Modes of Local Drug Delivery to the Musculoskeletal System

CLINICAL PHARMACOLOGY AND THERAPEUTICS

0749- 0739 /99 $8.00 + .00

MODES OF LOCAL DRUG DELIVERY TO THE MUSCULOSKELETAL SYSTEM Brian H. Anderson, BVSc, MVSc, MS, and Mark T. Ethell, BVSc, MVetClinStud

In recent years, there has been great interest in novel ways of distributing therapeutic agents, primarily antimicrobial drugs, by means of local application to target tissues within the musculoskeletal system of h orses. The primary goal has been to deliver high and sustained therapeutic concentrations of a drug to the site of action. Such modes of drug d elivery include local tissue injection, intrasynovial injection, regional limb perfusion, the use of synthetic implants and implantable pumps, and via percutaneous or iontophoretic application. Many of these techniques and much of the rationale and research behind their use have come from the human medical field. In this article, it is our aim to outline aspects of the principles associated with the use of these modes of local drug delivery to musculoskeletal tissues. Examples of the techniques and agents that have been used in horses together with newer techniques (used in human medicine) that may be applicable in horses are reviewed. LOCAL TISSUE INJECTION

For many years, equine veterinarians have treated musculoskeletal injuries with localized injection of a variety of agents. Anti-inflammatory agents such as corticosteroids, polysulfated glycosaminoglycans, and h yaluronic acid have been used to reduce pain and inflammation associated with injury or dysfunction of tendons, ligaments, "splints," and musculature of the back. 34• so. 72• 84 The primary aim has been to provide high concentrations of a drug directly to the source of

From the Institute of Veterinary, Animal, and Biomedical Sciences, Massey University, Palmerston North, New Zealand

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the problem for immediate effect. Little is known about the distribution, absorption, and elimination of drugs delivered in this way. Efficacy is often based on treatment response. Referenced sources for specific drugs used, dose, and duration are also limited, and it would appear that many are used by trial and error (R.L. Genovese, DVM, personal communication, 1998). In recent years, a number of these agents have been used for treating tendon and ligament injuries by local injection, and a brief review is presented below. Tendon and Ligament Injuries

The use of locally injected corticosteroids for tendon and ligament injuries is controversial. The anti-inflammatory properties of corticosteroids have been used to reduce the local tissue edema, swelling, pain, and reduction in mobility that accompanies such injuries. Although data on the effects of corticosteroids on the healing of tendons or ligaments are limited and conflicting, the use of intralesional or prolonged systemic therapy of tendon and ligament injuries with corticosteroids should be avoided, especially if vigorous early rehabilitation is planned.33• 62 • 97 Corticosteroids reduce collagen synthesis in young healing tendons and ligaments, and temporarily weaken these structures. Intratendinous corticosteroid injection of normal tendons results in collagen fiber disruption, necrosis, and possible development of dystrophic calcification. 33· 67• 97 The treatment of archilles tendinitis in human patients by intratendinous corticosteroid injection is also controversial. There are reports of archilles tendon ruptures after the use of corticosteroids either systemically or locally, but studies involving large numbers of patients are lacking. 44 Data on potential deleterious effects of peritendinous, periligamentous, or short-term systemic use of corticosteroids are also limited. In a series of studies performed in rabbits in which the medial collateral ligament of the stifle was sectioned and a single dose of betamethasone was injected into a fascia) pocket around the injured ligament, healing of the transected ligament was delayed . Mechanical strength was reduced, and there was inferior histologic organization in the healing ligament compared with that of sectioned but noninjected controls. These effects were evident up to 84 days after injection.97 Despite these concerns, successful use of the local injection of corticosteroids for tendinous and ligamentous injuries has been reported. 26· 62• 72 Because of the risk of serious breakdown injuries in racing Thoroughbreds, extreme caution should be used when contemplating local corticosteroid therapy of tendinous or ligamentous injuries. Because the risk of catastrophic breakdown in Standardbred racehorses seems to be lower and because some of these animals appear to be able to train and race following symptomatic therapy of lower grade tendon and ligament injuries, the use of local corticosteroid therapy in the management of these injuries may be useful (R.L. Genovese, DVM, personal communication, 1998).62 Tendinitis of the superficial digital flexor tendon (SDFT) in selected cases in Standardbred racehorses has been treated intralesionally or perilesionally with 5 to 10 mg of methylprednisolone acetate or 6 mg of triamcinolone with or without 10 to 20 mg of sodium hyaluronate. Perilesional injection is preferred, however. Such therapy may be particularly useful for resolution of peritendinous edema or hemorrhage. To avoid further injury or a new injury, it is important that this type of therapy be combined with regular ultrasonic monitoring, modifications to training and racing programs, and client education. 62 Proximal and main body suspensory d esmitis has also been treated with local injections of corticosteroids with or without sodium hyaluronate. 26• 72 Long-

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term resolution is unlikely, however, especially if there is significant fiber tearing. Low doses of corticosteroids (5-10 mg of methylprednisolone acetate or 6 mg of triamcinolone with or without sodium hyaluronate) have been used in Standardbred racehorses in cases in which minimal fiber disruption is present on ultrasound examination, and this is combined with rest or reduced exercise (R.L. Genovese, DVM, personal communication, 1998). 26 It is important that an avulsion fracture of the origin of the suspensory ligament or a palmar cortical fatigue fracture is first excluded before using local therapy in this area. Hyaluronate is apparently involved in the early stages of wound healing, and the positive effects on wound healing may occur by (1) hydration of the extracellular matrix, which promotes cellular migration; (2) a direct stimulatory effect on migrating repair cells; and (3) promotion of differentiation of mesenchymal cells into collagen-producing fibroblasts and the stimulation of angiogenesis, both of which follow the degradation of hyaluronate by hyaluronidase into lowmolecular-weight disaccharides.33• 34 In addition, injection of sodium hyaluronate into a tendon sheath may improve healing in the sheathed portion of the tendon and reduce adhesion formation .3 1 Because of these properties, it has been thought that sodium hyaluronate injected intra- or perilesionally may be beneficial in the treatment of tendinitis. Evidence for the efficacy of intralesional or perilesional sodium hyaluronate for improving tendon healing is conflicting, however. 16• 28• 3o. 31• 83 Recent controlled experiments did not identify any benefit on healing of collagenase-induced tendinitis of the SOFT when sodium hyaluronate was injected into the tendon 30 or into the peritendinous tissues. 28 In addition, no difference was found between the incidence of recurrent tendinitis in the superficial flexor tendon in 50 horses with naturally occurring tendinitis of the SOFT treated with intralesional sodium hyaluronate and a controlled exercise program and 50 horses treated with controlled exercise alone. 25 Treatment of tendinitis in horses with intramuscular or intralesional polysulfated glycosaminoglycans has been reported. 24 · 25• 49 • 80 Apparent benefits include the suppression of inflammation and the stimulation of collagen production. Glycosaminoglycan composition of the extracellular matrix changes during tendon repair and may be important in collagen regulation.32• 34 A recommended dose rate is 1 mg/kg intramuscularly every 4 days for 4 weeks. 32 In severe cases, the initial injection is given intralesionally, and subsequent treatments are given intramuscularly; however, recent studies have failed to document an improvement in return to racing or a reduction in recurrence of tendinitis compared with conservative treatment. 25• 49 Beta-aminoproprionitrile fumurate (f3APN-F) has recently been approved by the US Food and Drug Administration for the treatment of superficial digital flexor tendinitis in horses. Treatment is in conjunction with a controlled exercise program that is monitored using diagnostic ultrasound.68 This agent works by blocking the enzyme lysyl oxidase, which is responsible for mediating collagen cross-linking. In the presence of f3APN-F, newly formed collagen fibers that are not cross-linked are digested more rapidly and are replaced by new parallel collagen fibers that slowly cross-link to restore tendon strength.68 To stimulate collagen fiber alignment, gentle exercise is instituted following the course of injections. Treatment is started 1 to 3 months after injury. After sedation and appropriate preparation of the skin, 0.2 mL of [3APN-F is injected on the lateral, medial, and pal mar aspects of the tendon. The injections are spaced 0.5 cm apart and begin 1.5 cm proximal and 1.5 cm distal to the limits of the injured area. Injections are repeated every other day for five treatments (drug information insert). 68 Original recommendations for the use of [3APN-F were to inject as much of the 10 mL (0.7 mg/mL) supplied as possible into the tendon (drug

