Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

DRUGS WITH IMMUNOSUPPRESSIVE EFFECTS
● Optimmune® should not be administered where
there is suspected ocular infection. If persistent mild
ocular irritation is observed, the drug should be
discontinued.
● Ciclosporin is concentrated within the cornea and
is reported to have low systemic bioavailability.
However, one published study has demonstrated a
degree of systemic immunosuppression following
local ophthalmic absorption of 2% ciclosporin
applied for 1–3 months.
Known drug interactions
Much of the data on drug interactions with ciclosporin
is derived from human medicine.
● Drugs that elevate human blood ciclosporin
concentrations include: bromocriptine, danazol,
diltiazem, doxycycline, erythromycin, fluconazole,
itraconazole, ketoconazole, methylprednisolone,
nicardipine and verapamil. In dogs ketoconazole and
vitamin E are known to have this effect.
● Agents that can decrease human blood ciclosporin
concentrations include: carbamazepine, phenobarbital,
phenytoin, rifampicin (rifampin) and intravenous
trimethoprim-sulfamethoxazole.
● Ciclosporin may potentially induce signs of CNS
toxicity if coadministered with ivermectin or
milbemycin.
● Ciclosporin may increase the nephrotoxicity of aminoglycoside
antibiotics and trimethoprim and should
not be coadministered with these agents.
● In the dog ketoconazole given at 5–10 mg/kg can
increase the blood concentration of ciclosporin by up
to fivefold and this agent may be used to reduce
the required dose of ciclosporin. When ketoconazole
is used in this fashion, the dose of Neoral® should
be halved (i.e. 2.5 mg/kg q.24 h) or the treatment
interval should be doubled (i.e. 5 mg/kg q.48 h).
However, careful individualization of dose rates
will be necessary due to interanimal variation in
responses.
● Unlike the situation in humans, there is no interaction
between concurrently administered methylprednisolone
and ciclosporin in dogs.
● Animals treated with ciclosporin should not receive
a live attenuated vaccine whilst being treated, or
within 2 weeks before or after treatment.
Special considerations
Ciclosporin A remains a relatively expensive immunosuppressive
drug. Owners should be instructed to
administer the drug carefully to reduce their exposure.
For example, Optimmune® should be applied using
gloves and contact with the skin should be avoided.
Danazol
Clinical applications
In small animal medicine, danazol, a synthetic attenuated
androgen, has been used as an adjunct therapy for
canine immune-mediated hemolytic anemia (IMHA)
and thrombocytopenia (IMTP). The use of danazol
enables treatment with reduced doses of corticosteroid,
thus decreasing the likelihood of glucocorticoid side
effects in these patients. The use of danazol in this
manner is contentious and there have been few controlled
clinical trials demonstrating efficacy of the drug.
In fact, recent studies in dogs with IMHA have suggested
that danazol provides no benefit, above the
immunosuppression achieved with prednisolone and
azathioprine.
Mechanism of action
Use of danazol therapy in IMHA is based upon the following
reported actions of the drug.
● Downregulation of Fc-receptor expression by
macrophages, thereby decreasing extravascular
hemolysis mediated by erythrocyte-bound antibody.
● Reduced number of immunoglobulin molecules
coating erythrocytes.
● Alteration of T-lymphocyte immunoregulation.
● Incorporation of the drug into the erythrocyte
membrane, stabilizing the membrane so the
erythrocyte becomes less susceptible to hemolysis.
Formulations and dose rates
Danazol (Danocrine®; 50, 100 or 200 mg capsules; Winthrop Pharmaceuticals)
is not a licensed veterinary product.
Danazol is reported to have a slow onset of action (2–3 weeks),
so is administered at a dose of 3–5 mg/kg q.8 h PO, concurrently
with prednisolone (and/or azathioprine). Following tapering of the
prednisolone dose, danazol therapy is continued at 5 mg/kg
q.24 h. Danazol may then be tapered after 2–3 months of normal
hemograms.
Danazol therapy is suitable for dogs with chronic, stable IMHA but
not those animals with acute-onset, severe hemolysis.
Pharmacokinetics
The pharmacokinetics of danazol in the dog are virtually
unknown. By analogy with results from studies in
experimental animals and humans, danazol is assumed
to be largely metabolized in the liver of cats and dogs.
Adverse effects
● The most significant adverse effect reported in the
dog is hepatotoxicity.
● Danazol is not currently recommended for use in the
cat, as those few animals treated with the drug devel-
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