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

2007, Chappuis et al., 2005; Priotto et al., 2006, 2008; Robays et al.,
2008a). In contrast, the drug is largely ineffective for East African
trypanosomiasis. Eflornithine’s difficult treatment regimen is the
primary limitation to its use in the field. However, the negotiation of
the World Health Organization (WHO) of a stable supply of eflornithine
through 2011 has led to the widespread availability of the drug and to
its use in control and research programs run by world health agencies.
Eflornithine is both safer and more efficacious than melarsoprol
for late-stage Gambiense sleeping sickness, and it is now the
recommended first-line treatment for this disease when adequate
care can be provided for its administration. Eflornithine is no longer
available for systemic use in the U.S. but is available for treatment
of Gambian trypanosomiasis by special request from the CDC.
Antitrypanosomal Effects. The effects of eflornithine have been evaluated
both on drug-susceptible and drug-resistant T. brucei in vitro
and in infections with these parasites in rodent models (reviewed in:
Barrett et al., 2007). Eflornithine is a cytostatic agent that has multiple
biochemical effects on trypanosomes, all of which are a consequence
of polyamine depletion. The polyamine putrescine is depleted
to undetectable levels, intracellular levels of spermidine and trypanothine
are reduced by 25-50%, and methionine metabolism is altered.
Depletion of the polyamines, or of trypanothione, would be expected
to be lethal to the cells based on genetic studies that have disrupted the
biosynthetic genes in the pathway. As a consequence, macromolecular
biosynthesis is depressed, and the parasites transform from the
long, slender dividing forms into the short, stumpy nonreplicating
forms. These latter parasites are unable to synthesize variable cell surface
glycoprotein and eventually are cleared by the immune system.
The molecular mechanism of eflornithine action clearly is
inhibition of ornithine decarboxylase. Eflornithine irreversibly
inhibits both mammalian and trypanosomal ornithine decarboxylases,
thereby preventing the synthesis of putrescine, a precursor of
polyamines needed for cell division. Eflornithine inactivates the
enzyme through covalent labeling of an active-site cysteine residue,
and an X-ray structure of the T. brucei enzyme bound to the drug has
been reported (Grishin et al., 1999). A number of studies demonstrate
conclusively that ornithine decarboxylase is the target of eflornithine
action that leads to cell death. Mutant bloodstream trypanosomes
lacking ornithine decarboxylase or wild-type trypanosomes treated
with eflornithine cannot replicate, and mice inoculated with these null
parasites become resistant to infection by wild-type parasites
(Mutomba et al., 1999). The product of the ornithine decarboxylase
reaction, putrescine, rescues the growth deficit in both the mutant parasites
and eflornithine-treated cells. The null mutant parasites grown
with putrescine are not affected by eflornithine, demonstrating the
selectivity of the drug for the target enzyme.
The mechanisms of selective toxicity between the host and parasite,
or between the different species of T. brucei, are less clear
(Barrett et al., 2007). The parasite and human enzymes are equally
susceptible to inhibition by eflornithine; however, the mammalian
enzyme is turned over rapidly, whereas the parasite enzyme is stable,
and this difference likely plays a role in the selective toxicity. In addition,
mammalian cells may be able to replenish polyamine pools
through uptake of extracellular polyamines, whereas the slender
bloodstream forms of human trypanosomes divide within human
blood, which contains only very low levels of these essential compounds.
Further, the parasites lack efficient transport mechanisms.
T. brucei rhodesiense cells are less sensitive to eflornithine
inhibition than T. brucei gambiense cells, and studies in vitro suggest
that the effective doses are increased by 10-20 times in the refractory
cells. The molecular basis for the higher dose requirement in T. brucei
rhodesiense is still poorly understood; however, it has been postulated
to involve differences both in enzyme stability and in the
metabolism of S-adenosylmethionine compared with the sensitive
T. brucei gambiense cell lines.
Absorption, Fate, and Excretion. Eflornithine is given by intravenous
infusion. The drug does not bind to plasma proteins but is
well distributed and penetrates into the CSF, where it is estimated
that concentrations of at least 50 μM must be reached to clear parasites
(Burri and Brun, 2003). Despite the ability of the drug to penetrate
the blood-brain barrier, studies in mice suggest that
eflornithine crosses the healthy blood-CNS interface poorly, and that
it is the breakdown of this barrier caused by T. brucei infection that
allows greater penetration to occur (Sanderson et al., 2008). In
these studies, suramin enhanced eflornithine uptake into the CNS,
suggesting that this combination might lead to lower dose requirements
for eflornithine. Renal clearance after intravenous administration
is rapid (2 mL/minute per kilogram), with >80% of the drug
cleared by the kidney largely in unchanged form (Burri and Brun,
2003). There is some evidence that eflornithine displays dosedependent
pharmacokinetics at the highest doses used clinically.
Therapeutic Uses. Eflornithine is used for the treatment of late-stage
West African trypanosomiasis caused by T. brucei gambiense
(Balasegaram et al., 2006a, 2008; Chappuis, 2007; Chappuis et al.,
2005; Priotto et al., 2006, 2008; Robays et al., 2008a). Most patients
in the reported studies had advanced disease with CNS complications.
The preferred regimen for adult patients was found to be
100 mg/kg given intravenously every 6 hours as a 2-hour infusion for
14 days. Virtually all patients improved on this regimen unless they
were extremely ill, and the WHO and Médecins Sans Frontières
report improved rates >90%. The probability of disease-free survival
2 years after treatment was calculated to be 0.88 in one study (Priotto
et al., 2008) and the case-fatality rate of 1% for eflornithine was the
lowest reported for second-stage sleeping sickness in any study
(Chappuis et al., 2005). Children (<12 years of age) received higher
doses of eflornithine (150 mg/kg given intravenously every 6 hours
for 14 days) based on prior findings that eflornithine trough concentrations
in both the CSF and blood were significantly lower among
children than in adults (Milord et al., 1993). Patients who failed therapy
in this study tended to have trough CSF concentrations <50 μM.
Equal doses of eflornithine were less effective when given by the
oral route probably because of limited bioavailability. The problem
cannot be overcome simply by increasing the oral dose because of
ensuing osmotic diarrhea.
Eflornithine has proven to be less successful for treating
AIDS patients with West African trypanosomiasis, presumably
because host defenses play a critical role in clearing drug-treated
T. brucei gambiense from the bloodstream.
The standard course eflornithine treatment regime is very challenging
to administer in rural settings in Africa. A randomized phase
III trial testing nifurtimox-eflornithine combination therapy for second-stage
T. brucel gambiense suggested that the treatment course for
eflornithine could be reduced to 7 days in combination with nifurtimox.
A recently concluded clinical trial confirms the efficacy of
1425
CHAPTER 50
CHEMOTHERAPY OF PROTOZOAL INFECTIONS