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information insert). This would be suitable for the average "bowed" tendon. 68 Because of some reports of excessive swelling after treatment, however, especially in tendons with slight lesions (total lesion cross-sectional area <6% of the total cross-sectional area of the tendon), it has been recommended that 1 mL of [3APN-F per 3% of the total lesion be used (e.g., if the total lesion cross-sectional area is 6%, 2 mL of [3APN-F is used). In addition, symptomatic relief of swelling using nonsteroidal anti-inflammatory drugs (NSAIDs), cold therapy, and bandaging is indicated (R.L. Genovese, DVM, personal communication, 1999). More than 48% of racehorses treated with intralesional [3APN-F were able to complete five or more starts compared with only 33% of placebo-treated horses. The recurrence rate of superficial digital flexor tendinitis in [3APN-F-treated horses was 49.5% compared with 87.5% in the placebo-treated control group. 69 Growth factors are involved in wound healing in all tissues, particularly during the acute phase, and help to organize and coordinate cellular proliferation, migration, and differentiation. Insulin-like growth factor-I (IGF-I) has recently been shown to enhance collagen synthesis in explants of normal equine flexor tendons56 and to improve tendon healing in vitro and in vivo after collagenase-induced tendinitis. 19, 55 INTRASVNOVIAL INJECTION

Intrasynovial injection of therapeutic agents is an important mode of drug delivery to the synovium and articular cartilage. Antimicrobial, anti-inflammatory, and chondroprotective agents together with oxygen-derived free radical scavengers are commonly used in equine practice. 6, 52 (For a detailed review of the use of intrasynovial anti-inflammatory agents, the reader is referred to the article on the therapeutics of musculoskeletal disease in this issue.) Recent research on aspects of the pharmacology and therapeutic use of intrasynovial antimicrobial agents has been reported and is reviewed below. Use of lntrasynovial Antimicrobial Agents

Antimicrobial agents have been injected into synovial structures prophylactically as the sole treatment for infectious synovitis or after employing synovial drainage for infectious synovitis, 6 , 47, 48 ' 74 , 76 The aim of such therapy is to kill the microbes that colonize the synovial membrane and cause synovial infection, The possible harmful effects of antimicrobial agents on synovium and cartilage have raised concerns about this mode of delivery in the past. Intra-articular administration of gentamicin into the antebrachiocarpal joint has been shown to induce a mild to moderate aseptic inflammatory reaction, mainly mononuclear in nature, that resolves within 3 to 7 days. 47, 86 Recently, the effect of ceftiofur sodium (150 mg) was evaluated on the synovium and cartilage of the antebrachiocarpal joint after intra-articular administration. 53 Macroscopic and microscopic evaluation of the synovium and cartilage revealed minimal changes as did evaluation of changes in total synovial nucleated cell count and protein. Imipenim-cilastatin and ticarcillin-clavulanate also apparently cause little or no inflammation when injected into normal equine joints.74 More work is required to evaluate any harmful effects that other antimicrobial agents may have on synovium or articular cartilage. The benefits of intrasynovial injection of antimicrobial agents include the immediate and high concentration of agent that is available at the site of

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infection, minimal systemic levels (which is advantageous when using potentially toxic antimicrobials), and a reduction in cost. The initial high concentration is the result of a relatively large quantity of drug (thousands of micrograms) placed in a small volume of synovial fluid (< 100 mL). Following mixing and distribution, the synovial structure acts as a temporary "depot" from which drug is eventually returned to the systemic circulation by the process of diffusion. For drugs that have a concentration-dependent mode of action (such as gentamicin)/3 this method of delivery allows for excellent efficacy. The exact fate of antimicrobial molecules administered intrasynovially is not known, but once in the synovial fluid, these particles can bind extra- or intracellularly or diffuse down a concentration gradient into the subsynovial tissues; from there, they can be absorbed into the venous or lymphatic capillaries. It is thought that the majority of the antimicrobial is absorbed via subsynovial capillaries and returned to the systemic circulation.2 In two studies evaluating the disposition of gentamicin (150 mg) following intrasynovial administration, Lloyd et al 47 , 48 found that the concentration of gentamicin in the antebrachiocarpal joint 15 minutes after injection was 1828 ± 240 and 2680 ± 1069 µg/mL in normal joints and 4745 ± 1161 and 6190 ± 1326 µg/mL in joints infected with Escherichia coli. After 150 mg of gentamicin was injected into the hind limb fetlock joint in anesthetized horses, the concentration in synovial fluid 15 minutes later was 7244 ± 660 µg/mL. 2 When comparing the peak concentration of gentamicin in synovial fluid following parenteral administration (2.5-5 µg/mL) with that following intrasynovial administration, the difference is 1000-fold, and this is 2000 times the recommended minimum inhibitory concentration of 2 µg/mL for susceptible equine pathogens. In addition, the concentration of gentamicin in lymph (a reflection of subsynovial interstitial fluid) sampled from a cannulated lymph vessel that drained a normal hind limb fetlock joint reached approximately 50 µg/mL 1.7 hours after intrasynovial injection of 150 mg of gentamicin. 2 The high concentration of antimicrobial in the interstitial tissues of the synovium and perisynovial tissues is the result of the large diffusion gradient that is established between the synovial space and surrounding tissues when this route of administration is used. Pharmacokinetic studies to identify the optimal dose and dose interval of intra-articularly administered antimicrobials are limited, and the disposition of antimicrobial agents after intrasynovial administration has not been completely characterized.47 A biexponential pattern of disappearance from the joint for other drugs administered by this route, such as the corticosteroids indoprofen and methotrexate, has been observed. 92 Initially, intra-articular distribution and mixing occurs, followed by transsynovial exchange and disappearance from the joint. Lloyd et al47 • 48 used a monoexponential equation (first-order kinetics) to describe the elimination phase of the disposition (distribution and elimination) of gentamicin administered intra-articularly into the antebrachiocarpal joint. The apparent half-life for elimination from normal joints was approximately 4 hours, and in infected joints, it was approximately 5 hours. A single daily dose of 150 mg of gentamicin injected into the antebrachiocarpal joint maintained synovial fluid levels greater than the minimum inhibitory concentration recommended for common equine pathogens for up to 24 hours. Similar results were attained when 150 mg of ceftiofur sodium was injected into the antebrachiocarpal joint. 53 Intra-articular therapy with 150 mg of gentamicin was shown to be more effective than systemic administration at eliminating sensitive bacteria from the antebrachiocarpal joint.48 Apart from these studies, the appropriate dose, frequency, and efficacy of intra-articular antimicrobials have not been determined and are therefore some-

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Table 1. INTRASYNOVIAL ANTIMICROBIALS TO TREAT SYNOVIAL INFECTIONS Antimicrobial

Dose

Amikacin Gentamicin Cefazolin Aqueous penicillin Ceftiofur Ticarcillin-clavulanate (Timentin) Imipenin-cilastatin (Primaxin)

0.5-1 g 150-500 mg 250-500 mg 2-5 X 106 JU 150 mg Unknown Unknown

Data from references 6, 47, 48, 53, and 76.

