OTHER DRUGS FOR TRYPANOSOMIASIS
& LEISHMANIASIS
Available therapies
for all forms of trypanosomiasis are seriously deficient in efficacy, safety,
or both. Availability of these therapies is also a concern, since they are
supplied mainly through donation or nonprofit production by pharmaceutical
companies. For vis-ceral leishmaniasis, three new promising therapies are
liposomal amphotericin, miltefosine, and paromomycin.
Suramin
is a sulfated naphthylamine that was introduced in the 1920s. It is the
first-line therapy for early hemolymphatic East African trypanosomiasis (T brucei rhodesiense infection), but
because it does not enter the central nervous system, it is not effec-tive
against advanced disease. Suramin is less effective than pent-amidine for early
West African trypanosomiasis. The drug’s mechanism of action is unknown. It is
administered intravenously and displays complex pharmacokinetics with very
tight protein binding. Suramin has a short initial half-life but a terminal
elimi-nation half-life of about 50 days. The drug is slowly cleared by renal
excretion.
Suramin is
administered after a 200-mg intravenous test dose. Regimens that have been used
include 1 g on days 1, 3, 7, 14, and 21 or 1 g each week for 5 weeks.
Combination therapy with pen-tamidine may improve efficacy. Suramin can also be
used for chemoprophylaxis against African trypanosomiasis. Adverse effects are
common. Immediate reactions can include fatigue, nausea, vomiting, and, more
rarely, seizures, shock, and death. Later reac-tions include fever, rash,
headache, paresthesias, neuropathies, renal abnormalities including
proteinuria, chronic diarrhea, hemo-lytic anemia, and agranulocytosis.
Melarsoprol is a
trivalent arsenical that has been available since 1949 and is first-line
therapy for advanced central nervous system East African trypanosomiasis, and second-line
therapy (after eflornithine) for advanced West African trypanosomiasis. After
intravenous administration it is excreted rapidly, but clinically relevant
concentrations accumulate in the central nervous system within 4 days.
Melarsoprol is administered in propylene glycol by slow intravenous infusion at
a dosage of 3.6 mg/kg/d for 3–4 days, with repeated courses at weekly
intervals, if needed. A new regi-men of 2.2 mg/kg daily for 10 days had
efficacy and toxicity similar to what was observed with three courses over 26
days. Melarsoprol is extremely toxic. The use of such a toxic drug is justified
only by the severity of advanced trypanosomiasis and the lack of available
alternatives. Immediate adverse effects include fever, vomiting, abdominal pain,
and arthralgias. The most impor-tant toxicity is a reactive encephalopathy that
generally appears within the first week of therapy (in 5–10% of patients) and
is probably due to disruption of trypanosomes in the central nervous system.
Common consequences of the encephalopathy include cerebral edema, seizures,
coma, and death. Other serious toxicities include renal and cardiac disease and
hypersensitivity reactions. Failure rates with melarsoprol appear to have
increased recently in parts of Africa, suggesting the possibility of drug
resistance.
Eflornithine
(difluoromethylornithine), an inhibitor of ornithine decarboxylase, is the only
new drug registered to treat African trypanosomiasis in the last half-century.
It is now the first-line drug for advanced West African trypanosomiasis, but is
not effec-tive for East African disease. Eflornithine is less toxic than
melar-soprol but not as widely available. The drug had very limited availability
until recently, when it was developed for use as a topi-cal depilatory cream,
leading to donation of the drug for the treat-ment of trypanosomiasis.
Eflornithine is administered intravenously, and good central nervous system
drug levels are achieved. The elimination half-life is about 3 hours. The usual
regimen is 100 mg/kg intravenously every 6 hours for 7–14 days (14 days was
superior for a newly diagnosed infection). Eflornithine appears to be as
effective as melarsoprol against advanced T
bruceigambiense infection, but its efficacy against T brucei rhodesiense islimited by drug resistance. Toxicity from
eflornithine is signifi-cant, but considerably less than that from melarsoprol.
Adverse effects include diarrhea, vomiting, anemia, thrombocytopenia,
leukopenia, and seizures. These effects are generally reversible. Increased
experience with eflornithine and increased availability of the compound in
endemic areas may lead to its replacement of suramin, pentamidine, and
melarsoprol in the treatment of Tbrucei
gambiense infection.
