Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

NEW TRIAZOLES
Pharmacokinetics
As previously mentioned, clotrimazole has very poor
oral bioavailability. Less than 3% is absorbed from
mucosal surfaces and less than 0.5% is absorbed through
the skin. Most of the absorbed drug is metabolized on
first pass through the liver.
Adverse effects
● Pharyngeal and upper airway irritation is a potential
complication. Care should be taken to allow all of
the solution to drain from the nasal cavity by keeping
the head tilted ventrally over the edge of the table
for a short period of time after the procedure. In
addition, gauze sponges should be packed into the
pharynx during the procedure to catch any of the
solution that may leak from the nasopharynx.
● In dogs with cribriform invasion, clotrimazole
may cause CNS irritation, which may result in
seizures.
NEW TRIAZOLES
The emergence in human patients of azole-resistant
fungal pathogens (zygomycetes, dematiaceous fungi,
Candida krusei, C. glabrata, some strains of C. albicans,
Trichosporon spp, Fusarium spp, Scedosporium spp
and some Aspergillus spp) has prompted a search for
new triazoles with greater potency and a wider spectrum
of activity. The first of these new-generation triazoles
to undergo clinical evaluation are voriconazole,
posaconazole, ravuconazole and albaconazole. Of these,
only voriconazole has achieved FDA approval and is
currently available for clinical use in humans in the
USA. Both voriconazole and posaconazole are approved
for medical clinical use by the European Union.
Voriconazole
Voriconazole (Vfend®, Pfizer) is a fluconazole derivative
that has demonstrated potent activity against many
common opportunistic and endemic fungal pathogens
in both laboratory animals and humans, with the
notable exception of zygomycosis caused by pathogens
in the order Mucorales. In human patients, voriconazole
is indicated for the treatment of invasive aspergillosis,
esophageal candidiasis and infections caused by Scedosporium
apiospermum and Fusarium spp. Although
there are no reports to date of the clinical use of voriconazole
in veterinary patients, its pharmacokinetic
behaviour in the dog has been described. Its expected
clinical applications include the treatment of localized
fungal infections that are often poorly responsive to
itraconazole (such as pheohyphomycosis and mycetoma)
and the topical treatment of fungal keratitis in
horses. It may also be considered an alternative to
amphotericin B for the treatment of systemic aspergillosis,
disseminated hyalohyphomycosis and endemic
mycoses. Unfortunately, its high expense significantly
limits its use in veterinary patients.
The recommended dose of voriconazole in human
patients is 6 mg/kg q.12 h for 24 h, followed by 4 mg/kg
q.12 h thereafter. Voriconazole has excellent oral bioavailability
and can be administered either orally or
intravenously. It has also been shown to penetrate the
anterior and posterior segments of the eye following
topical or oral administration in people and horses. A
recent study in healthy horses showed that a 1% voriconazole
solution applied topically to the eye was well
tolerated and is a reasonable choice for future clinical
studies of equine fungal keratitis.
Posaconazole
Posaconazole (Noxafil®, Schering-Plough), a highly
potent itraconazole analog, is arguably the most broadspectrum
azole to be approved by the FDA. Data from
in vitro studies, animal studies and clinical trials support
its activity against a wide variety of fungal pathogens,
including Candida spp (including azole-resistant species),
Aspergillus spp, Fusarium spp, Scedosporium spp,
dematiaceous fungi and the causative agents of the
endemic mycoses.
In addition, posaconazole is the first azole to show
significant efficacy for the treatment of zygomycosis
caused by molds in the order Mucorales. In clinical
trials, posaconazole has been shown to be as effective
as liposomal amphotericin B and voriconazole for the
treatment of refractory aspergillosis. The anticipated
clinical applications of posaconazole in human patients
include the treatment of invasive fungal infections
that are resistant to itraconazole (e.g. aspergillosis,
zygomycosis, pheohyphomycosis, fusariosis and scedosporiosis),
refractory endemic mycoses (e.g. coccidioidomcyosis,
histoplasmosis and cryptococcosis) and
azole-resistant candidiasis. Posaconazole was approved
in the European Union in October 2005 for the treatment
of certain serious invasive fungal infections and it
was released in Germany in November 2005. It was
approved by the FDA in September 2006 for treatment
of aspergillosis and candidiasis.
Albaconazole
Albaconazole (Uriach & Co, Barcelona, Spain) is a new
broad-spectrum triazole that has good in vitro activity
against azole-resistant yeasts, as well as Aspergillus spp
and Scedosporium spp. Interestingly, albaconazole has
been reported to induce parasitic cure in a dog model
of Chagas disease (caused by the protozoan Trypano-
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