In ‘Laminitis – understanding, cure, prevention’ you can read how an imbalance between the protein degrading enzymes MMP-2, MMP-9, ADAMTS-4 and their endogenous enzyme inhibitors (TIMPs) can contribute to the progress of laminitis during the acute phase of the disease. Administration of exogenous (synthetic) enzyme inhibitors could reduce the activity of MMPs and ADAMTs – significantly slowing this progress or even stopping it altogether. Enzyme inhibiting drugs used for this purpose – although as yet experimentally – are Marimastat and Batimastat.
Intravenous administration
Unfortunately the active ingredients in these drugs break down rapidly when administered intravenously. In addition it appears to be difficult to get them to reach the appropriate location in the hoof. It should be added that this applies to many other drugs targeting the lamellar tissue. In addition, these drugs can cause many and serious side effects when administered this way.
Basement membrane
The basement membrane is located between the dermal lamellae and the epidermal lamellae. This membrane is a connective tissue which attaches the dermal and epidermal lamellae to each other, in the same way as the dermis and the epidermis are held together in human skin. The basal cells that are responsible for the lamellar attachment are located at the avascular epidermal side of the basement membrane. Oxygen, nutrients and hormones reach these cells by means of diffusion through the basement membrane, from the capillaries of the dermal lamellae. This same process of diffusion applies to the active agents of the enzyme inhibiting drugs described here.
Shunting
The circulation in the capillaries is, however, influenced to a significant extent by the action of arteriovenous anastomoses (shunts) in the hoof. These direct connections between arteries and veins can open or close, through which they control the blood supply to the hoof. This mechanism, called shunting, makes it difficult to predict if, and to which extent, the active ingredients of the drug will achieve proximity to the basal cells.
Intraosseous administration
The blood supply to the dermal lamellae is established, for the most part, through blood vessels that come from the coffin bone. It seems more effective, therefore, to inject the drug directly into the marrow of the coffin bone. This must be done with the animal under sedation and a regional nerve blockade in place. A disadvantage is that each leg has to be treated separately.
Regional limb perfusion
In this procedure, the blood supply of the leg is temporarily isolated from the rest of the body using a tourniquet. Then (with sedation and a nerve blockade) the drug is injected into the blood vessels. Subsequently, the drug circulates for approximately 45 minutes in the lower leg. The treatment is repeated a few times, at 6-hour intervals. Because the drug doesn’t reach vital body parts a relatively high dose can be used. In the case of Marimastat and Batimastat, regional limb perfusion appears to be much more effective than intravenous administration. The risk of systemic side effects is lower.
As with intraosseous administration, each leg must be treated separately. There is also a risk of complications, such as vascular inflammation (vasculitis), inflammation of subcutaneous tissue (cellulitis), limb swelling, or haematoma formation. Nerve or tissue damage may also result if the tourniquet is kept on for too long.
