The Veterinary Journal 206 (2015) 121–122
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The Veterinary Journal
j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / t v j l
Editorial
Acute equine laminitis: Exciting prospects afoot
Equine laminitis continues to present considerable challenges
to clinicians, with limited treatment options in terms of blocking
the disease processes within the foot effectively, or even limiting
the ongoing tissue damage. As we understand more about the disease
mechanisms, additional therapeutic targets will present them-
selves, but as we find ways to block these pathways, a further
challenge will be to determine the optimum means of delivering
drugs to the lamellar tissues in order to achieve adequate local
concentrations.
The equine digital lamellar tissues present a considerable chal-
lenge for drug delivery. The key cells responsible for maintaining
attachment to the basement membrane that forms the interface
between the dermal and epidermal tissues are the lamellar basal
epithelial cells. These cells are on the epidermal side of the base-
ment membrane, which is avascular, and receive their oxygen and
nutrients via diffusion across the membrane from capillaries located
within the primary and secondary dermal lamellae. The vascula-
ture of the digit also has several particular characteristics, including
an extensive series of arteriovenous anastomoses between the ar-
terial and venous sides of the lamellar circulation that plays a role
in heat loss, but makes nutrient capillary blood flow difficult to
predict or quantify. From the terminal arterial arch within the pedal
bone, there are extensive vascular channels through foramina in the
dorsal aspect of the pedal bone, and this forms the major source
of blood supply to the lamellae (Pollitt, 1992).
In a recent issue of The Veterinary Journal, Dr. Claire Under-
wood of the Australian Equine Laminitis Research Unit in the School
of Veterinary Science at The University of Queensland, and her col-
leagues, described a study where they employed the technique of
intraosseous infusion into the distal phalanx to deliver a drug com-
pound to the lamellar tissues, comparing tissue concentrations with
those following systemic intravenous (IV) infusion (Underwood et al.,
2015b).
The drug chosen for this study was a potent inhibitor of matrix
metalloproteinase (MMP) enzymes. The activation of MMPs has been
associated with the breakdown of the lamellar basement mem-
brane in the inflammatory forms of laminitis (Mungall and Pollitt,
1999). While some MMPs are now only thought to play a role during
the acute phase of the disease, others may be involved in the earlier
developmental stages (Visser and Pollitt, 2012; Wang et al., 2014).
The most potent drug inhibitors of these enzymes, such as batimastat
and marimastat, are broad spectrum and tend to be very effective
in vitro. However, they are rapidly cleared following IV adminis-
tration in vivo; also they may have systemic side effects, and in any
case they are prohibitively expensive for use in large animals such
as the horse. Nevertheless, given the significant role that MMP
http://dx.doi.org/10.1016/j.tvjl.2015.07.034
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enzymes are thought to play in causing dermo-epidermal separa-
tion in laminitis (leading to pedal bone rotation, sinking and
unrelenting pain), it is important to evaluate MMP inhibitor drugs
such as these in the treatment of this condition.
Of course, there are many other novel potential therapeutic targets
being considered for the treatment of laminitis. It is now becom-
ing clear that the particular form of laminitis that occurs secondary
to grain overload, colitis and colic, involves systemic inflamma-
tion and inflammatory changes within the lamellae that may have
some similarities with those occurring in organ dysfunction in sepsis
(Belknap and Black, 2012). Recognising these pathways will enable
more targeted and effective anti-inflammatory drugs to be devel-
oped (Leise et al., 2012).
Interest has also been directed towards the mechanism by which
the lamellar basal epithelial cells may fail to maintain their attach-
ments to the basement membrane (in addition to basement
membrane damage caused by MMPs), leading to dermo-epidermal
separation. These mechanisms may include apoptosis (Faleiros et al.,
2004) and perhaps also a process called epithelial-mesenchymal tran-
sition (EMT; Wang et al., 2013). However, any drugs or agents which
might be used to manipulate these processes may have signifi-
cant widespread effects on epithelial cells in other body tissues;
therefore, in order to exploit these potential therapeutic targets in
the management of laminitis, a means of targeting them to the la-
mellar tissues is likely to prove crucial.
