Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 10 ANTIPARASITIC DRUGS
In another study, dogs were experimentally infected
with Leishmania spp and treated with meglumine antimonate
at 75 mg/kg SC q.12 h for 10 days. Peak plasma
concentrations of 31 µg/mL were observed and antimony
concentrations above 1 µg/mL were detected
throughout the study.
It is hypothesized on the basis of mechanism of action
that the most efficacious dose regimen is likely to be one
that ensures that antimony concentrations in blood and
at the site of action are maintained for as long as possible
above a yet to be confirmed minimum concentration.
Divided doses given repeatedly are likely to yield better
outcomes in terms of efficacy and safety than the same
total dose given less frequently.
In cases of antimony toxicity, the use of the chelating
agent DMSA (2,3,dimercapto-succinic acid) has been
proposed but not evaluated in dogs.
Adverse effects
● Relapses are the rule and it is to be expected that
multiple treatment courses will be necessary.
● Infrequently, intravenous administration is associated
with thrombophlebitis, intramuscular administration
with severe muscle fibrosis and lameness, and
subcutaneous administration with painful local
swelling.
● The least significant reactions favor the adoption of
subcutaneous administration.
Atovaquone
2-[trans-4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-
naphthoquinone.
Atovaquone, a hydroxynaphthoquinone, is highly
lipophilic with structural similarity to ubiquinone,
whose activity it has been shown to inhibit. Atovaquone
selectively blocks mitochondrial electron transport and
ATP and pyrimidine biosynthesis in susceptible protozoa.
It is administered orally but has poor bioavailability
unless coadministered with a fatty meal, which
increases the fraction absorbed threefold. The drug is
highly protein bound, does not appear to be metabolized
and has an elimination half-life of 2–3 days in
humans. It is administered to dogs at 15 mg/kg PO
q.12 h for 3 weeks and is active against Pneumocystis
and (uniquely) Toxoplasma tissue cysts (bradyzoites).
The activity of atovaquone in a mouse model of
toxoplasmosis was significantly improved by coadministration
of sulfadiazine or pyrimethamine. Recently,
liposome-encapsulated atovaquone has been shown to
be active in the experimental treatment of visceral
leishmaniasis.
Parvaquone and buparvaquone, the butyl analog of
parvaquone, have not been found to be effective antiprotozoal
drugs in dogs or cats.
Benznidazole
N-benzyl-2-(2-nitroimidazole-1-yl)acetamide.
Benznidazole, a 2-nitroimidazole and analog of the
more familiar 5-nitroimidazole metronidazole, acts by
interfering with polymerases and DNA templates of susceptible
protozoa, inhibiting RNA and protein synthesis.
The nitro group is reduced by parasite metabolic
pathways, resulting in the formation of reactive anion
species, toxic to a parasite that is deficient in catalase
and peroxidase activity.
Following oral administration, benznidazole is
absorbed rapidly and completely, with peak plasma
concentrations achieved in 3–4 h. Benznidazole appears
to be extensively metabolized, with only 5% of
unchanged drug excreted in urine. The elimination halflife
is approximately 12 h.
Benznidazole is indicated for the treatment of infection
with Trypanosoma cruzi. In humans it is administered
orally at 2–4 mg/kg q.12 h for 30–60 days. The
dose regimen in dogs has not been clearly defined.
Relapses are frequent and parasitological cure is not
reliably achieved. Best results are associated with treatment
of early infections.
Adverse effects include vomiting, skin reactions and
encephalopathy, frequently leading to cessation of
treatment.
Decoquinate
Ethyl 6-(n-decycloxy)-7-ethoxy-4-hydroxyquinoline-3-
carboxylate.
Decoquinate, used currently as an anticoccidial agent
in cattle and formerly in poultry (before resistant
Eimeria were rapidly selected, rendering efficacy insufficient),
has recently been evaluated for a possible role
in the management of a variety of protozoal infections,
including hepatozoonosis.
Decoquinate is a potent inhibitor of mitochondrial
respiration in susceptible protozoal species, acting at a
site near cyctochrome b. However, alternative respiratory
pathways appear to be selected rapidly, consistent
with field experience of the early emergence of decoquinate-resistant
Eimeria in poultry and experimental
selection of resistant Toxoplasma. In poultry Eimeria,
the species most studied, decoquinate has various
effects according to the stage of the protozoal life-cycle,
including a static effect on sporozoites, a lethal
effect on schizonts and an inhibitory effect on oocyst
sporulation.
The pharmacokinetic profile of decoquinate has not
yet been described in the dog. However, aqueous solubility
of decoquinate is very low and gastrointestinal
absorption is therefore expected to be very low, but
influenced by feeding regimen. In poultry, parenteral
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