DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1434 whereas children have been treated with 25-30 mg/kg per day in
three divided oral doses. Paromomycin formulated as a 6.25% cream
has been used to treat vaginal trichomoniasis in patients who had failed
metronidazole therapy or could not receive metronidazole. Some cures
have been reported, but vulvovaginal ulcerations and pain have complicated
treatment and absorption via this route (and the possibility of
aminoglycoside-related toxicities) must be anticipated.
Paromomycin is also efficacious as a topical formulation containing
15% paromomycin in combination with 12% methylbenzonium
chloride for the treatment of cutaneous leishmaniasis (Alvar
et al., 2006). The drug has been administered parenterally alone or
in combination with antimony to treat visceral leishmaniasis.
Paromomycin (intramuscular injection, 11 mg/kg per day for
21 days) produced a cure rate for visceral leishmaniasis (94.6%) that
was statistically equivalent to liposomal amphotericin B (Sundar et
al., 2007). However, adverse events were more common with paromomycin
than with liposomal amphotericin B.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Pentamidine
Pentamidine is a positively charged aromatic diamine
that was discovered in 1937 as a fortuitous consequence
of the search for hypoglycemic compounds that might
compromise parasite energy metabolism. Of the compounds
tested, three were found to possess outstanding
activity: stilbamidine, pentamidine, and propamidine.
Pentamidine was the most useful clinically because of
its relative stability, lower toxicity, and ease of administration.
Pentamidine is a broad-spectrum agent with
activity against several species of pathogenic protozoa
and some fungi.
Pentamidine as the di-isethionate salt is marketed for injection
(PENTAM 300, others) or for use as an aerosol (NEBUPENT). One
milligram of pentamidine base is equivalent to 1.74 mg of the pentamidine
isethionate. The di-isethionate salt is highly water soluble;
however, solutions should be used promptly after preparation
because pentamidine is unstable in solution.
Antiprotozoal and Antifungal Effects. The positively charged aromatic
diamidines are toxic to a number of different protozoa yet
show rather marked selectivity of action. Pentamidine is used for
the treatment of early-stage T. brucei gambiense infection (Barrett
et al., 2007; Kennedy, 2008) but is ineffective in the treatment of
late-stage disease and has reduced efficacy against T. brucei rhodesiense.
Its use is therefore limited to treatment of first-stage T. brucei
gambiense sleeping sickness. Pentamidine is an alternative agent
for the treatment of cutaneous leishmaniasis (Alvar et al., 2006;
Croft, 2008). It has been used for the treatment of visceral disease
but less toxic agents are preferred. Pentamidine is an alternative
agent for the treatment and prophylaxis of Pneumocystis pneumonia
caused by the ascomycetous fungus Pneumocystis jiroveci (formerly
known as Pneumocystis carinii) (Thomas and Limper, 2004).
Diminazene (BERENIL) is a related diamidine that is used as an inexpensive
alternative to pentamidine for the treatment of early African
trypanosomiasis and has been used outside the U.S. for the treatment
of early-stage T. b. gambiense in periods of pentamidine
shortage.
Mechanism of Action and Resistance. The mechanism of action
of the diamidines is unknown. The dicationic compounds appear to
display multiple effects on any given parasite and act by disparate
mechanisms in different parasites (Barrett et al., 2007). In T. brucei,
for example, the diamidines are concentrated via an energy-dependent
high-affinity uptake system to millimolar concentrations in cells;
this selective uptake is essential to their efficacy. The best-characterized
diamidine transporter is the P2 purine transporter used by the
melamine-based arsenicals, which explains the cross-resistance to
diamidines exhibited by certain arsenical-resistant strains of T. brucei
in vitro (de Koning, 2008). It is increasingly clear that multiple
transporters are responsible for pentamidine uptake, and this may
account for the fact that little resistance to this drug is observed in
field isolates despite its years of use as a prophylactic agent.
Although failure to concentrate diamidines is the usual cause of pentamidine
resistance in vitro, other mechanisms also may be involved.
The positively charged hydrophobic diamidines may exert
their trypanocidal effects by reacting with a variety of negatively
charged intracellular targets. Indeed, ribosomal aggregation, inhibition
of DNA and protein synthesis, inhibition of several
enzymes, and loss of trypanosomal kinetoplast DNA have been
reported. The loss of kinetoplast DNA may be mediated through
inhibition of topoisomerase II. It is doubtful that an effect on
topoisomerase accounts for the drug’s broad antimicrobial activity
or fully explains its mechanism of action. Inhibition of S-
adenosyl-L-methionine decarboxylase in vitro (but no change in
polyamine levels in vivo) and inhibition of a plasma Ca 2+ , Mg 2+ -
ATPase also have been reported.
Absorption, Fate, and Excretion. The pharmacokinetics and biodisposition
of pentamidine isethionate have been studied most extensively
in AIDS patients with P. jiroveci infections (Vöhringer and
Arastéh, 1993); information from patients with Gambian trypanosomiasis
is more limited (Bronner et al., 1995). Pentamidine isethionate
is fairly well absorbed from parenteral sites of administration.
Following a single intravenous dose, the drug disappears from
plasma with an apparent t 1/2
of several minutes to a few hours and
maximum plasma concentrations after intramuscular injection occurring
at 1 hour. The t 1/2
of elimination is very slow, lasting from weeks
to months, and the drug is 70% bound to plasma proteins. This
highly charged compound is poorly absorbed orally and does not
cross the blood-brain barrier, explaining why it is ineffective against
late-stage trypanosomiasis.
After multiple parenteral doses, the liver, kidney, adrenal, and
spleen contain the highest concentrations of drug, whereas only
traces are found in the brain (Donnelly et al., 1988). The lungs contain
intermediate but therapeutic concentrations after five daily doses
of 4 mg/kg. Inhalation of pentamidine aerosols is used for prophylaxis
of Pneumocystis pneumonia; delivery of drug by this route
results in little systemic absorption and decreased toxicity compared
with intravenous administration in both adults and children (Hand
et al., 1994; Leoung et al., 1990). The actual dose delivered to the