Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

DRUGS WITH IMMUNOSUPPRESSIVE EFFECTS
epitheliotrophic lymphoma, reactive histiocytosis,
sebaceous adenitis and inflammatory bowel disease.
By contrast, ciclosporin appears not to be of clinical
benefit in the treatment of canine immune-complex
glomerulonephritis.
Topical ocular ciclosporin has immunosuppressive,
anti-inflammatory and lacrimomimetic properties and is
therefore indicated for immune-mediated diseases such
as keratoconjunctivitis sicca (KCS, ‘dry eye’), chronic
superficial keratitis (‘pannus’) and nictitans plasmacytic
conjunctivitis (plasmoma) in the dog. The efficacy of
ciclosporin in KCS probably results from local (lacrimal
gland) anti-inflammatory effects, although a direct stimulatory
effect on glandular tissue by binding to lacrimal
gland receptors has been proposed.
It has been shown that topical ciclosporin reduces
apoptosis (‘programmed cell death’) by lacrimal epithelium
and enhances apoptosis of infiltrating lymphocytes
in canine KCS. The clinical effects of ciclosporin are
greater in the early stages of KCS. Where the Schirmer
tear test value is 0–1.0 mm/min, improved lacrimation
may only occur in 50% of cases. In the cat, topical
ciclosporin has been used for cases of eosinophilic keratoconjunctivitis,
but variable efficacy is reported. The
ocular application of ciclosporin is also discussed in
Chapter 25.
Mechanism of action
Ciclosporin is a cyclic polypeptide containing 11 amino
acids derived from a Norwegian soil fungus, Tolypocladium
inflatum. The agent binds specifically to a cytoplasmic
molecule (cyclophilin) that is expressed in high
concentration in T lymphocytes. The complex of
ciclosporin-cyclophilin in turn binds to and blocks
another cytoplasmic molecule known as calcineurin. In
a normal T cell, calcineurin is activated by the cytoplasmic
influx of Ca 2+ that follows T cell-receptor engagement
by antigen presented by major histocompatibility
molecules on the surface of an antigen-presenting cell.
In turn, calcineurin activates the ‘nuclear factor of activated
T cells’ (NF-AT), which migrates to the nucleus
and binds the transcription factor AP-1. The complex
of AP-1 with NF-AT induces the transcription of genes
required for T-cell activation, particularly the gene
encoding the cytokine interleukin 2 (IL-2).
The effects of ciclosporin on T lymphocytes include
reduced production of IL-2, IL-3, IL-4, granulocyte
colony-stimulating factor (G-CSF) and tumor necrosis
factor (TNF-α), in addition to reduced clonal proliferation
of the cell. This in turn results in reduced clonal
proliferation of B lymphocytes and has indirect effects
on a range of other cell types (granulocytes, macrophages,
natural killer (NK) cells, eosinophils, mast cells).
A recent in vitro study of the effects of ciclosporin on
cultured feline lymphocytes has shown that this agent
can potently suppress the proliferative response of both
CD4 + and CD8 + T cells. Ciclosporin is also known
to directly affect granulocyte function via reducing
Ca 2+ -dependent exocytosis of granule-associated serine
esterases. In vitro studies of isolated canine skin mast
cells have shown that ciclosporin is a potent inhibitor
of histamine release induced by nonimmunological or
immunological stimuli. Finally, the immunosuppression
mediated by ciclosporin may reflect the induction of
transforming growth factor β (TGF-β), a potent inhibitor
of IL-2 stimulated T-cell proliferation.
Two further molecules have now been developed for
such selective T-cell immunosuppression but are not yet
used widely in veterinary medicine. The agent tacrolimus
(formerly FK506) is derived from the bacterium
Streptomyces tsukabaensis and the drug rapamycin (or
sirolimus) is obtained from Streptomyces hygroscopicus
(originally obtained from Rapa Nui or Easter Island).
Tacrolimus selectively binds the T-cell cytoplasmic molecules
known as FK-binding proteins (FKBP), while the
complex of tacrolimus-FKBP also binds and inhibits
calcineurin. FKBP and cyclophilin are both members
of the family of intracellular immunophilin proteins.
Tacrolimus blocks transcription of genes encoding IL-2
and IL-4. By contrast, rapamycin acts in a different
fashion from ciclosporin or tacrolimus; it binds FKBP
but the complex does not affect calcineurin, but blocks
the complex signal transduction pathway triggered by
binding of IL-2, IL-4 or IL-6 to their specific membrane
receptors.
Formulations and dose rates
The licensed veterinary formulation of ciclosporin for systemic
administration is Neoral® (Novartis). This is an orally administered,
microemulsion formulation of ciclosporin, which has greater bioavailability
and less variability in pharmacokinetics than the earlier human
formulation that was used in companion animals (Sandimmun®,
Novartis). The advantage of Neoral® is that it produces more stable
blood concentrations, thus reducing the need for regular monitoring
of this parameter. Neoral® is available as soft capsules containing
either 10, 25, 50 or 100 mg of ciclosporin. Sandimmun® was used
as either an oral capsule formulation or as a solution for intravenous
injection.
For topical ophthalmic use, Optimmune® (Schering-Plough) is a
0.2% w/w ciclosporin ointment that is also a licensed veterinary formulation.
A human formulation of tacrolimus ointment is currently
being evaluated for topical cutaneous application in canine atopic
dermatitis, anal furunculosis or deep pyoderma with localized sinus
tract formation.
The recommended dose rate for Neoral® in the treatment of canine
atopic dermatitis is 5 mg/kg q.24 h given at least 2 h before or after
feeding. The aim of therapy is to achieve a blood trough concentration
of 400–600 ng/mL of ciclosporin and appropriate assays for determination
of blood concentration are generally accessible. Whilst
such assays were routinely performed following administration of
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