Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 12 IMMUNOMODULATORY THERAPY
T and B lymphocytes that lack a pyrimidine salvage
pathway.
Formulations and dose rates
In the studies cited above, lefl unomide was initially administered in
conjunction with other immunosuppressive therapy (with progression
to lefl unomide monotherapy) at a dose of 4 mg/kg q.24 h PO, with
the plasma trough level adjusted to 20 µg/mL. Lefl unomide is not a
licensed veterinary medicine.
Pharmacokinetics
Following oral administration, leflunomide is almost
completely absorbed and immediately subject to nonenzymatic
conversion in the intestinal mucosa, portal
circulation and liver to the active metabolite A77 1726
(3 cyano-3-hydroxy-N-[4-trifluoromethylphenyl] crotonamide
or M1). Little leflunomide is detectable in
plasma, indicative of the extensive metabolism. M1 is
further biotransformed in the liver and excreted by both
biliary and renal routes. Reabsorption from the small
intestine after biliary excretion leads to enterohepatic
recycling, contributing to the long elimination half-life
of M1 of more than 7 d.
Megestrol acetate
Clinical applications
Megestrol acetate is an oral progestin most commonly
used for prevention or postponement of estrus in the
bitch or queen and a range of canine reproductive and
behavioral problems (see Chapters 7 and 23). The drug
is also used in the management of feline miliary dermatitis
and the eosinophilic granuloma complex, both of
which are manifestations of cutaneous hypersensitivity
in the cat. However, because of the high incidence of
adverse effects, the drug is not recommended for management
of these disorders unless there is no alternative.
Mechanism of action
The mechanism of action of megestrol acetate in these
disorders is not completely understood. The drug has
more potent anti-inflammatory and adrenal-suppressive
effects than corticosteroids, but the additional possibility
of immunosuppressive properties has been discussed
by some authors.
Formulations and dose rates
CATS
• The dosage regimen for feline cutaneous hypersensitivity
disease is 2.5–5 mg/cat q.48–72 h PO until a response is
observed and then the dose is reduced to 2.5–5 mg/cat q.7 d
• A maintenance dose of 2.5 mg/cat q.7–14 d may be required to
prevent recurrence, or repeated courses of treatment may be
given
Adverse effects
Multiple side effects have been reported and include:
● increased appetite
● weight gain
● depression/lethargy
● mammary gland hyperplasia and carcinoma
● diabetes mellitus (transient and permanent)
● bone marrow suppression
● endometrial hyperplasia
● pyometra
● adrenocortical suppression
● thinning and increased fragility of the skin.
Contraindications and precautions
● Progestins should not be used in intact females,
breeding animals and in animals with diabetes
mellitus (increases insulin resistance)
● Concurrent corticosteroid use is contraindicated.
Pentoxifylline
Clinical applications
Pentoxifylline (Trental®, Hoechst) has found application
in the therapy of a range of canine skin diseases,
including vasculitis, rabies vaccine-induced ischemic
dermatitis, dermatomyositis, ulcerative dermatosis of
shelties and collies, and contact allergy. There is some
evidence that the drug has a useful adjunct role in the
therapy of atopic dermatitis.
Mechanism of action
Pentoxifylline is a methylxanthine derivative and nonselective
inhibitor of the cyclic nucleotide phosphodiesterases
that increase the rate of breakdown of cAMP
and cGMP. The drug has two major clinical effects:
● increasing microvascular blood flow, thereby enhancing
oxygenation of ischemic tissue. This effect is
attributed to increased erythrocyte membrane
deformability, vasodilation, reduced erythrocyte and
platelet aggregation and enhanced fibrinolysis
● immunomodulation, particularly by suppressing synthesis
of proinflammatory cytokines (IL-1, IL-6, IL-
12, TNF-α) by lymphocytes and keratinocytes and
inhibiting adhesion between leukocytes and endothelial
or epithelial cells. There may also be inhibitory
effects on neutrophil, T and B lymphocytes and NK
cell activity.
Formulations and dose rates
• A range of dose rates is reported and long-term therapy is
generally indicated with a trial period of 2–3 months
• Pentoxifylline has been administered to dogs with dermatomyositis
or ulcerative dermatosis at 400 mg/dog q.12 h (or for small
dogs 200 mg/dog q.12 h) and to dogs with contact dermatitis or
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