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

1436 2006), where lipid-based amphotericin B and miltefosine
are now recommended instead.
antimony in macrophages also may contribute to the prolonged
antileishmanial effect after plasma antimony levels have dropped
below the minimal inhibitory concentration observed in vitro.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Clinical formulations of sodium stibogluconate consist of
multiple uncharacterized molecular forms, some of which have
higher molecular masses than the compound shown. Typical
preparations contain 30-34% pentavalent antimony by weight and
m-chlorocresol (as a preservative). In the U.S., sodium stibogluconate
can be obtained from the CDC.
Antiprotozoal Effects and Drug Resistance. The mechanism of the
antileishmanial action of sodium stibogluconate remains an active
area of research, and recent studies have provided interesting new
insights (Croft et al., 2006). These studies support the old hypothesis
that relatively nontoxic pentavalent antimonials act as prodrugs.
These compounds are reduced to the more toxic Sb 3+ species that
kill amastigotes within the phagolysosomes of macrophages. This
reduction preferentially occurs in the intracellular amastigote stage,
and recently an enzyme, As 5+ reductase, was characterized that is
able to reduce Sb 5+ to the active Sb 3+ form. Furthermore, the overexpression
of this enzyme in promastigotes increased their sensitivity
to the drugs. Classically, it was thought that the antiparasitic
effects of antimonials occurred through inhibition of glucose catabolism
and fatty acid oxidation; however, recent studies suggest that
the drugs operate by interfering with the trypanothione redox system.
In drug-sensitive cell lines, Sb 3+ induces a rapid efflux of trypanothione
and glutathione from the cells, and also inhibits trypanothione
reductase, thereby causing a significant loss of thiol reduction potential
in the cells. This hypothesis is further supported by the observation
that laboratory-generated resistance to antimonials leads to
overexpression of glutathione and polyamine biosynthetic enzymes,
resulting in increased trypanothione levels, which conjugate to the
drug. Elevated levels of ABC efflux transporters (see Chapter 5)
were observed, though these transporters seem to play only a minor
role in drug resistance.
Absorption, Fate, and Excretion. The pentavalent antimonials attain
much higher concentrations in plasma than do the trivalent compounds.
Consequently, most of a single dose of sodium stibogluconate
is excreted in the urine within 24 hours. Its pharmacokinetic
behavior is similar whether the drug is given intravenously or intramuscularly;
it is not active orally (Chulay et al., 1988). The agent is
absorbed rapidly, distributed in an apparent volume of ~0.22 L/kg,
and eliminated in two phases. The first has a t 1/2
of ~2 hours, and the
second is much slower (t 1/2
= 33-76 hours). The prolonged terminal
elimination phase may reflect conversion of the Sb 5+ to the more
toxic Sb 3+ that is concentrated and slowly released from tissues.
Indeed, ~20% of the plasma antimony is present in the trivalent
form after pentavalent antimonial administration. Sequestration of
Therapeutic Uses. The changing use of sodium stibogluconate, meglumine
antimonate, and other agents for the chemotherapy of leishmaniasis
has been reviewed extensively (Alvar et al., 2006; Croft,
2008; Olliaro et al., 2005). Sodium stibogluconate is given parenterally,
with the dosage regimen individualized depending on the local
responsiveness of a particular form of leishmaniasis to this compound.
The standard course is 20 mg/kg per day for 21 days for cutaneous
disease and for 28 days for visceral disease. In some regions
of the world prolonged dosage schedules with maximally tolerated
doses are now needed for successful therapy of visceral, mucosal,
and some cutaneous forms of leishmaniasis, in part to overcome
increasing clinical resistance to antimonial drugs. Even high-dose
regimens may no longer produce satisfactory results. Increased
resistance has greatly compromised the effectiveness of these drugs,
and the drug is now obsolete in India. This is in contrast to previous
cure rates of >85% for both visceral and cutaneous disease.
Liposomal amphotericin B is the recommended alternative for treatment
of either visceral leishmaniasis (kala azar) in India or mucosal
leishmaniasis in general; the orally effective compound miltefosine
is likely to see much wider use in the coming years. Intralesional
treatment has also been advocated as a safer, alternative method for
treating cutaneous disease (Munir et al., 2008).
Children usually tolerate the drug well, and the dose per kilogram
is the same as that given to adults. Patients who respond favorably
show clinical improvement within 1-2 weeks of initiation of
therapy. The drug may be given on alternate days or for longer intervals
if unfavorable reactions occur in especially debilitated individuals.
Patients infected with HIV present a challenge because they
usually relapse after successful initial therapy with either pentavalent
antimonials or amphotericin B.
Toxicity and Side Effects. The toxicity of the pentavalent antimonials
is best evaluated in patients without systemic disease (i.e., visceral
leishmaniasis). In general, high-dose regimens of sodium
stibogluconate are fairly well tolerated; toxic reactions usually are
reversible, and most subside despite continued therapy. Effects noted
most commonly include pain at the injection site after intramuscular
administration; chemical pancreatitis in nearly all patients; elevation
of serum hepatic transaminase levels; bone marrow suppression
manifested by decreased red cell, white cell, and platelet counts in
the blood; muscle and joint pain; weakness and malaise; headache;
nausea and abdominal pain; and skin rashes. Changes in the electrocardiogram
that include T-wave flattening and inversion and prolongation
of the QT interval found in patients with systemic disease are
uncommon in other forms of leishmaniasis (Navin et al., 1992).
Reversible polyneuropathy has been reported. Hemolytic anemia and
renal damage are rare manifestations of antimonial toxicity, as are
shock and sudden death.
Suramin
Based on the trypanocidal activity of the dyes trypan
red, trypan blue, and afridol violet, research in
Germany resulted in the introduction of suramin into
therapy in 1920. Today, the drug is used primarily for