Nifurtimox,
a nitrofuran, is the most commonly used drug for American trypanosomiasis
(Chagas’ disease). Nifurtimox is also under study in the treatment of African
trypanosomiasis, particu-larly in combination with eflornithine. Nifurtimox is
well absorbed after oral administration and eliminated with a plasma half-life
of about 3 hours. The drug is administered at a dosage of 8–10 mg/ kg/d
(divided into three to four doses) orally for 3–4 months in the treatment of
acute Chagas’ disease. Nifurtimox decreases the sever-ity of acute disease and
usually eliminates detectable parasites, but it is often ineffective in fully
eradicating infection. Thus, it often fails to prevent progression to the
gastrointestinal and cardiac syndromes associated with chronic infection that
are the most important clini-cal consequences of Trypanosoma cruzi infection. Efficacy may vary in different parts
of South America, possibly related to drug resis-tance in some areas.
Nifurtimox has not been proved effective in the treatment of chronic Chagas’
disease. Toxicity related to nifurtimox is common. Adverse effects include
nausea, vomiting, abdominal pain, fever, rash, restlessness, insomnia,
neuropathies, and seizures. These effects are generally reversible but often
lead to cessation of therapy before completion of a standard course.
Benznidazole is an
orally administered nitroimidazole that appears to have efficacy similar to
that of nifurtimox in the treatment of acute Chagas’ disease. Availability of
the drug is currently limited. Important toxicities include peripheral
neuropathy, rash, gastro-intestinal symptoms, and myelosuppression.
This
important antifungal drug is an
alternative therapy for visceral leishmaniasis, especially in parts of India
withhigh-level resistance to sodium stibogluconate. Liposomal ampho-tericin has
shown excellent efficacy at a dosage of 3 mg/kg/d intravenously on days 1–5,
14, and 21. Nonliposomal amphoteri-cin (1 mg/kg intravenously every other day
for 30 days) is much less expensive, also efficacious, and widely used in
India. Amphotericin is also used for cutaneous leishmaniasis in some areas. The
use of amphotericin, and especially liposomal prepara-tions, is limited in
developing countries by difficulty of adminis-tration, cost, and toxicity.
Miltefosine is an
alkylphosphocholine analog that is the first effec-tive oral drug for visceral
leishmaniasis. It has recently shown excellent efficacy in the treatment of
visceral leishmaniasis in India, where it is administered orally (2.5 mg/kg/d
with varied dosing schedules) for 28 days. It was also recently shown to be
effective in regimens including a single dose of liposomal ampho-tericin
followed by 7–14 days of miltefosine. A 28-day course of miltefosine (2.5 mg/kg/d)
was also effective for the treatment of New World cutaneous leishmaniasis.
Vomiting and diarrhea are common but generally short-lived toxicities.
Transient elevations in liver enzymes and nephrotoxicity are also seen. The
drug should be avoided in pregnancy (or in women who may become pregnant within
2 months of treatment) because of its teratogenic effects. Miltefosine is
registered for the treatment of visceral leishmaniasis in India and some other
countries, and—considering the serious limitations of other drugs, including
parenteral administration, toxicity, and resistance—it may become the treatment
of choice for that disease. Resistance to miltefosine develops readily in
vitro. To circumvent this problem, various drug combinations, includ-ing miltefosine
with antimonials, amphotericin, or paromomycin, are under study.
Paromomycin sulfate is
an aminoglycoside antibiotic that until recently was used in parasitology only
for oral therapy of intestinal parasitic infections (see previous text). It has
recently been devel-oped for the treatment of visceral leishmaniasis. A phase 3
trial in India showed excellent efficacy for this disease, with a daily
intra-muscular dosage of 11 mg/kg for 21 days yielding a 95% cure rate, and
noninferiority compared with amphotericin. The drug was registered for the
treatment of visceral leishmaniasis in India in 2006. However, a recent trial
showed poorer efficacy in Africa, with the cure rate for paromomycin
significantly inferior to that with sodium stibogluconate. In initial studies,
paromomycin was well tolerated, with common mild injection pain, uncommon
ototoxicity and reversible liver enzyme elevations, and no nephro-toxicity.
Paromomycin is much less expensive than liposomal amphotericin or miltefosine,
the other promising new therapies for visceral leishmaniasis.
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