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

approved in India as the first orally active treatment
available for visceral leishmaniasis. Miltefosine is the
first orally available therapy for leishmaniasis. It is
highly curative against visceral leishmaniasis in the
trials conducted to date and also appears to be effective
against the cutaneous forms of the disease
(Berman, 2008; Bhattacharya et al., 2007). Its main
drawback is its teratogenicity; consequently, it must
not be used in pregnant woman.
Antiprotozoal Effects. In vitro analysis of a large number of alkylglycerophosphoethanolamines
(AGPEs), alkylglycerophosphocholines
(AGPCs), and APCs, originally developed as anticancer
agents, demonstrated that a number of these compounds had potent
antileishmanial activity against cultured promastigote or amastigote
parasites (Croft et al., 2003). Of the APCs, miltefosine demonstrated
the best activity against both stages of parasites. The potency of miltefosine
varies for different Leishmania spp., with L. donovani
being the most sensitive (1.2<ED 50
<5 μM against amastigotes) and
L. major being the least sensitive (8<ED 50
<40 μM against amastigotes).
Several phospholipid analogs also had good potency against
cultured T. cruzi parasites, whereas they were relatively inactive
against T. brucei. In vivo, miltefosine had the best activities of the
tested APCs, and by 5 days of treatment with 20 mg/kg orally, it gave
>95% suppression of L. donovani and L. infantum amastigotes in
the affected organs of mice. It also had good activity when administered
as a 6% ointment to skin lesions of L. mexicana or L. major on
BALB/c mice.
Against visceral leishmaniasis, 95-98% cure rates were
observed with a 100 mg/day oral dose for 28-42 days (Croft et al.,
2003) and 95% with a 28-day regimen of 100 mg/day orally for
adults and 2.5 mg/kg daily for children (Bhattacharya et al., 2007).
Thus, oral miltefosine appears to be a safe and effective treatment for
visceral leishmaniasis (Berman, 2008). Recent studies of oral miltefosine
also have shown >90% efficacy against some species of cutaneous
leishmaniasis (registered in Colombia for this use in 2005).
However, significant strain variation has been observed in the clinical
trials (Soto and Berman, 2006; Soto et al., 2007): For L. panamensis
in Colombia, cure rates were from 84-91% (versus the
placebo cure rate of 37%), and it was considerably less effective for
L. brasiliensis in Guatemala.
The mechanism of action of miltefosine is not yet understood.
Potential targets in mammalian cells include PKC;
CTP:phosphocholine-cytidylyltransferase inhibition, which disrupts
phosphatidylcholine biosynthesis; and altered sphingomyelin
biosynthesis, where increased levels of cellular ceramide may trigger
apoptosis (Croft et al., 2003). Studies in Leishmania suggest that
the drug may alter ether-lipid metabolism, cell signaling, or glycosylphosphatidylinosital
anchor biosynthesis. A transporter for miltefosine
has been cloned recently by functional rescue of a
laboratory-generated resistant strain of L. donovani. The transporter
is a P-type ATPase that belongs to the aminophospholipid translocase
subfamily, and the basis for the drug resistance appears to be point
mutation in the transporter leading to decreased drug uptake.
Mutations in this transporter lead to miltefosine resistance in laboratory
models (Croft et al., 2006; Seifert et al., 2007).
Absorption, Fate, and Excretion. Miltefosine is well absorbed
orally and distributed throughout the human body. Detailed pharmacokinetic
data are lacking, with the exception that miltefosine has a
long t 1/2
in humans (Berman, 2008). Plasma concentrations are proportional
to the dose, and maximum serum concentrations for dosing
of 50-150 mg per day were 20-70 μg/mL with a t 1/2
of 1 week
and a terminal t 1/2
of ~4 weeks. The C max
in children was ~30% less
than in adults.
Therapeutic Uses. Oral miltefosine is registered for use in India for
the treatment of visceral leishmaniasis with clinical trial study
patients receiving the following oral doses (Bhattacharya, 2007): for
adults >25 kg, 100 mg daily divided into two parts, and for adults
<25 kg, 50 mg daily in 1 dose for 28 days; for children, 2.5 mg/kg/day
in two divided doses. For cutaneous disease, the dose in clinical testing
is 2.5 mg/kg per day orally (maximum, 150 mg/day) for 28 days.
In the U.S., the recommended dose for both visceral and cutaneous
disease is 2.5 mg/kg per day (maximum dose of 150 mg/day) for
28 days, given in two divided doses (Medical Letter, 2007).
Miltefosine is also available in Afghanistan, Pakistan, and South
America. Because of its teratogenic potential, miltefosine is contraindicated
in pregnant women. Women should receive a negative
pregnancy test prior to treatment, and birth control is required during
and for at least 2 months after treatment. The compound cannot
be given intravenously because it has hemolytic activity.
Toxicity and Side Effects. Vomiting and diarrhea have been reported
as frequent side effects in up to 60% of the patients. Elevations in
hepatic transaminases and serum creatinine also have been reported.
These effects are typically mild and reversible, and they resolve
quickly once the drug is withdrawn.
Nifurtimox and Benznidazole
A variety of nitrofurans and nitroimidazole analogs are
effective in experimental infections with American trypanosomiasis
caused by T. cruzi (Bern et al., 2007;
Tarleton et al., 2007). Of these, nifurtimox and benznidazole
are currently used clinically to treat the disease.
Nifurtimox (Bayer 2502, LAMPIT), a nitrofuran
analog, and benznidazole (Roche 7-1051, ROCHAGAN),
a nitroimidazole analog, can be obtained in the U.S.
from the CDC.
O
O
CH 3
O
+
S N – N O
N
O –
NIFURTIMOX
Antiprotozoal Effects and Mechanisms of Action. Nifurtimox and benznidazole
are trypanocidal against both the trypomastigote and
amastigote forms of T. cruzi. Nifurtimox also has activity against
H
N
N
N
O
BENZNIDAZOLE
+ O
N
O –
1431
CHAPTER 50
CHEMOTHERAPY OF PROTOZOAL INFECTIONS