what empiric. It has been recommended not to exceed a single systemic dose of drug, and this should not be repeated within 24 hours (Table 1). 6 When combined with open drainage and systemic antimicrobials, the use of intra-articular antimicrobials has resulted in improved outcomes in the treatment of naturally occurring synovial infections.7 6 Prior to starting intrasynovial antimicrobial administration, a sample of synovial fluid should be obtained for culture and sensitivity analysis. Because of its efficacy against a wide range of bacteria, amikacin (administered intrasynovially) has been recommended as a first-choice drug to use while awaiting culture results. 74 A number of unanswered questions remain. Experimental studies to precisely characterize the disposition of antimicrobials in various joints are required. Factors such as joint volume and geometry (which affect surface area-to-volume ratios), the presence of synovial inflammation or infection, and concurrent synovial drainage all affect the dose, frequency of administration, and systemic concentrations of antimicrobials after intrasynovial administration. The concurrent use of systemic antimicrobials is currently recommended when treating septic synovial structures.74 The effect that systemic administration of antimicrobials has on the disposition of intrasynovially administered antimicrobials is not known, and the necessity of both for efficacious treatment of septic synovial structures also needs further study. Theoretically, concurrent systemic and intrasynovial administration of antimicrobials should delay the disappearance of an antimicrobial from the synovial cavity. Therefore, the combination of these two routes of administration would be therapeutically advantageous. REGIONAL LIMB PERFUSION

Regional limb perfusion involves the delivery of antimicrobials to a selected region of the limb through the venous system. 95 The aim is to provide and maintain high concentrations of drug in the tissues of the limb. This includes bone, synovium, and other soft tissues. 94- 96 A tourniquet is placed proximal to the site of perfusion for infections in the distal limb and proximal and distal to the infected site if the infection is located more proximally in the leg. An antimicrobial agent is injected into a superficial vein or into the medullary cavity; because systemic absorption is prevented, the agent diffuses into the local tissues in high concentrations. In cases of severe or chronic infections in which vascular thrombosis, ischemia, and tissue necrosis may preclude adequate delivery of systemically administered antimicrobials, regional limb perfusion allows antimicrobials to reach necrotic infected tissue by diffusion from the surrounding vascular tissue. 96

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One indication for retrograde intravenous perfusion of antimicrobials in man is the treatment of skin ulcers on the feet of diabetic patients. In this disease, the microcirculation to the foot is damaged. Recent research has shown that enhanced filtration and diffusion of drug molecules into the interstitium occur with this technique, leading to high local tissue concentrations of the antimicrobial. Retrograde intravenous perfusion resulted in a dilatation of venous capillaries and postcapillary venules, loosening of contacts between endothelial cells with focal formation of small gaps in the vessel wall, and widening of the space between endothelial cells and pericytes. Arterioles showed no signs of morphologic alteration, and cellular damage to blood and lymphatic vessels was not apparent. 42 Retrograde venous perfusion was superior to systemic therapy in achieving effective levels of netilmycin in patients with diabetic neuropathic plantar ulcers. 77 Regional Perfusion By Way of the Medullary Cavity

Regional limb perfusion has been used in horses for the treatment of bone and joint infections of the distal limb, during surgical repair of fractures at high risk for subsequent infection, and as an adjunctive treatment for osteomyelitis associated with orthopedic implants.6• 96 In one report, regional limb perfusion (using gentamicin) was performed via intramedullary infusion of the third metacarpus after a 4.5-mm hole was drilled into the medullary cavity 9 cm distal to the carpometacarpal joint. A catheter adapter attached to an angiographic catheter was secured to the hole. A tourniquet was applied proximal and distal to the carpus, and 1 g of gentamicin in 53 mL of a balanced electrolyte solution was infused through the angiographic catheter with an angiographic injector for 30 minutes at a rate of 2 mL / min, with a maximum infusion pressure of 450 psi. The tourniquet and infusion adapter were removed immediately following perfusion. The mean peak gentamicin concentration in the synovial fluid and membrane of the perfused normal antebrachiocarpal joint was more than 100 times the peak concentration reported after a recommended intravenous dose of 2.2 mg / kg. In addition, the synovial fluid gentamicin concentration remained above the minimum inhibitory concentration reported for most organisms sensitive to gentamicin for 24 hours. India ink perfusions showed that the perfusion fluid reached periarticular tissue and synovium of the carpal joints. Following release of the Esmarch (latex rubber bandage; Smith-Nephew, Memphis, TN) bandage, systemic gentamicin levels were similar to those observed after an intravenous injection. If using this technique, additional gentamicin should therefore not be given for at least 8 hours or until systemic levels decrease below a desired trough concentration of 1 µg/ mL. In studies on experimentally induced septic arthritis of the antebrachiocarpal joint, regional limb perfusion with gentamicin was more effective than intravenous therapy in eliminating joint infection. 94 More recent reports have documented the use of a hollowed out 4.5- or 5.5mm cortical bone screw with a luer-lock head. 6 The adapted screw is placed within one cortex of the bone to be infused after appropriate drilling and tapping, and 30 to 60 mL of sterile diluted antimicrobial fluid is injected via the Luer lock head. Intravenous Regional Perfusion

A technique for intravenous infusion of the distal limb of horses has been described. 57• 73 In an adult horse, an over-the-needle catheter (20 g, 1 in) is placed

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in the lateral or medial digital vein at the level of the proximal sesamoid bones, and a heparinized extension set is attached. The catheter and extension set are glued in place and then taped to the skin. An Esmarch bandage is then applied distally to proximally to force blood out of the distal superficial vasculature. The Esmarch bandage ends at a pneumatic cuff in the midmetacarpal-midmetatarsal region. Sixty milliliters of a balanced electrolyte solution containing 125 to 500 mg of amikacin or 100 to 300 mg of gentamicin is perfused by hand over 1 minute. The tourniquet and catheter are removed after 30 minutes. In foals, a 22-g X 1-in catheter is used, and 50 mg of gentamicin or amikacin is delivered in 10 to 12 mL of sterile fluid . Experimental studies using 125 mg of amikacin delivered by intravenous digital perfusion resulted in mean peak synovial fluid concentrations that were 25 to 50 times the minimum inhibitory concentration of most pathogens and distributed amikacin to synovial tissue and bone of the digit. 57 The efficacy of intravenous digital perfusion in horses for the treatment of experimentally induced digital sepsis has not been reported. When used as an adjunctive therapy for the treatment of digital sepsis in horses, however, an improved clinical response and a better survival rate have been reported. 73 The high tissue concentrations of antimicrobial are thought to increase bacterial killing in poorly perfused tissues and promote rapid elimination of infection. Secure tourniquet placement is important to prevent leakage of an antimicrobial into the systemic circulation. Large doses of antimicrobials (> 1 g) should be avoided because of anecdotal reports of cellulitis and soft tissue necrosis in horses 73 and distal limb venous thrombosis in cows. 29 In human patients, systemic antimicrobials are given prior to intravenous perfusion because of the risk of septicemia. Septicemia has been observed in foals (but not adult horses) when they are treated for large areas or multiple sites of sepsis with intravenous regional perfusion. 73 Regional limb perfusion in standing horses has been reported in a small number of cases.21 A tourniquet is placed around the proximal radius and tibia as high as possible, and a catheter is placed in the direction of venous flow in the radial and cranial branches of the medial saphenous veins, respectively. Blood is drained from the vein for 0.5 to 1 minute prior to injection. The tourniquet is removed 4 to 5 minutes following injection of crystalline penicillin (10-20 million U) or prednisolone (100-500 mg) in a total injection volume of not more than 20 mL. The main condition treated was cellulitis, with daily treatments for up to 3 days. Stamping of the horses' feet during tourniquet application was the only reported complication. In the case of more distal perfusions, it would be feasible to first produce distal limb analgesia with appropriate perineural anesthesia and then to apply the tourniquet prior to venous catheterization. NONBIODEGRADABLE SYNTHETIC IMPLANTS Antibiotic-Impregnated Polymethylmethacrylate

Polymethylmethacrylate (PMMA) is an acrylic polymer that has been used as a bone cement to secure prosthetic joints in human beings for many years. For three decades, antibiotics have been combined with PMMA to prevent deepseated infection following cemented arthroplasties in people" and more recently in dogs. 60 Subsequently, antibiotic-impregnated PMMA (AIPMMA) has been molded into beads and implanted to treat orthopedic and other infections as