Regional limb perfusion has been used quite commonly as a
means of maximising local concentrations of drugs in the distal limbs
of the horse, although normally this is assessed by measuring sy-
novial fluid drug concentrations (Kelmer et al., 2013). The technique
involves the use of a tourniquet, placed dorsal to the metacarpo-
phalangeal joint for 30–45 min, to restrict blood flow (and drug) in
and out of the limb. The drug is typically administered into the
palmar digital vein. Recently, Dr Underwood and her colleagues
evaluated this technique for delivering local concentrations of the
MMP inhibitor drug marimastat to the lamellar tissues (Underwood
et al., 2015a). They found that regional limb perfusion did provide
greater maximum local concentrations of the drug within the la-
mellar tissues compared with systemic IV bolus dosing, although
frequent dosing was still required to maintain therapeutic
concentrations.
In the subsequent paper, Underwood et al. (2015b) trialled an
ingenious method of delivering marimastat to the lamellar tissues,
by placing an intraosseous needle into the distal phalangeal bone
(under sedation and local anaesthesia), so that the administration
of drug into this space would allow it to drain through the vascu-
lar channels in the dorsal surface of the pedal bone directly into the
122 Editorial/The Veterinary Journal 206 (2015) 121–122
lamellar dermis. Another novel part of this remarkable study was
the use of probes placed within the lamellar tissues to collect an
ultrafiltrate of the interstitial fluid in order to measure tissue con-
centrations (Underwood et al., 2015b). This provided a serial
measurement of local drug concentrations for pharmacokinetic anal-
yses, and the successful validation of this technique could be most
useful in investigating the delivery of other novel therapeutic com-
pounds. However, the authors found that there was considerable
variability in the local tissue concentrations achieved using the
intraosseous delivery method and further work is required to de-
termine the optimal site for local delivery of compounds to this
region.
Another approach to maximising local drug concentrations is to
incorporate them into ‘carrier’ particles which can associate with
particular characteristics of the target tissues. For example, lipo-
somes are composed of a phospholipid bilayer surrounding an
aqueous core, and can deliver high concentrations of therapeutic
agents to a target site while reducing their delivery to non-target
organs. This method may be particularly useful for the targeted de-
livery of therapeutic agents to inflamed tissues, since they tend to
extravasate at sites of increased vascular permeability. The safety
and biodistribution of these carrier particles in the horse has been
assessed by members of the same group in a proof of concept study,
using liposomes radiolabelled with technetium-99m (Underwood
et al., 2012). This may well become an attractive method for de-
livering drugs to the inflamed tissues of the digital lamellae during
laminitis. Liposomes are classed as a type of nanoparticle (colloi-
dal particles <1000 nm diameter), and this area of nano-
biotechnology is likely to offer a great deal in terms of more effective
and potent therapeutic products. Antibody-coated nanoparticles also
have potential for targeted drug delivery, but these have yet to be
trialled in the horse.
Larger particles may also be worth considering as reservoirs for
sustained drug release. For example, microspheres just large enough
to be trapped in capillaries have been used to carry growth factors,
such as vascular endothelial cell growth factor, into ischaemic heart
tissue to significantly improve microvascular density and tissue re-
covery (Uitterdijk et al., 2015). However, the large number of
arteriovenous anastomoses in the equine lamellar circulation may
be an impediment to the employment of this technique for drug
delivery to the equine lamellae.
As well as the physical targeting of drugs to sites of action, the
more effective targeting of biological pathways must also play a role.
Pain management is another important area of laminitis therapy,
and our understanding of the nature of laminitis pain has in-
creased greatly in recent years, and, for example, the contribution
of neuropathic pain is now much better recognised (Jones et al.,
2007). Drugs such as gabapentin, tramadol and other more exper-
imental analgesic drugs are now being investigated in the
management of the condition (Guedes et al., 2013, 2015).
The development of novel techniques for delivering therapeu-
tic agents to the equine lamellar tissues may well become an
important component in the quest for more effective treatments and
management strategies for equine laminitis. Optimising and vali-
dating these methods will improve our ability to take advantage of
the discovery of new therapeutic targets and of potentially useful
compounds that might otherwise be unsuitable for systemic ad-
ministration. The evaluation of more selective drugs such as specific
analgesics, anti-inflammatories and MMP inhibitors, will also be
another key objective.
The series of papers from the Queensland group are enhancing
knowledge of novel ways to address this serious and painful con-
dition in the horse. Good progress is being made by this and other
groups across the world and we can be hopeful that a break-
through will emerge soon to the benefit of affected animals,
distressed owners and frustrated veterinarians currently faced with
the management of clinical cases of laminitis.
Simon R. Bailey
Scientific Editor
The Veterinary Journal
Faculty of Veterinary and Agricultural Sciences, University of
Melbourne, Parkville, Victoria, Australia.
E-mail address: bais@unimelb.edu.au
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