Therapeutic agents such as glucocorticosteroids, hyaluronic acid, glycosaminoglycans, and antimicrobials are commonly used IA in equine athletes for the treatment of joint disease. The temporal relationship between medications administered IA and athletic performance is the subject of much debate and regu-lation.1–4 The distribution of IA therapeutic agents, including retention within the joint over time, requires investigation to ensure the safety of the equine athlete, riders, and drivers. The rate-limiting step in elimination of clinically detectable concentrations of glucocor-ticosteroids within the joint is believed to be transfer from synovial fluid to plasma.5
Previous studies6,7 reveal that synovial solutes, in addition to several radioisotopes of various molecular sizes, are cleared from the human knee joint at constant rates. The clearance of these solutes, expressed as a clearance constant per minute, can be compared among individuals and longitudinally within an individual.7–10 These articular clearance values have not been investigated in horses. Clearance rates of 99mtechnetium (as 99mTc-DTPA), a freely diffusible water-soluble molecule, have been used to represent other synovial molecules that equilibrate with plasma in human studies. This method provides a measurement of joint perfusion and drainage and subsequent transfer of solutes from the IA joint space to circulating blood. Clearance of IA-administered 99mtechnetium, measured by serial counts of emitted γ rays, is significantly increased by dynamic exercise in humans with knee joint effusion.11 It is thought that increased clearance of synovial fluid and solutes following exercise is directly related to increased blood flow to the synovium as well as increased IA hydrostatic pressure leading to altered Starling forces across the synovium.12–22 These studies of joint fluid dynamics support the notion that exercise of a cyclic nature leads to earlier synovial solute clearance, compared with synovial solute clearance without exercise.
Although various human, canine, and rabbit studies have used radiopharmaceuticals for investigating synovial fluid exchange, a similar technique for evaluating the distribution of IA administered γ-emitting radioisotopes in horses has not been reported. The goals of the study reported here were to evaluate the safety of 99mTc-MDP IA injection in clinically normal horses and to define the effect of exercise on the blood and joint distribution of 99mTc-MDP by use of both noncompartmental analysis and compartmental modeling. The hypotheses were that 99mTc-MDP is safe when administered IA in clinically normal horses and that exercise affects the distribution and pharmacokinetics of 99mTc-MDP following IA injection in horses.
Technetium Tc 99m medronate
Technetium Tc 99m pentetate
Area under the quantifiable radioactivity-time curve
Observed apparent clearance
Maximum observed plasma radioactivity
Counts per minute
Disintegrations per minute
Terminal phase elimination rate constant
Region of interest
Observed apparent volume of distribution
Sato I equine treadmill, Uppsala, Sweden.
BD Angiocath, BD, Franklin Lakes, NJ.
BD Vacutainer, BD, Franklin Lakes, NJ.
Omega 500s, Technicare, Solon, Ohio.
Cell Dyn 3500R hematology analyzer, Abbott, Abbott Park, Ill.
TS Meter, American Optical Corp, Southbridge, Mass.
Atomlab Dose Calibrator (scintillation counter), Biodex Medical Systems, Shirley, NY.
Mirage, version 5.4, Segami Corp, Columbia, Md.
Kobalt 6-inch Electronic Caliper with Digital Display, Kobalt, North Wilkesboro, NC.
WinNonlin, version 5.2.1, Pharsight Inc, Mountain View, Calif.
GraphPad Prism, version 5.02 for Windows, GraphPad Software Inc, San Diego, Calif.
McKay AG, Milne FJ. Observations on the intraarticular use of corticosteroids in the racing Thoroughbred. J Am Vet Med Assoc 1976; 168:1039–1041.
Owen RA, Marsh JA, Hallett FR, et al. Intra-articular corticosteroid- and exercise-induced arthropathy in a horse. J Am Vet Med Assoc 1984; 184:302–308.
Trotter GW. Intra-articular corticosteroids. In: McIlwraith CW, Trotter GW, eds. Joint disease in the horse. Philadelphia: WB Saunders Co, 1996;237–256.
Trotter GW, McIlwraith CW, Yovich JV, et al. Effects of intra-articular administration of methyprednisolone acetate on normal equine articular cartilage. Am J Vet Res 1991; 52:83–87.
Soma LR, Uboh CE, Luo Y, et al. Pharmacokinetics of methylprednisolone acetate after intra-articular administration and its effect on endogenous hydrocortisone and cortisone secretion in horses. Am J Vet Res 2006; 67:654–662.
Simkin PA, Pizzorno JE. Transynovial exchange of small molecules in normal human subjects. J Appl Physiol 1974; 36:581–587.