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reviewed by Tobias et al. 87 AIPMMA beads have been successfully used in human patients in the management of chronic osteomyelitis,8 infected nonunions, 14 and infected hand and burn wounds98 as well as in the prevention of infection following soft tissue surgeries of the abdomen, perineum, 4 and head and neck.5 The rationale for using AIPMMA is that high concentrations of antibiotics can be achieved in wounds far exceeding those occurring after systemic administration of antimicrobials.40 At the same time, serum levels remain low or immeasurable, resulting in a reduced risk of toxicity.15• 91 Production of a high concentration of antibiotic locally is not the only advantage of AIPMMA, however. The AIPMMA implants act as a depot or reservoir that allows continuous release of antibiotic for prolonged periods. Gentamicin has been shown to be released from PMMA in vivo for many months; in fact, in one patient, gentamicin was detected in adjacent connective tissue and bone more than 5 years after implantation.9 ' In some cases, this prolonged local antibacterial effect obviates systemic antibiotic therapy. 8 • 14 This can be exploited in wild or intractable animals in which frequent systemic administration of antibiotics is not practical or is stressful to the patient.87• 88 In most cases, use of AIPMMA complements systemic antimicrobial therapy. In human patients with severe open fractures, those individuals treated with adjunctive use of AIPMMA beads were three times less likely to become infected than control patients receiving systemic antimicrobials alone. 61 There are only limited reports on the use of AIPMMA in large animals. Open or infected joints or fractures in horses and cattle have been successfully treated with AIPMMA. 12• 36• 75· 89 Although antibiotics were also administered systemically in these cases, the use of AIPMMA implants is likely to have improved success rates. The clearest demonstration of the efficacy of AIPMMA beads in horses has been shown in the treatment of infection of the distal tarsal joints. 13 In seven of eight horses, infection was successfully resolved by the implantation of commercially available gentamicin-impregnated beads (Septopal, E. Merck, Darmstadht, Germany) into the joints. In each case, a chain of several 7-mm in diameter spherical beads was inserted in a hole 7 to 8 mm-diameter that was drilled through the joint space. The beads were removed in all but one animal, in which extraction was impossible, 14 days postimplantation. Seven horses returned to athletic use, including four that were completely sound. Where commercially made gentamicin-impregnated PMMA beads are not available or where culture and sensitivity test results indicate that a different antibiotic should be chosen, the surgeon can fabricate AIPMMA. Whether commercially available gentamicin-impregnated PMMA beads are superior in their elution properties appears to be controversial.59• 78 Regardless, therapeutic concentrations of antibiotics can be achieved with handmade AIPMMA implants27• 78; however, this depends on a number of factors, including the particular antibiotic chosen, its formulation and dose, the brand of PMMA used,59 • 9 1 the size and shape of the AIPMMA implants, and the conditions under which the implants are fabricated. The particular antibiotic chosen can significantly influence the rate of elution of drug from PMMA. Gentamicin has long been considered to be the ideal antibiotic to combine with PMMA because of the high concentrations in wound fluid that can be achieved and because it is released for prolonged periods. Other aminoglycosides such as tobramycin39• 78 and amikacin27 also elute from PMMA in a comparable fashion. Cephalosporins are typically eluted for relatively shorter periods27• 37; however, they are commonly chosen to combine with PMMA because of their pattern of sensitivity against organisms frequently

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encountered in orthopedic infection54• 8 1 and because they are readily available in powdered form. Surgeons have been warned against the use of antibiotics in liquid form because of anecdotal reports suggesting that elution can be variable.15• 93 A recent study has demonstrated that amikacin elutes faster from PMMA when the powdered rather than injectable form is used, although no difference was noted when powdered and injectable gentamicin were compared.27 Antibiotic dose also influences the elution rates from PMMA. The incorporation of higher doses of antibiotics into PMMA results in more rapid and prolonged release of antibiotic from the implant. 27· 39• 5" This is in part a direct dose effect, but it is also a result of an increase in pore size within the PMMA. Pore size, and thus elution rates, can be manipulated in the fabrication process. Fabrication of AIPMMA under negative atmospheric pressure reduces pore size and results in a relatively lower rate of elution of antibiotic. 41 In contrast, the addition of substances such as dextran increases p ore size and results in a more rapid elution of antibiotic from the cement. 41 Construction of Antibiotic-Impregnated Polymethylmethacrylate Beads

Normally, w hen making PMMA implants, the powdered PMMA polymer (20 g, or half of a pack) is mixed with the liquid monomer (10 mL) until doughy

It is then used to cement prosthetic joints or for plate luting. If antibiotic is to be incorporated, it is added to the powdered PMMA polymer before the addition of liquid monomer and is thoroughly mixed. Mixing can be achieved using a sterile plastic bowl and a tongue depressor or using a commercially available mixer. Powdered antibiotic has been recommended, but if unavailable, liquid antibiotics are commonly used. It is our clinical impression that the addition of more than 10 mL of antibiotic solution to 20 g of PMMA powdered polymer interferes with PMMA polymerization and leaves some antibiotic liquid unincorporated in the bottom of the mixing bowl. In an in vitro study, the addition of 10 mL of gentamicin (100 mg / mL) or 5 to 10 mL of amikacin (250 mg / mL) to half of a pack (20 g) of PMMA produced AIPMMA beads that eluted at rates likely to result in antibiotic concentrations in w ound fluid that are bactericidal for at least 30 days.27 Because the elution rate is directly related to the surface area, fabrica tion of spherical AIPMMA implants is recommended because these spherical shap es have greater surface area-to-volume ratios than other shapes.87 Many surgeons roll doughy AIPMMA into cylinders by hand, because these are more readily retrieved later if implant removal becomes indicated. 87 When packing small infected cavities, tiny beads can be produced by squeezing doughy AIPMMA out of a syringe and onto a sterile surface much like toothpaste and then sectioning these long cylinders into short segments with a scalpel blade (R.A. Bennett, DVM, personal communication, 1999). If the need for subsequent removal of AIPMMA implants is likely, a chain can be produced by setting multiple beads onto a strand of suture material or surgical wire during the fabrication process. Even so, removal may be difficult, especially if attempted after 10 to 14 days postoperatively, because of encapsulation of the beads within granulation or fibrous tissue. In some cases, the suture or wire may break. In general, unless implanted within synovial structures, there may be fewer complications if AIPMMA beads are not removed. 35 The elution of many antibiotics from PMMA has been found to be too poor to be clinically useful, and this is thought to be at least in part a result of

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insufficient heat stability. 15 The polymerization of PMMA during hardening is an exothermic reaction, with temperatures reaching up to 100°C. 20 Despite this, the aminoglycosides and cephalosporins are known to elute well from PMMA. 87 The incorporation into PMMA of an antibiotic from each of these classes is rational when preventing or treating orthopedic infection in horses. The addition of different antibiotics into the same batch of PMMA is not recommended, however, because their interaction is unknown. Instead, aminoglycoside-impregnated PMMA and cephalosporin-impregnated PMMA should be fabricated independently but implanted together in the same wound. It has been extrapolated that the addition of more than 2.25 g of any antibiotic powder to 20 g of PMMA may reduce the compressive strength to below what is considered to be the minimum acceptable strength for weightbearing implants. 43 Many surgeons add only 0.5 to 1 g of antibiotic powder if the PMMA (20 g) is to be used in load sharing. 58 When liquid antibiotics are added to PMMA, the diametral and compressive strength is significantly compromised even with relatively low antibiotic doses. 58 For bead fabrication, much greater quantities of antibiotic can be used. For example, up to 3 g of cefazolin, 3 g of tobramycin, or 4 g of ticarcillin can be added to each 20 g of PMMA. 15 When treating infections with AIPMMA without the need for weightbearing function, the only limitations to the doses of antibiotic incorporated are inhibition of PMMA polymerization and production of beads that are brittle and liable to break on removal. Antibiotic-Impregnated Hoof Acrylic

