Equine Practitioners. Detailed guidelines for AMD use in specific equine diseases supported by clinical trials and results of surveillance studies focused on resistance among equine bacterial pathogens are lacking. Studies that could lead to detailed and justifiable use recommendations would allow the equine practitioner to make more informed decisions regarding when to use AMDs, which drugs should be used and how they should be used (e.g. dose, route and duration).     

Cellular aspects of inflammation. The Ciba-Geigy Prize for Research in Animal Health

The migration of leucocytes to sites of acute and chronic inflammation is an event of central importance to the maintenance of inflammatory processes; extravascular leucocytes are responsible for generating chemical mediators of inflammation and the phagocytosis of particulate matter. They may also be involved in the conversion of acute to chronic inflammatory lesions. Leucocytes are attracted to sites of tissue injury by a range of chemoattractants. This paper describes the development of a method for separating on Percoll gradients purified populations of equine polymorphonuclear and mononuclear leucocytes and use of the isolated cells in vitro studies. Two independent assay methods, the agarose microdroplet and the Boyden chamber microfilter techniques, were used. The assays were utilised in three ways: (a) to investigate the sensitivity of polymorphonuclear and mononuclear leucocytes to two standard chemoattractants, zymosan activated plasma and n-formyl-methionyl-leucyl phenylalanine; (b) to study the chemoattractant properties of leukotriene B4 and prostaglandin E2 for equine leucocytes; and (c) to investigate the inhibitory actions of several nonsteroidal anti-inflammatory drugs (NSAIDs) on equine leucocyte movement.     

Motility of the equine gastrointestinal tract: Physiology and pharmacotherapy

Normal gastrointestinal (GI) motility patterns are necessary to maintain transit of ingesta and to facilitate digestion and absorption of nutrients. Disorders of the equine GI tract are frequently encountered by the equine practitioner and these disorders are often associated with an interruption in normal intestinal motility patterns, thus complicating treatment of the primary disease. Consequently, numerous treatments have been investigated in horses to facilitate the return of normal intestinal motility. The purpose of this article is to provide a brief review of the anatomy and physiology of the GI tract in the horse and review medications available to the equine veterinarian that may potentially promote intestinal motility.     

The treatment of diarrhoea in the adult horse

The priority in treating the equine patient with acute diarrhoea is to stabilise the haemodynamic aberrations secondary to the fluid and electrolyte losses. Once this has been initiated and the patient is stabilised ancillary treatments may be beneficial. Besides the well established effects of NSAIDs and polymixin B on systemic inflammation, recent studies suggest that the use of DTOS to bind bacterial toxins and Saccharomyces boulardii to reduce the severity and duration of diarrhoea may be beneficial. The justification for using probiotic products is scant. There is no evidence to suggest that systemic use of antimicrobials benefits equine patients with colitis, with the exception of metronidazole in cases of clostridial diarrhoea. In light of their potentially detrimental effects, their use can, in the opinion of the authors, not be advocated. Better understanding of the pathways of systemic inflammation and more selective anti‐inflammatory drugs may be of great benefit in the future.     

Nonsteroidal anti-inflammatory drugs in veterinary ophthalmology.

Uveitis is a common sequela to many ocular diseases. Primary treatment goals for uveitis should be to halt inflammation, prevent or control complications caused by inflammation, relieve pain, and preserve vision.Systemic and topical NSAIDs are essential components of the pharmaceutic armamentarium currently employed in the management of ocular inflammation by general practitioners and veterinary ophthalmologists worldwide. NSAIDs effectively prevent intraoperative miosis; control postoperative pain and inflammation after intraocular procedures, thus optimizing surgical outcome; control symptoms of allergic conjunctivitis;alleviate pain from various causes of uveitis; and circumvent some of the unwanted side effects that occur with corticosteroid treatment. Systemic NSAID therapy is necessary to treat posterior uveitis, because therapeutic concentrations cannot be attained in the retina and choroid with topical administration alone, and is warranted when diseases, such as diabetes mellitus or systemic infection, preclude the use of systemic corticosteroids.Risk factors have been identified with systemic and topical administration of NSAIDs. In general, ophthalmic NSAIDs may be used safely with other ophthalmic pharmaceutics; however, concurrent use of drugs known to affect the corneal epithelium adversely, such as gentamicin, may lead to increased corneal penetration of the NSAID. The concurrent use of NSAIDs with topical corticosteroids in the face of significant preexisting corneal inflammation has been identified as a risk factor in precipitating corneal erosions and melts in people and should be undertaken with caution[8]. Clinicians should remain vigilant in their screening of ophthalmic and systemic complications secondary to drug therapy and educate owners accordingly. If a sudden increase in patient ocular pain (as manifested by an increase in blepharospasm, photophobia, ocular discharge, or rubbing)is noted, owners should be instructed to contact their veterinarian promptly.     

Mechanisms of aquatic therapy and its potential use in managing equine osteoarthritis

Aquatic therapy has become increasingly popular in its use for rehabilitation of equine musculoskeletal injuries. Unfortunately, there has been no scientific evaluation of its clinical application for the treatment of osteoarthritis (OA) or associated musculoskeletal injuries in horses. The purpose of this review is to describe mechanisms of action of aquatic therapy and its potential use in the clinical management of equine OA.     

Serum amyloid A in equine health and disease

Serum amyloid A (SAA) is the major acute phase protein in horses. It is produced during the acute phase response (APR), a nonspecific systemic reaction to any type of tissue injury. In the blood of healthy horses, SAA concentration is very low, but it increases dramatically with inflammation. Due to the short half-life of SAA, changes in its concentration in blood closely reflect the onset of inflammation and, therefore, measurement of SAA useful in the diagnosis and monitoring of disease and response to treatment. Increases in SAA concentration have been described in equine digestive, reproductive and respiratory diseases and following surgical procedures. Moreover, SAA has proven useful for detection of some subclinical pathologies that can disturb training and competing in equine athletes. Increasing availability of diagnostic tests for both laboratory and field use adds to SAA's applicability as a reliable indicator of horses’ health status. This review article presents the current information on changes in SAA concentrations in the blood of healthy and diseased horses, focussing on clinical application of this biomarker.