Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

DRUGS WITH IMMUNOSUPPRESSIVE EFFECTS
Known drug interactions
● There are few data for veterinary patients, but in
humans the potential for toxicity is elevated with
concurrent administration of penicillamine or antimalarial
drugs.
● Gold salts should not be administered concurrently
with cytotoxic immunosuppressive drugs.
Special considerations
The use of gold salts should only be considered following
unsuccessful trials of other less toxic and expensive
immunosuppressive agents. Animals receiving chrysotherapy
should have regular monitoring of hematological
and renal (urinalysis) parameters at baseline, then
every 2 weeks initially and then every 1–2 months. Gold
salts are potentially teratogenic and their use is contraindicated
in pregnancy.
Intravenous immunoglobulin
Clinical applications
Intravenous infusion of a preparation of intact human
immunoglobulin (IVIG) precipitated from pooled
plasma (Gamimune®, Miles Inc.) has been used in the
treatment of canine nonregenerative IMHA or IMTP
refractory to standard immunosuppressive therapy.
IVIG has more recently found application in the treatment
of some forms of immune-mediated skin disease
(in particular those of the erythema multiforme–toxic
epidermal necrolysis spectrum).
Mechanism of action
The mode of action of the immunoglobulin is probably
via:
● saturation of Fc receptors on macrophages, preventing
binding of cell-bound autoantibody. IVIG inhibits
the binding of canine IgG to monocytes and
inhibits phagocytosis of antibody-coated canine
erythrocytes in vitro. This effect likely underlies the
mode of action of IVIG in the treatment of IMHA
and IMTP.
● modulation of T- and B-lymphocyte function via
binding of immunoglobulin to molecules on the
surface membrane of these cells. IVIG has been
shown to bind to canine T (CD4 + and CD8 + ) and B
lymphocytes in vitro. In humans, there is evidence
that the immunoglobulin in IVIG blocks the interaction
between the molecules Fas (CD95) and Fasligand
(CD95R) which are involved in the induction
of apoptosis in lymphocyte-mediated cytotoxic
destruction of target cells. This effect likely underlies
the mode of action of IVIG in the treatment of
immune-mediated skin diseases such as erythema
multiforme which involve lymphocyte-mediated
killing of epidermal keratinocytes.
Formulations and dose rates
• The immunoglobulin is administered at a dose of 0.5–1.5 g/kg
by IV infusion over a 6–12 h period and is generally given
concurrently with other immunosuppressive therapy. In most
cases only a single treatment is performed
• Following infusion, canine patients develop a rapid, transient
elevation of hematocrit and evidence of reticulocytosis
Adverse effects
No adverse effects have been recorded in dogs transfused
with IVIG; however, the half-life of human
immuno globulin in dogs (7–9 days) is shorter than in
humans, which might suggest that the dog makes an
endogenous antibody response to the human molecules.
Repeated administration will likely sensitize a dog such
that hypersensitivity reactions may occur on subsequent
exposures.
Special considerations
The product is expensive and may have limited availability
when demand is high for human patients.
Leflunomide
Clinical applications
Leflunomide, a synthetic isoxazole derivative and
disease-modifying antirheumantic drug, has been shown
to be a potent immunosuppressive agent in experimental
models of immune-mediated disease and in the
therapy of human autoimmune disease, particularly
rheumatoid arthritis. In veterinary medicine, this agent
has to date found widest application in experimental
studies of transplantation in the dog, where it is
used in combination with other immunosuppressive
modalities.
One study has shown that leflunomide can also be
effective in the treatment of canine immune-mediated
diseases that are refractory to standard therapies,
or where there are side effects from glucocorticoid
administration. Leflunomide treatment has been
reported as being of benefit for dogs with IMHA, IMTP,
Evans’ syndrome, multifocal nonsuppurative encephalitis/meningomyelitis,
immune-mediated polymyositis
and pemphigus foliaceus. The drug is particularly effective
in the therapy of canine reactive histiocytosis. Combination
therapy with leflunomide and methotrexate
has recently been reported as efficacious in cats with
immune-mediated polyarthritis.
Mechanism of action
The primary immunomodulation mechanism of action
of leflunomide is selective inhibition of dihydro-orotate
dehydrogenase, a mitochondrial enzyme essential for de
novo pyrimidine biosynthesis, which particularly affects
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