Equilox I (Gauthier Medical, Rochester, MN) is 35% PMMA that has been "rubberized" to provide flexibility and reduce hardness. It has been used to repair hoof wall defects and cracks in horses. Because infection can develop under the acrylic patches used for hoof wall repair, local delivery of an antimicrobial may be useful. Because Equilox is partly composed of PMMA, it was hypothesized that an antibiotic incorporated into the adhesive would be slowly leached out to the surrounding tissues. In vitro studies (B.H. Anderson, BVSc, unpublished data, 1994) showed that when powdered gentamicin was incorporated into Equilox, it eluted in a similar manner to PMMA bone cement that was impregnated with gentamicin. Potential applications of medicated hoof acrylic (that would release antibiotic to surrounding tissues) include the treatment of "white line disease" and other hoof wall conditions that require hoof wall reconstruction. The efficacy of this acrylic-antibiotic combination has not been tested, but successful treatment of clinical cases with hoof acrylic impregnated with metronidazole has been reported. 90 SYNTHETIC BIODEGRADABLE IMPLANTS

The use of a nonbiodegradable implant system such as AIPMMA for delivery of antimicrobial agents to the musculoskeletal system has some disadvantages. The implants are of limited use in some joints, may have to be removed at a second surgical procedure, and antimicrobial elution is not complete. 23 A controlled drug-release biodegradable implant system would ameliorate such problems. The findings of studies on the potential use of biodegradable drug delivery systems for the treatment of septic arthritis in horses have been reported. 17• 18• 82 Cook et al1 7 evaluated two different biodegradable drug delivery systems in vitro. Polylactide-co-glycolide 50:50 and poly {D,L}-lactide impregnated with

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gentamicin were shown to release bioactive gentamicin (> 180 µg / mL) for 10 days. Release was then less than 10 µg / mL until 14 days postimplantation. No detrimental effects on synovial morphology, viability, or function were noted, and the addition of a biodegradable drug delivery system to infected synovial explants eliminated the infection within 24 hours. These experiments showed that despite the elimination of synovial infection, synovial cellular viability, function, and morphology were not returned to normal. In a follow-up study, 18 biodegradable beads of a polyanhydride copolymer matrix of C44 fatty acid and sebacic acid impregnated with 20% gentamicin (G-BDB) were used to treat experimentally induced synovial infection of the tarsocrural joint. Synovial fluid gentamicin concentrations peaked at 24 hours (mean, 82 µg/mL) and remained greater than 10 µg/mL for 12 days in infected joints. Although the presence of gentamicin-impregnated biodegradable beads significantly reduced lameness, joint circumference, and synovial nucleated blood cell count 3 days after implantation, only 33% of infected joints were culture-negative at this time, and only 66% were culture-negative after 6 days. This system may therefore assist in the elimination of joint infection rather than providing the sole means of killing bacteria. Systemic administration of antimicrobials would also be required. Sondhof et al82 conducted similar studies and determined the biocompatibility and in vitro release of gentamicin from poly-ortho ester, an injectable biodegradable polymer. A double diffusion chamber separated by a millipore membrane was used. The donor side contained 1 g of polymer loaded with 5% gentamicin in synovial fluid, and the receiver side contained only synovial fluid. In addition, polymer impregnated with gentamicin was incubated with synovial membrane explants that had been inoculated with Staphylococcus aureus. The in vitro release of gentamicin from the polymer averaged 3217.4 µg / mL over a IOday period. When treated with the polymer, infection was eliminated within 24 hours. Excellent in vitro biocompatibility with synovium was demonstrated. The advantage of this material is that polymer erosion time and rate of drug release can be varied readily. A variety of other antibiotic-impregnated biodegradable drug delivery systems could be used to treat synovial and bone infections in horses, including collagen sponges,38• 85 hydroxyappatite cement,27 plaster of paris beads,51 and many other synthetic polymers. 22 In addition, the use of antimicrobial-laden cancellous bone grafts could be useful for providing brief local antimicrobial coverage involving cases of fracture repair or joint arthrodesis, or in the treatment of osteomyelitis.6 IMPLANTABLE PUMPS

A subcutaneously implanted pump for the controlled release of antibiotics has been evaluated experimentally and clinically in rabbits, dogs, humans, and horses. 3• 6• 45• 63• 64 An osmotic pump and a freon pump have been used. The osmotic pump consists of a collapsible reservoir of flexible impermeable material surrounded by a sealed layer containing an osmotic agent, all of which is contained by a semipermeable membrane. When put in an aqueous environment, water is drawn into the cavity surrounding the reservoir and creates hydrostatic pressure, which produces a constant flow of its contents through the delivery portal. Two models are available: model 2001 or 2MLI (Alza Corporation, Palo Alto, CA). Each of these models has a capacity of 0.2 or 2 mL and pumps for 7 days at a constant rate of 1 or 10 mL/h, respectively.64 In studies on rabbits with osteomyelitis experimentally induced with

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S. aureus, amikacin was delivered via a catheter into a drill hole in the metaphysis of the distal femur. 64 Three of five rabbits cultured negative after 1 week of therapy. The remaining two did not appear to be infected. The same investigators subsequently reported on the use of a freon pump to treat osteomyelitis in human patients.63 The pump was used as an adjunct to surgical debridement. This implantable infusion pump consists of two chambers separated by a flexible metal bellows. As liquid freon in the charging fluid changes to a gas, it expands and compresses the medicine chamber, forcing drug into the outflow tube and then into outflow catheters. These catheters are positioned at the site of infection. In patients with osteomyelitis, surgical debridement of the lesion and implantation of the pump are undertaken during the same surgery. The pump's drug reservoir is refilled percutaneously at intervals based on its flow rate. In a series of 21 patients, serum amikacin levels remained at or below trough levels at all times. Two patients developed slight decreases in creatinine clearance. The pumps remained in place for 32 to 140 days (mean, 63 days). They were removed if the area of debridement was well healed and the erythrocyte sedimentation rate was less than 20 mm /h. 63 The use of implantable pumps in horses has been reported. A pump was used to treat an infected olecranon fracture in a pony. 3 Experimental evaluation of an osmotic pump was performed in ponies (A.H. Parks, VetMB, unpublished data). The pumps were implanted subcutaneously in the cervical region, and tubing was tunneled to the medial radius. Cortical bone concentrations of amikacin were found to be much higher than those achieved by systemic administration. Only a tenth of the daily dose of amikacin (6.6 mg/kg administered three times daily) was used. Beyond 1 to 2 cm of catheter implantation, however, amikacin levels were less than those that could be achieved by systemic administration. An osmotic pump designed to deliver 10 mL/h of gentamicin continuously over 7 days into the antebrachiocarpal joint of the horse was evaluated recently. 45 Mean synovial fluid concentration was over 30 times greater than the minimum inhibitory concentration for common equine pathogens on day 3 after implantation and remained over 10 times the minimum inhibitory concentration until day 7. The pump was implanted subcutaneously in the depression between the radius and the muscle belly of the ulnaris lateralis. Sterile polyethylene tubing was used to attach the pump to the joint cavity, and this was inserted through a needle into the palmarolateral aspect of the joint. Gentamicin was delivered to the joint continuously from the pump reservoir at a rate of 1 mL/h. The total treatment dose over 7 days using this route of administration was only 200 mg, which is well below a single daily dose of gentamicin (6.6 mg/kg) for a 450-kg horse. Serum levels throughout this period were less than 1 µg / mL; therefore, the risk for nephrotoxicity was reduced. Unfortunately, 5 of the 12 catheters bent following implantation and contributed to a variable concentration of gentamicin in the joint. In two cases, gentamicin levels were only 0.8% and 2.3% of the other joint samples measured. The investigators concluded that a more reliable catheter system was required before recommendations for the clinical use of this delivery system could be made. PERCUTANEOUS DELIVERY OF DRUGS Dimethyl Sulfoxide

Dimethyl sulfoxide (DMSO) is a hydroscopic solvent derived from wood pulp 9 and is used commonly in horses to treat acute soft tissue inflammation

