Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

DRUGS WITH IMMUNOSTIMULATORY EFFECTS
● immunostimulation in neoplastic disease. Limited
studies of levamisole used in this context have
shown no significant benefit when used as an
adjuvant to surgical management of mammary
adenocarcinoma (cat and dog), or when given with
combination chemotherapy for canine lymphoma.
In the dog, levamisole has also been used in combination
with prednisolone for the treatment of SLE. The
drug has occasionally been used as adjunct therapy in
feline chronic gingivostomatitis or eosinophilic granuloma
complex, but there appears to be little conclusive
evidence for an effect in these conditions. The antiparasitic
effects of levamisole are discussed in Chapter 10.
Mechanism of action
The mechanism by which levamisole causes immunomodulation
is poorly understood and there have been
very few studies of the effect of this drug on immune
parameters in the dog and cat. Properties that have been
attributed to this agent include:
● enhancement of T-lymphocyte number and
function, but no direct effect on B lymphocytes or
antibody production
● enhanced chemotaxis, phagocytosis and
intracellular killing by granulocytes and monocytes.
Levamisole will not enhance immune function to ‘supranormal’
levels but may improve subnormal immunity.
The drug may enhance the immune response to an antigenic
stimulus (e.g. vaccine) given concurrently. It has
been suggested that levamisole may affect the metabolism
of cyclic nucleotides, by increasing cAMP breakdown
and decreasing cGMP inactivation.
Early studies of dogs with generalized demodicosis
demonstrated that levamisole therapy was able to
restore the depressed blood lymphocyte mitogen responsiveness
that accompanies this disease without altering
cutaneous mite populations. In dogs with SLE, there is
a peripheral blood lymphopenia with an alteration in
the CD4 : CD8 T-lymphocyte ratio in circulating blood,
due to a decrease in the number of CD8 + T cells. Following
successful levamisole therapy, there is elevation
in CD8 + T-cell number, but if therapy is clinically unsuccessful
the number of CD8 + cells remains low.
Formulations and dose rates
Levamisole is the levoenantiomer of the synthetic anthelmintic tetramisole
and is most widely available as levamisole hydrochloride. As
levamisole is not currently licensed for companion animal use, the
forms of the drug most commonly administered to dogs and cats are
those produced for large animal purposes – either an oral bolus, an
oral solution or an injectable solution (e.g. Levadin®, Vetoquinol). The
diffi culty in accurately breaking the bolus makes this form more suit-
able for larger dogs, whereas for smaller companion animals oral
administration of the injectable or oral solutions is the method of
choice.
• A range of dosages is reported for the use of levamisole as an
adjunct immunostimulant in the dog, but those most commonly
quoted are 2.2 mg/kg PO every other day, or 0.5–2.0 mg/kg PO
given three times per week. It has been suggested that dosage
out of this range may cause immunosuppression rather than
enhancement
• In the therapy of canine SLE, oral levamisole is administered at
2.0–5.0 mg/kg (to a maximum of 150 mg per dog) on alternate
days, concurrently with prednisolone at 0.5–1.0 mg/kg q.12 h.
The prednisolone is tapered and eliminated over 1–2 months,
whereas levamisole is continued at the same dose for a 4-
month period. If an animal undergoes disease relapse,
treatment with levamisole alone for 4 months is recommended
• In the cat, the reported immunomodulatory dose of levamisole
is again variable, but one regimen uses the drug at 25 mg/cat
PO q.24 h for three doses only
Pharmacokinetics
Levamisole is rapidly absorbed from the gut and becomes
widely distributed throughout the body, with peak
plasma levels obtained in 1–2 h. The plasma elimination
half-life in the dog is 2–4 h and the majority (95%) of
the drug is metabolized in the liver and excreted in urine
(primarily) and feces.
Adverse effects
● In the dog: lethargy, vomiting, diarrhea, panting,
shaking, agitation, behavioral changes, hemolytic
anemia, agranulocytosis, dyspnea, pulmonary edema
and cutaneous drug eruption (particularly of the
erythema multiforme–toxic epidermal necrolysis
spectrum).
● In the cat: hypersalivation, excitement, mydriasis and
vomiting.
Contraindications and precautions
● Levamisole should not be given to lactating animals
or to animals that are debilitated or have marked
impairment of renal or hepatic function.
● There is no information regarding the safety of the
drug in pregnant companion animals. However, no
embryotoxicity or teratogenicity was noted in continuous
feeding studies of pregnant rats, rabbits or
pigs.
Known drug interactions
The toxic effects may be enhanced by the use of
concurrent cholinesterase inhibitors (e.g. neostigmine,
organophosphates) or nicotine-like agents (e.g.
diethylcarbamazine).
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