Regional intravenous limb perfusion compared to systemic intravenous administration for marimastat delivery to equine lamellar tissue.

This research explores how the best delivery method for a pharmaceutical agent, Marimastat, can prevent laminitis in horses. The study found that regional limb perfusion, a technique for delivering the drug locally, appears to be a superior method than systemic intravenous bolus dosing.

Introduction

• This research was grounded on the premise that laminitis, a painful and serious disease in horses, might be effectively prevented by certain pharmaceutical agents, including an MMP (Matrix Metalloproteinase) inhibitor named Marimastat.
• The challenge with Marimastat is that it’s not practical for systemic administration, in other words, it’s inefficient to deliver it to the entire body through the bloodstream.
• The key purpose of this study was to compare two methods of Marimastat delivery: regional limb perfusion (RLP) and systemic intravenous bolus dosing (SIVB), with a specific focus on the lamellar tissues of horses.

Methodology

• To carry out the comparison, six adult horses received two rounds of treatment. In the first round, 0.23 mg/kg of Marimastat was delivered via RLP, while in the second round, the same amount was delivered via SIVB, with a 24-hour washout period in between.
• Lamellar ultrafiltration probes were used to sample the lamellar interstitial fluid, yielding what the researchers call lamellar ultrafiltrate (LUF).
• The concentrations of Marimastat in both the LUF and the plasma were then measured for 24 hours following each treatment.

Results

• The findings revealed that following regional limb perfusion, the maximum concentration of Marimastat (LUF C(max)) in the lamellar tissues was between 34 to 457 times higher than that achieved through systemic intravenous bolus dosing.
• Moreover, after employing RLP, the Marimastat concentrations in the lamellar tissues were consistently higher than those obtained through SIVB for up to 18 hours.
• The median Marimastat concentrations were found to be greater than the IC90 (the concentration of a drug that gives 90% of the maximum response) of equine lamellar MMP-2 and MMP-9 for approximately 9 hours after tourniquet removal.
• The researchers conclude, therefore, that regional limb perfusion is superior to systemic intravenous bolus dosing for delivering Marimastat to the lamellar tissues of horses.

Implications and Future Research

• Despite the favorable results with RLP, the researchers suggest that frequent dosing is necessary in order to achieve therapeutic lamellar concentrations of Marimastat.
• They propose that RLP could also be used to investigate whether Marimastat can prevent experimentally induced laminitis.
• However, the researchers caution that more refinement to the RLP technique, as well as to the dosing interval, is necessary before a clinical application for preventing laminitis can be envisioned.