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caused by trauma. DMSO has been used alone or in combination with corticosteroids. Because DMSO is a skin penetration enhancer (at concentrations >50'1/o60%), the percutaneous absorption of corticosteroids and many other compounds such as water, salicylic acid, antibiotics, estradiol, hexachlorophene, insulin, and heparin is increased.7° The exact mechanism by which DMSO (and other penetration enhancers) accelerates percutaneous absorption is not known but is believed to be the result of modification of lipid and aqueous bilayers of the intercellular lipid matrix of the stratum corneum. In addition to penetration enhancement, DMSO is bacteriostatic, vasodilatory, fibrinolytic, anti-inflammatory, and produces some degree of topical analgesia.70 The primary anti-inflammatory effect of DMSO is probably mediated through scavenging of free oxygen radicals. 9 DMSO traps free radical hydroxide, and its reduction metabolite dimethylsulfide traps free radical oxygen.rn DMSO works synergistically with corticosteroids. DMSO was shown to produce a threefold increase in the percutaneous absorption of hydrocortisone and testosterone. The amount of cortisone required for lysosomal stabilization was reduced 1000-fold when combined with DMSO, and the apparent local antiarthritic effect noted when cortisone was combined with DMSO increased ten-fold. 1 The topical application of DMSO and dexamethasone for the treatment of flexor tendinitis was associated with rupture of the SDFT in 5 of 11 horses, however. It has therefore been recommended that vigorous athletic activity be avoided if using this combination for the treatment of soft tissue inflammation. 84 Recently, the anti-inflammatory effects of topical (DMSO) gel on endotoxininduced synovitis in horses were studied. 79 Six horses had each intercarpal joint injected with lipopolysaccharide (LPS) to induce synovitis. Six joints had 15 g of DMSO gel applied topically over the dorsal aspect of the joint at 12-hour intervals for 60 hours. Six control joints received no topical application. Serial lameness and synovial fluid evaluations were performed at 12-hour intervals for 60 hours post-LPS injection. Plasma and synovial fluid samples were obtained before and at 36 hours after LPS injection to measure DMSO content. No difference in lameness scores between groups was noted. DMSO was detected in only one plasma sample. DMSO was detected in the synovial fluid of five of six treated joints at 36 hours postinjection. At 24 hours postinjection, the total nucleated cell counts and neutrophil counts were significantly lower in treated versus control joints (37% reduction). Minimal differences in total protein concentration were noted between control and treated joints. It was concluded that topically applied DMSO penetrates into synovial fluid in sufficient quantities to be detected and reduces neutrophilic joint inflammation. The likely effect is a reduction in oxygen-derived free radicals that results in a decrease in white blood cell and neutrophil chemotaxis. No appreciable effect on joint-associated pain was found. lontophoresis

Iontophoresis means ion transfer. Iontophoretic drug delivery is the permeation of ionized molecules across biological membranes under the influence of electric current.7· 46 An iontophoretic system basically consists of two electrodes connected to a source of electric current. The electrodes are then applied to the skin (Fig. 1). During the passage of electric current, positively or negatively charged drug particles are repelled into the skin and subcutaneous tissues by an identical charge on the electrode surface placed over them." 5 The electrode serves as a

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Power Source

Drug solution in reserv~

Skin

+-+ -+

Electrodes

+

/

.--------,

-+-+- + +-+-+-

+

+

Figure 1. lontophoretic process.

drug reservoir, a conductive medium, and an interface converting electric current into an ionic current within the drug solution. Iontophoresis is a new technique for transdermal drug delivery in equine therapeutics but has been used in human medicine since the mid-1980s. In human patients, iontophoresis has been used as an adjunctive therapy for a variety of acute and chronic musculoskeletal conditions, including bicipital tendinitis, patellar tendinitis, rheumatoid arthritis, and shin splints.4 6 Hydrophilic drugs such as dexamethasone, which are normally excluded by the stratum corneum, can readily be delivered through the dermis by electrophoresis.46 Suggested benefits include rapid noninvasive drug entry into the skin and underlying tissues, avoidance of painful local injection, and reduced risk for infection. In addition, the rate of drug administration is controlled and is unaffected by the first-pass effect of the liver. 71 Disadvantages include occasional burns, the need for specialized equipment, and cost. 65 The most common drugs delivered via this method have been dexamethasone and lidocaine. Other ions are also suitable for iontophoresis and include acetic acid, aspirin, diclofenac sodium, potassium chloride, morphine, and salicylate. A number of factors affect iontophoretic drug delivery, including drug lipophilicity, current density and type of current (constant versus pulsed), skin impedance, ion mobility and conductivity, ionic valance, pH of a drug solution, state of ionization, duration of iontophoresis, effect of iontophoresis on drug metabolism and degradation in the skin, and concentration of drug ion in the solution.4 6 The value of iontophoresis as a means of drug delivery compared with systemic or local injection is not clear, and controlled studies of efficacy are limited. The most effective current parameters for the delivery of individual ions are not known. The depth of penetration of various drugs is also not clear, and before ions penetrate to deeper tissues (percutaneous absorption), they may be rapidly absorbed by the dermal circulation. 71 When high concentrations of a drug are required, direct injection or parenteral therapy would seem logical. There are some obvious benefits for equine patients, including noninvasive drug therapy and localized drug delivery directly to injured structures and areas difficult to bandage (e.g., hock and stifle) or inject (e.g., bursae and tendon sheaths). A commercial iontophoresis delivery system called Relion (Empi, St Paul, MN) has been developed specifically for equine applications. In this system, a treatment pad is applied to the area of interest. Manufacturer recommendations are that the drug reservoir be filled with at least 6 mL of drug solution. Lead wires are attached to each electrode according to drug polarity

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(for negatively charged ions, the negative electrode is used), and the appropriate current level is selected. No controlled clinical studies in horses have been reported at this time, but anecdotal reports from equine veterinarians on the benefits of this therapy for such conditions as splints, septic tenosynovitis, tendinitis, and " capped hock" have been reported . One study (reported in Relion information packet) documented the measurement of clinically effective concentrations of betamethasone (212.5-392.6 ng/mL) following 3 days of iontophoresis using a 2.4% betamethasone solution delivered at a current of 40 mA/min. Betamethasone was not found in urine samples taken at 7, 24, 48, and 72 hours after the final iontophoresis treatment. Betamethasone was found in serum 7 hours (50 ng/ mL) after the last treatment but was not detected at 24 hours after the last treatment.

SUMMARY

A number of methods for the local delivery of drugs to musculoskeletal tissues in the horse are now available. Further research is required to document the disposition of drugs delivered by such methods and to correlate this information with efficacy. Perhaps the greatest potential area for the methods discussed is the treatment of synovial and bone infections. To be able to provide high and sustained therapeutic concentrations of antimicrobials to the site of infection should increase the chances of success in such cases. These methods of drug delivery need to be used in conjunction with other management procedures, however, including bacterial culture and sensitivity procedures, systemic antimicrobials, surgical drainage, removal of dead bone or surgical implants, establishment of fracture stability, use of autogenous bone grafts, systemic NSAIDs, and rest.

