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

1422 African (Gambian), caused by T. brucei rhodesiense and T. brucei
gambiense, respectively. T. brucei rhodesiense produces a progressive
and rapidly fatal form of disease marked by early involvement of
the CNS and frequent terminal cardiac failure; T. brucei gambiense
causes illness that is characterized by later involvement of the CNS
and a more long-term course that progresses to the classical symptoms
of sleeping sickness over months to years. Neurological symptoms
include confusion, poor coordination, sensory deficits, an array
of psychiatric signs, disruption of the sleep cycle, and eventual progression
into coma and death.
being exploited to develop publicly accessible databases that organize
data relevant to drug discovery projects (Aguero et al., 2008).
From these efforts an orally available novel diamidine, pafuramidine
maleate (DB289), was recently advanced to phase IV trials for the
treatment of early-stage (stage 1) sleeping sickness, representing
the only new clinical candidate since the discovery of eflornithine
(Mdachi et al., 2009). Although the trials were stopped due to toxicity
issues (Kennedy, 2008), the discovery of pafuramidine provides
hope that the current approaches and increased effort will yield new
clinical entities for these diseases in the near future.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Four drugs are used for the treatment of sleeping
sickness, and only one, eflornithine, has been developed
since the 1950s (Barrett et al., 2007; Croft, 2008;
Fries and Fairlamb, 2003; Kennedy, 2008; Stuart et al.,
2008). Standard therapy for early-stage disease is pentamidine
for T. brucei gambiense and suramin for
T. brucei rhodesiense. Both compounds must be given
parenterally over long periods and are not effective
against late-stage disease. The CNS phase has traditionally
been treated with melarsoprol (available from the
CDC), which is a highly toxic agent that causes a fatal
reactive encephalopathy in 2-10% of treated patients.
Moreover, lack of response to this agent is leading to
increasing numbers of treatment failures (Pepin and
Mpia, 2005, Robays et al., 2008b). Eflornithine, which
was developed originally as an anticancer agent and
approved as an orphan drug, offers the only alternative
for the treatment of late-stage disease. This compound
is an inhibitor of ornithine decarboxylase, a key enzyme
in polyamine metabolism. It has shown marked
efficacy against both early and late stages of human
T. brucei gambiense infection; however, it is ineffective
as monotherapy for infections of T. brucei rhodesiense.
Notably, eflornithine has significantly fewer side
effects than melarsoprol and is more effective than
melarsoprol for treatment of late-stage Gambian trypanosomiasis,
suggesting that eflornithine is the best
available first-line treatment for this form of the disease
(Chappuis, 2007). Although eflornithine is expensive
and difficult to administer, nifurtimox-eflornithine combination
therapy (NECT) allows a shorter exposure to
eflornithine with good efficacy and a reduction in
adverse events (Priotto et al., 2009).
Recent efforts by not-for-profit agencies have fostered significant
new efforts to develop new therapies for the neglected tropical
diseases including African sleeping sickness, Chagas’ disease,
and Leishmaniasis (Croft, 2007; Frearson et al., 2007; Nwaka and
Hudson, 2006; Pink et al., 2005; Stuart et al., 2008). These efforts
involve partnerships with academic and industrial groups. The recent
increase in high throughput screening centers within academic
groups with interest in developing drugs for these applications is also
helping to fuel discovery of lead compounds. The genome data is
American trypanosomiasis, or Chagas’ disease, a
zoonotic infection caused by Trypanosoma cruzi,
affects ~15 million people from Mexico to Argentina
and Chile, with 50,000-200,000 new infections added
each year (Bern et al., 2007; Stuart et al., 2008; Tarleton
et al., 2007). The chronic form of the disease in adults
is a major cause of cardiomyopathy, megaesophagus,
megacolon, and death. Blood-sucking triatomid bugs
infesting poor rural dwellings most commonly transmit
this infection to young children; transplacental transmission
also may occur in endemic areas.
Reactivation of disease also may occur in patients who are
immunosuppressed after organ transplantation or because of infection
(e.g., AIDS, leukemia, and other neoplasias). Occurrences of T. cruzi
infection in transplant patients or through blood transfusions have been
reported in the U.S., and as a consequence the FDA-approved diagnostic
blood screening for the parasite (Bern et al., 2008). Reports of
autochthonous Chagas cases are also on the rise in the U.S. Acute
infection is evidenced by a raised tender skin nodule (chagoma) at the
site of inoculation; other signs may be absent or range from fever,
adenitis, skin rash, and hepatosplenomegaly to, albeit rarely, acute
myocarditis, and death. Invading metacyclic trypomastigotes penetrate
host cells, especially macrophages, where they proliferate as amastigotes.
These then differentiate into trypomastigotes that enter the
bloodstream. Circulating trypomastigotes do not multiply until they
invade other cells or are ingested by an insect vector during a blood
meal. After recovery from the acute infection that lasts a few weeks to
months, individuals usually remain asymptomatic for years despite
sporadic parasitemia. During this period, their blood can transmit the
parasites to transfusion recipients and accidentally to laboratory workers.
Approximately 20-30% of infected individuals eventually progress
to clinically evident disease that is characterized by chronic disease
of the heart and GI tract as they age. Progressive destruction of
myocardial cells and neurons of the myenteric plexus results from the
special tropism of T. cruzi for muscle cells. Recent studies with
improved techniques indicate the presence of T. cruzi at sites of cardiac
lesions, and it is now well recognized that parasite persistence is
linked directly to pathology and disease outcome (Tarleton, 2003).
Whether an undefined autoimmune response also contributes to the
pathogenesis of Chagas’ disease is unknown; however, the data indicate
that immunological defenses, especially cell-mediated immunity,
do modulate the course of disease.
Two nitroheterocyclic drugs, nifurtimox (available
from the CDC) and benznidazole are used to treat