Intraosseous infusion of the distal phalanx compared to systemic intravenous infusion for marimastat delivery to equine lamellar tissue.

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.

Pharmacokinetics of the novel atypical opioid tapentadol following oral and intravenous administration in dogs.

Tapentadol (TAP) is a novel opioid pain reliever drug with a dual mechanism of action (mu opioid receptor agonist and noradrenaline reuptake inhibitor). It is used as an analgesic in humans, but could be of interest for veterinary species if it has a suitable pharmacokinetic profile. Six dogs were randomly assigned to two treatment groups, using an open, single-dose, two-treatment, two-period, and randomised cross-over design. Each subject received TAP at 50 and 200mg by intravenous (IV) and oral route, respectively, with a 1-week wash-out period between administrations. Blood was collected at regular intervals and the plasma concentration of TAP in each sample was measured using a validated HPLC-FL method. After IV administration, concentrations of TAP were detectable in plasma for up to 6h with a half-life in the range 38-68 min. After oral administration, drug absorption was rapid (T(max), time required to reach the maximum concentration of 47.5 min), but its bioavailability was low (4.4%). Some dose-related adverse effects, including salivation and sedation, were observed, particularly following IV administration. In summary, this study showed that TAP may be useful as an analgesic in the dog, but further studies, including in dogs requiring analgesia, are required to confirm efficacy.