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11. Buchholz HW, Elson RA, Heiner K: Antibiotic-loaded acrylic cement: Current concepts. Clin Orthop 190:96, 1984 12. Butson R, Schramme M, Garlick M, et al: Treatment of intrasynovial infection with gentamicin-impregnated polymethylmethacrylate beads. Vet Rec 138:460, 1996 13. Butson R, Schramme M, Smith R, et al: The use of gentamicin impregnated beads in small tarsal joint infection. In Proceedings of the European College of Veterinary Surgeons Sixth Annual Scientific Meeting, 1997 14. Calhoun J, Henry SL, Anger OM, et al: The treatment of infected nonunions with gentamicin-polymethylmethacrylate antibiotic beads. Clin Orthop 295:23, 1993 15. Calhoun JH, Mader JT: Antibiotic beads in the management of surgical infections. Am J Surg 157:443, 1989 16. Churchill EA: Treating tendinitis with sodium hyaluronate. J Equine Vet Sci 5:240, 1985 17. Cook VL, Bertone AL, Kowalski ]J, et al: Biodegradable drug delivery systems for gentamicin release and the elimination of synovial membrane infection. Vet Surg 25:421, 1996 18. Cook VL, Bertone AL, Kowalski JJ, et al: Gentamicin-impregnated biodegradable polymer for the treatment of equine joint infection in vivo: Preliminary study. Vet Surg 26:411, 1997 19. Dahlgren LA, Nixon AJ, Starrak GS, et al: The effects of insulin-like growth factor 1 on the healing of coUagenase-induced tendonitis in the horse [abstract]. In Scientific Presentation Abstracts of the Eighth Annual College of Veterinary Surgeons Symposium, Chicago, 1998, p 7 20. Deyerle WM, Crossland S, Sullivan HG: Methylmethacrylate: Uses and complications. AORN J 29:696, 1979 21. Dietz 0, Kehnscherper C: Intravenose strauungs antibiose bei pyogenen infektion en der distalen gliedma J3enabschnitte des pferdes. Der Praktische Tierarzt 8:30, 1990 22. Domb AJ: Implantable biodegradable polymers for site-specific drug delivery. In Polymeric Site-Specific Pharmacotherapy. West Sussex, John Wiley and Sons, 1994, p 1 23. Domb AJ, Amselem S: Antibiotic delivery systems for the treatment of chronic bone infections. In Domb AJ (ed): Polymeric Site-Specific Pharmacotherapy. West Sussex, John Wiley and Sons, 1994, p 243 24. Dow SM, Wilson AM, Goodship AE: Treatment of superficial digital flexor tendon injury in horses with polysulfated glycosaminoglycan. Vet Rec 139:413, 1996 25. Dyson SJ: Treatment of superficial digital flexor tendinitis: A comparison of conservative management, sodium hyaluronate, and glycosarninoglycan polysulfate. In Proceedings of the 43rd Annual Convention of the American Association of Equine Practitioners, Phoenix, 1997, p 297 26. Dyson SJ, Arthur RM, Palmer SE, et al: Suspensory ligament desmitis. Vet Clin North Arn Equine Pr act 11 :177, 1995 27. Ethell M, Brown M, Bennett R, et al: Gentarnicin, arnikacin and ceftiofur elution from polyrnethylrnethacrylate and hydroxyappatite cement. Transactions of the 45th Annual Meeting of the Orthopaedic Research Society [CD Rom] 43:1999 28. Foland JW, Trotter CW, Powers BE, et al: Effect of sodium hyaluronate in collagenaseinduced superficial digital flexor tendinitis in horses. Am J Vet Res 53:2371, 1992 29. Gagnon H, Ferguson JG, Papich MG, et al: Single-dose pharrnacokinetics of cefazolin in bovine synovial fluid after intravenous regional injection. J Vet Pharmacol Ther 17:31, 1994 30. Gaughan EM, Gift LJ, DeBowes RM, et al: The influence of sequential intratendinous sodium hyaluronate on tendon healing in horses. Vet Comp Orthop Traurnatol 8:40, 1995 31. Gaughan EM, Nixon AJ, Knook LP, et al: Effects of sodium hyaluronate on tendon healing and adhesion formation in horses. Arn J Vet Res 5:764, 1991 32. Goodship AE, Birch HL, Wilson AM: The pathobiology and repair of tendon and ligament injury. Vet Clin North Arn Equine Pract 10:323, 1994 33. Henninger R: Superficial digital flexor tendinitis. In White NA, Moore JN (eds): Current Concepts in Equine Surgery and Lameness, ed 2. Philadelphia, WB Saunders, 1998, p 341

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34. Henninger R: Treatment of superficial digital flexor tendinitis. Vet Clin N orth Am Equine Pract 10:409, 1994 35. Henry SL, Hood GA, Seligson D: Long-term implantation of gentamicin-polymethylmethacrylate antibiotic beads. Clin Orthop 295:47, 1993 36. Holcombe S, Schneider R, Bramlage L, et al: Use of antibiotic-impregnated polymethyl methacrylate in horses with open or infected fractures or joints: 19 cases (1987-1995). J Am Vet Med Assoc 211:889, 1997 37. Hughes S, Field CA, Kennedy RK, et al: Cephalosporins in bone cement: Studies in vitro and in vivo. J Bone Joint Surg Br 61:96, 1979 38. Ipsen T, Jorgensen PS, Damholt V, et al: Gentamicin-collagen sponge for local applications: 10 cases of chronic osteomyelitis followed for 1 year. Acta Orthop Scand 62:592, 1991 39. Kirkpatrick DK, Trachtenberg LS, Mangino PD, et al: In vitro characteristics of tobramycin-PMMA beads: Compressive strength and leaching. Orthopedics 8:1130, 1985 40. Klemm KW: Antibiotic bead chains. Clin Orthop 295:63, 1993 41. Kuechle DK, Landon GC, Musher OM, et al: Elution of vancomycin, daptomycin and amikacin from acrylic bone cement. Clin Orthop 264:302, 1991 42. Langer K, Seidler C, Partsch H: Ultrastructural study of dermal microvasculature in patients undergoing retrograde intravenous pressure infusions. Dermatology 192:103, 1996 43. Lautenschlager EP, Jacobs JJ, Marshall GW, et al: Mechanical properties of bone cements containing large doses of antibiotic powders. J Biomed Mater Res 10:929, 1976 44. Leppilahti J, Orava S: Total achilles tendon rupture: A review. Sports Med 25:79, 1998 45. Lescun TB, Adams SB, Bill RP: Constant ge ntamicin administration into the antebrachio-carpal joint of the horse using a subcutaneously implanted osmotic pump. In Proceedings of the 25th Annual Conference of the Veterinary Orthopedic Society, Snowmass, 1998, p 49 46. Li LC, Scudds RA: lontophoresis: An overview of the mechanisms and clinical application. Arthritis Care and Research 8:51, 1995 47. Lloyd KCK, Stover SM, Pascoe JR, et al: Plasma and synovial fluid concentrations of gentamicin in horses after intra-articular administration of buffered and unbuffered gentamicin. Am J Vet Res 49:644, 1988 48. Lloyd KCK, Stover SM, Pascoe JR, et al: Synovial fluid pH, cytological characteristics, and gentamicin concentrations after intra-articular administration of the drug in an experimental model of infectious arthritis in horses. Am J Vet Res 51 :1363, 1990 49. Marr CM, Love S, Boyd JS: Factors affecting the clinical outcome of injuries to the superficial digital flexor tendon in National Hunt and point-to-point race horses. Vet Rec 132:476, 1993 50. Martin BM, Klide A: Diagnosis and treatment of chronic back pain in horses. In Proceedings of the 43rd Annual Convention of the American Association of Equine Practitioners, Phoenix, 1997, p 310 51. McGarvey L, Santchii EM: Elution of gentamicin from plaster of paris-gentamicin beads [abstract]. In Poster Session Abstracts of the Eighth Annual American College of Veterinary Surgeons Symposium, Chicago, 1998, p 27 52. Mcllwraith CW: Intra-articular and systemic therapy. In White NA, Moore JN (eds): Current Techniques in Equine Surgery and Lameness, ed 2. Philadelphia, WB Saunders, 1998, p 481 53. Mills MJ, Moore BR, St Jean G, et al: Synovial fluid concentrations, cytologic characteristics, and effect on synovium of ceftiofur sodium after intra-articular injection in horses. In Proceedings of the 24th Scientific Meeting of the Veterinary Orthopedic Society, Big Sky, 1997 54. Moore RM, Schneider RK, Kowalski J, et al: Antimicrobial susceptibility of bacterial isolates from 233 horses with musculoskeletal infection during 1979-1989. Equine Vet J 24:450, 1992 55. Murphy DJ, Nixon AJ: The biochemical and site specific effects of IFG-1 on intrinsic tendon repair of collagenase-induced tendonitis in the horse. Vet Surg 25:434, 1996 56. Murphy DJ, Nixon AJ: Biochemical and site-specific effects of insulin-like growth factor 1 on intrinsic tenocyte activity in equine flexor tendons. Am J Vet Res 58:103, 1997