Levick JR, Thompson PW. Intra-articular volume as an important factor governing macromolecular half life in synovial fluid. Ann Rheum Dis 1988; 47:701–704.
Simkin PA, Bassett JE, Koh EM. Synovial perfusion in the human knee: a methodologic analysis. Sem Arth Rheum 1995; 25:56–66.
Wallis WJ, Simkin PA, Nelp WB, et al. Intraarticular volume and clearance in human synovial effusions. Arthritis Rheum 1985; 28:441–449.
James MJ, Cleland LG, Gaffney RD, et al. Effect of exercise on 99mTc-MDP clearance from knees with effusions. J Rheum 1994; 21:501–504.
Simkin PA, Huang A, Benedict RS. Effects of exercise on blood flow to canine articular tissues. J Orthop Res 1990; 8:297–303.
Dyson S, Lakhani K & Wood J. Factors influencing blood flow in the equine digit and their effect on uptake of 99m technetium methylene diphosphonate into bone. Equine Vet J 2001; 33:591–598.
Macoris DDG, Bertone AL. Intra-articular pressure profiles of the cadaveric equine fetlock joint in motion. Equine Vet J 2001; 33:184–190.
Levick JR. An investigation into the validation of subatmo-spheric synovial pressure recordings and their dependence on joint angle. J Physiol 1979; 289:56–68.
Levick JR. The influence of hydrostatic pressure on trans-synovial fluid movement and on capsular expansion in the rabbit knee. J Physiol 1979; 289:69–82.
O'Driscoll SW, Kumar A, Salter RB. The effect of the volume of effusion, joint position, and continuous passive motion on intra-articular pressure in the rabbit knee. J Rheum 1983; 10:360–363.
Nade S, Newbold PJ. Factors determining the level and change in pressure in the knee joint of the dog. J Physiol 1983;338:21–36.
Stolk PW, Firth EC. The relationship between intra-articular and juxta-articular intraosseous pressures in the metatarsophalangeal region of the pony. Vet Q 1994; 16:81–86.
Levick JR. Blood flow and mass transport in synovial joints. In: Renkin EM, Michel CC, eds. Handbook of physiology, the cardiovascular system. Vol 4. Baltimore: Microcirculation American Physiologic Society, 1984;917–947.
Hardy J, Bertone AL, Muir WW. Pressure-volume relationships in equine midcarpal joint. J Appl Physiol 1995; 78:1977–1984.
Hardy J, Bertone AL, Muir WW. Joint pressure influences synovial tissue blood flow as determined by colored microspheres. J Appl Phsiol 1996; 80:1225–1232.
American Association of Equine Practitioners. Lameness exams: evaluating the lame horse. Available at: www.aaep.org/health_articles_view.php?id=280. Accessed Sep 10, 2010.
Wallis WJ, Simkin PA, Nelp WB. Low synovial clearance of iodide provides evidence of hypoperfusion in chronic rheumatoid synovitis. Arthritis Rheum 1985; 28:1096–1104.
Wisham LH, Davison S & Gordon L. The effect of weight bearing exercise on radioactive sodium clearance from normal and osteoarthritis knee joints. Arch Phys Med Rehabil 1960; 41:587–590.
Wagner AE, McIlwraith CW, Martin GS. Effect of intra-articular injection of orgotein and saline solution on equine synovia. Am J Vet Res 1982; 43:594–597.
White KK, Hodgson DR, Hancock D, et al. Changes in equine carpal joint synovial fluid in response to the injection of two local anesthetic agents. Cornell Vet 1989; 79:25–38.
Smith JM, Ratzlaff MH, Grant BD. The synovial fluid volume of the radiocarpal, intercarpal and tibiotarsal joint of the horse. J Equine Med Surg 1979; 3:479–483.
Bertone AL, Hardy J, Simmons EJ, et al. Vascular and transsynovial forces of the isolated stationary equine joint. Am J Vet Res 1998; 59:495–503.
Shargel L & Yu A. Pharmacokinetics of oral absorption. In: Shargel L, Yu A, eds. Applied biopharmaceutics and pharmacokinetics. 4th ed. Stamford, Conn: Appleton & Lange, 1999;223–245.
Bragdon B, Bertone AL, Hardy J, et al. Use of an isolated joint model to detect early changes induced by intra-articular injection of paclitaxel-impregnated polymeric microspheres. J Invest Surg 2001; 14:169–182.
Endo MY, Suzuki R, Nagahata N, et al. Differential arterial blood flow response of splanchnic and renal organs during low-intensity cycling exercise in women. Am J Physiol Heart Circ Physiol 2008; 294:H2322–H2326.