title: Intraosseous infusion of the distal phalanx compared to systemic intravenous infusion for marimastat delivery to equine lamellar tissue.
abstract: No validated laminitis drug therapy exists, yet pharmaceutical agents with potential for laminitis prevention have been identified. Many of these are impractical for systemic administration but may be effective if administered locally. This study compared intraosseous infusion of the distal phalanx (IOIDP) with systemic intravenous constant rate infusion (CRI) to determine which was more effective for lamellar marimastat delivery. Ultrafiltration probes were placed in both forefeet of five horses to collect lamellar interstitial fluid as lamellar ultrafiltrate (LUF). Marimastat solution (3.5 mg/mL) containing lidocaine (20 mg/mL) was infused by IOIDP at 0.15 mL/min for 12 h. After a 12 h wash-out, marimastat (3.5 mg/mL) and lidocaine were infused by constant rate infusion (CRI) at 0.15 mL/min for 12 h. LUF, plasma and lamellar tissue marimastat concentrations were quantified using UPLC-MS. Zymography was used to establish the inhibitory concentrations of marimastat for equine lamellar matrix metalloproteinases (MMPs). Data were analysed non-parametrically. There was no difference between the steady-state marimastat concentration in lamellar ultrafiltrate (LUF[M]) during IOIDP (139[88-497] ng/mL) and CRI (136[93-157] ng/mL). During IOIDP, there was no difference between marimastat concentrations in the treated foot (139[88-497] ng/mL), the untreated foot (91[63-154] ng/mL) and plasma (101[93-118] ng/mL). LUF[M] after IOIDP and CRI were >IC50 of lamellar MMP-2 and 9, but below the concentration considered necessary for in vivo laminitis prevention. Lamellar drug delivery during IOIDP was inconsistent and did not achieve higher lamellar marimastat concentrations than CRI. Modification or refinement of the IOIDP technique is necessary if it is to be consistently effective.
authors.affiliation: Australian Equine Laminitis Research Unit, School of Veterinary Science, The University of Queensland, Gatton, Queensland, Australia. Electronic address: c.underwood1@uq.edu.au.
authors.forename: Claire
authors.initials: C
authors.lastname: Underwood
authors.affiliation: Australian Equine Laminitis Research Unit, School of Veterinary Science, The University of Queensland, Gatton, Queensland, Australia.
authors.forename: Simon N
authors.initials: SN
authors.lastname: Collins
authors.affiliation: Australian Equine Laminitis Research Unit, School of Veterinary Science, The University of Queensland, Gatton, Queensland, Australia.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: van Eps
authors.affiliation: Australian Equine Laminitis Research Unit, School of Veterinary Science, The University of Queensland, Gatton, Queensland, Australia.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Mills
authors.affiliation: Australian Equine Laminitis Research Unit, School of Veterinary Science, The University of Queensland, Gatton, Queensland, Australia.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Allavena
authors.affiliation: Faculty of Veterinary Science, The University of Melbourne, Werribee, Victoria, Australia.
authors.forename: Simon R
authors.initials: SR
authors.lastname: Bailey
authors.affiliation: Australian Equine Laminitis Research Unit, School of Veterinary Science, The University of Queensland, Gatton, Queensland, Australia.
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Medina Torres
authors.affiliation: Innovative Methods (Queensland) Ltd., 27 Price Street, Riverview, Queensland, Australia.
authors.forename: Alon
authors.initials: A
authors.lastname: Meizler
authors.affiliation: Australian Equine Laminitis Research Unit, School of Veterinary Science, The University of Queensland, Gatton, Queensland, Australia.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Pollitt
mesh_terms: D000818:Animals; D005260:Female; D005534:Foot Diseases / Q000662:veterinary*; D006724:Hoof and Claw; D006734:Horse Diseases / Q000188:drug therapy*; D006736:Horses; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000627:therapeutic use; D017148:Infusions, Intraosseous / Q000662:veterinary*; D007262:Infusions, Intravenous / Q000662:veterinary*; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use
chemical_list: D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; C100342:marimastat
keywords: Horse; Laminitis; MMP-inhibitor; Pharmacokinetics; Ultrafiltration