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57. Murphy ED, Santschi EM, Papich MC: Local antibiotic perfusion of the distal limb of horses. In Proceedings of the 40th Annual Convention of the American Association of Equine Practitioners, Denver, 1996, p 141 58. Murray WR: Use of antibiotic-containing bone cement. Clin Orthop 190:89, 1984 59. Nelson CL, Griffin FM, Harrison BH, et al: In vitro elution characteristics of commercially and noncommercially prepared antibiotic PMMA beads. Clin Orthop 284:303, 1992 60. Olmstead M: The canine cemented modular total hip prosthesis. J Am Anim Hosp Assoc 31:109, 1995 61. Ostermann PAW, Seligson D, Henry SL: Local antibiotic therapy for severe open fractures: A review of 1085 consecutive cases. J Bone Joint Surg Br 77:93, 1995 62. Palmer SE, Genovese R, Longo KL, et al: Practical management of superficial digital flexor tendinitis in the performance horse. Vet Clin North Am Equine Pract 10:425, 1994 63. Perry CR, Davenport K, Vossen MK: Local delivery of antibiotics via an implantable pump in the treatment of osteomyelitis. Clin Orthop 226:222, 1988 64. Perry CR, Rice S, Ritterbusch ]K, et al: Local administration of antibiotics with an implantable osmotic pump. Clin Orthop 192:284, 1985 65. Peteleriz TJ, Buttke JA, Bonds C, et al: Iontophoresis of dexamethasone: Laboratory studies. Journal of Controlled Release 20:55, 1992 66. Plumb DC: Dimethylsulfoxide. In Veterinary Drug Handbook, ed 2. Ames, Iowa State University Press, 1995, p 202 67. Pool RR, Wheat JD, Ferraro CL: Corticosteroid therapy in common joint and tendon injuries of the horse. Part II. Effects on tendons. In Proceedings of the 26th Annual Convention of the American Association of Equine Practitioners, Anaheim, 1980, p 407 68. Reef VB: Managing superficial digital flexor tendinitis in horses. In The Veterinary CE Advisor, a Supplement to Veterinary Medicine. Lenexa, KS, Veterinary Medicine Publishing Group, 1998 69. Reef VB, Genovese RL, Davis WM: Initial long-term results of horses with superficial digital flexor tendinitis treated with intralesional 13-amino proprionitrile fumurate. In Proceedings of the 43rd Annual Convention of the American Association of Equine Practitioners, Phoenix, 1997, p 301 70. Reviere JE, Spoo JW: Dermatopharmacology: Drugs acting locally on the skin. In Adams HR (ed): Veterinary Pharmacology and Therapeutics, ed 7. Ames, Iowa State University Press, 1995, p 1050 71. Roberts MS: Targeted drug delivery to the skin and deeper tissues: Role of physiology, solute structure and disease. Pharmacology and Physiology 24:874, 1997 72. Ross MW: Suspensory desmitis and proximal metacarpal injury. In White NA, Moore JN (eds): Current Concepts in Equine Surgery and Lameness, ed 2. Philadelphia, WB Saunders, 1998, p 347 73. Santchii EM, Adams SB, Murphy ED: How to perform equine intravenous digital perfusion. In Proceedings of the 44th Annual Convention of the American Association of Equine Practitioners, Baltimore, 1998, p 198 74. Schneider RK: Treatment of post traumatic septic arthritis. In Proceedings of the 44th Annual Convention of the American Association of Equine Practitioners, Baltimore, 1998, p 167 75. Schneider RK, Andrea R, Barnes HG: Use of antibiotic-impregnated polymethylmethacrylate for treatment of an open radial fracture in a horse. J Am Vet Med Assoc 207:1454, 1995 76. Schneider RK, Bramlage LR, McKlenburg LM, et al: Open drainage, intra-articular and systemic antibiotics in the treatment of septic arthritis/ tenosynovitis in horses. Equine Vet J 24:443, 1992 77. Seidel C, Buhler-Suger S, Tacke J, et al: Influx of antibiotics into diabetic legs with plantar ulcerations: Regional and systemic netilmycin levels compared after retrogradevenous and systemic-venous application. Vasa 24:19, 1995 78. Seligson D, Popham GJ, Voos K, et al: Antibiotic leaching from polymethylmethacrylate beads. J Bone Joint Surg Am 75:714, 1993 79. Smith C, Bertone AL, Kaeding C, et al: Anti-inflammatory effects of topical dimethyl sulfoxide gel on endotoxin-induced synovitis in horses [abstract]. In Scientific Presenta-

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tion Abstracts of the Eighth Annual American College of Veterinary Surgeons Symposium, Chicago, 1998, p 4 Smith RKW: A case of superficial digital flexor tendinitis: Ultrasonographic examination and treatment with intralesional polysulphated glycosaminoglycans. Equine Vet Educ 4:280, 1992 Snyder J, Pascoe J, Hirsh D: Antimicrobial susceptibility of microorganisms isolated from equine orthopedic patients. Vet Surg 16:197, 1987 Sondhof AF, Booth LC, Rosenbusch RF, et al: In vitro biocompatibili ty of a novel biodegradable local drug delivery system intended for the treatment of orthopedic infections in the horse. In Proceedings of the 25th Annual Conference of the Veterinary Orthopedic Society, Snowmass, 1998, p 49 Spurlock GH, Spurlock SL, Parker GA: Evaluation of hylartin-V therapy for induced tendinitis in the horse. J Equine Vet Sci 9:242, 1989 Stashak TS: Methods of therapy. In Adam's Lameness in Horses, ed 4. Philadelphia, Lea & Febiger, 1987, p 840 Steiner A, Hirsbrunner G: Use of gentamicin-impregnated collagen implants for treatment of chronic synovial infections in ruminants: Preliminary results. Vet Surg 26:256, 1997 Stover SM, Pool RR: Effect of intra-articular gentamicin sulfate on normal equ ine synovial membrane. Am J Vet Res 46:2485, 1985 Tobias KMS, Schneider RK, Besser TE: Use of antimicrobial-impregnated polymethyl methacrylate. J Am Vet Med Assoc 208:841, 1996 Tobias KS, Robbins CT, Ferner WT: Treatment of cellulitis in an American black bear (Ursus americanus) with antibiotic-impregnated implants. Journal of Zoo and Wildlife Medicine 27:109, 1996 Trostle SS, Hendrickson DA, Stone WC: Use of antimicrobial-impregnated polymethyl methacrylate beads for treatment of chronic, refractory septic arthritis and osteomyelitis of the digit in a bull. J Am Vet Med Assoc 208:404, 1996 Turner TA, Anderson BH: Use of antibiotic impregnated hoof repair material for the treatment of hoof wall separation: A promising new treatment. In Proceedings of the 42nd Annual Convention of the American Association of Equine Practitioners, Denver, 1996, p 205 Wahlig H, Dingeldein E: Antibiotics and bone cements: Experimental and clinical longterm observations. Acta Orthop Scand 51:49, 1980 Wallis WJ, Simpkin PA: Antirheumatic drug concentrations in human synovial fluid and synovial tissue observations on extravascular pharmacokinetics. Clin Pharmacokinet 8:496, 1983 Welch AB: Antibiotics in acrylic bone cement: In vitro studies. J Biomed Mater Res 12:679, 1978 Whitehair KJ, Adams SB, Parker JE, et al: Regional limb perfusion with antibiotics in three horses. Vet Surg 21 :286, 1992 Whitehair KJ, Blevins WE, Fessler JF, et al: Regional perfusion of the equine carpus for antibiotic delivery. Vet Surg 21:279, 1992 Whitehair KJ, Bowersock TL, Blevins WE: Regional limb perfusion for antibiotic treatment of experimentally induced septic arthritis. Vet Surg 21:367, 1992 Wiggins ME, Fadale PD, Ehrlich MG, et al: Effects of local injection of corticosteroids on the healing of ligaments: A follow-up report. J Bone Joint Surg Am 77:1682, 1995 Zellweger G, Simmen H, Meyer V, et al: Infection in the u pper body: Hand and bumwound microbiology and considerations for antimicrobial therapy. JBurn Care Rehabil 13:298, 1992 Address reprint requests to Brian H . Anderson, BVSc, MVSc, MS Institute of Veterinary, Animal, and Biomedical Sciences Massey Uni versity Palmerston North New Zealand

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