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

1428 encephalopathy (the treatment-related death rate was still 5.9% for
this protocol), but it has the advantage of easier administration, and
in an area where hospitalization is difficult, this is particularly important.
These studies further demonstrated that historically used graded
dosing schemes led to increased incidence of convulsions and
reduced efficacy; thus these schedules should not be used for the
treatment of T. brucei gambiense (Pepin and Mpia, 2006).
The 10-day therapy is currently undergoing clinical testing for
T. brucei rhodesiense. However, until clinical data are available to
support a dosing change, patients with Rhodesian sleeping sickness
should instead receive one of several older schedules developed for
this disease. A number of dosing schemes are in use or recommended
by various agencies, including the WHO (1998) and Médecins Sans
Frontières (2007). In the U.S., the CDC recommends the following
treatment schedule: three series of three daily doses with a 7-day
rest period between series. The first series gives 1.8, 2.7, and 3.6
mg/kg on days 1, 2, and 3, respectively. The subsequent series are 3.6
mg/kg daily. Encephalopathy develops more frequently in patients
with T. brucei rhodesiense compared to T. brucei gambiense, possibly
related to this graded dosing regimen. Concurrent administration
of prednisolone is frequently employed throughout the treatment
course; prednisolone it is not proven to reduce the frequency of reactive
encephalopathy (Schmid et al., 2005) but it does help to control
hypersensitivity reactions that occur most often during the second or
subsequent courses of melarsoprol therapy.
Toxicity and Side Effects. Treatment with melarsoprol is associated
with significant toxicity and morbidity (Balasegaram et al., 2006b;
Burri and Brun, 2003; Kennedy, 2008; Schmid et al., 2005). A febrile
reaction often occurs soon after drug injection, especially if parasitemia
is high. The most serious complications involve the nervous
system. A reactive encephalopathy occurs in ~5-10% of patients,
leading to death in about half of these. The cause is unknown, but
encephalopathy, when it occurs, typically develops 9-11 days after
treatment starts (Schmid et al., 2005). Peripheral neuropathy, noted
in ~10% of patients receiving melarsoprol, probably is due to a direct
toxic effect of the drug. Hypertension and myocardial damage are
not uncommon, although shock is rare. Albuminuria occurs frequently,
and occasionally the appearance of numerous casts in the
urine or evidence of hepatic disturbances may necessitate modification
of treatment. Vomiting and abdominal colic also are common,
but their incidence can be reduced by injecting melarsoprol slowly
into the supine, fasting patient. The patient should remain in bed and
not eat for several hours after the injection is given.
Precautions and Contraindications. Melarsoprol should be given only
to patients under hospital supervision so that the dosage regimen
may be modified if necessary. Initiation of therapy during a febrile
episode has been associated with an increased incidence of reactive
encephalopathy. Administration of melarsoprol to leprous patients
may precipitate erythema nodosum. Use of the drug is contraindicated
during epidemics of influenza. Severe hemolytic reactions have
been reported in patients with deficiency of glucose-6-phosphate
dehydrogenase. Pregnancy is not a contraindication for treatment
with melarsoprol.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Metronidazole
Isolation of the antibiotic azomycin (2-nitro-imidazole)
from a streptomycete by Maeda and collaborators in
1953 and demonstration of its trichomonacidal properties
by Horie in 1956 led to the chemical synthesis and
biological testing of many nitroimidazoles. One compound,
1-(β-hydroxyethyl)-2-methyl-5-nitroimidazole,
or metronidazole (FLAGYL, others), had especially high
activity in vitro and in vivo against the anaerobic protozoa
T. vaginalis and E. histolytica. In 1960, Durel and
associates reported that oral doses of the drug imparted
trichomonacidal activity to semen and urine and that
high cure rates could be obtained in both male and
female patients with trichomoniasis. Later studies
revealed that metronidazole had extremely useful clinical
activity against a variety of anaerobic pathogens
that included both gram-negative and gram-positive
bacteria and the protozoan G. lamblia (Freeman et al.,
1997). Other clinically effective 5-nitroimidazoles
closely related in structure and activity to metronidazole
include tinidazole (TINDAMAX, FASIGYN, others),
secnidazole (SECZOL-DS, others), and ornidazole
(TIBERAL, others). Among these, only tinidazole is
available in the U.S. Benznidazole (ROCHAGAN), another
5-nitroimidazole derivative, is unusual in that it is effective
in acute Chagas’ disease.
Antiparasitic and Antimicrobial Effects. Metronidazole and related
nitroimidazoles are active in vitro against a wide variety of anaerobic
protozoal parasites and anaerobic bacteria (Freeman et al., 1997).
The compound is directly trichomonacidal. Sensitive isolates of
T. vaginalis are killed by <0.05 μg/mL of the drug under anaerobic
conditions; higher concentrations are required when 1% oxygen is
present or to affect isolates from patients who display poor therapeutic
responses to metronidazole. The drug also has potent amebicidal
activity against E. histolytica. Trophozoites of G. lamblia are
affected by metronidazole at concentrations of 1-50 μg/mL in vitro.
In vitro studies on drug-sensitive and drug-resistant protozoan parasites
indicate that the nitro group on C5 of metronidazole is essential
for activity and that substitutions at the 2 position of the
imidazole ring that enhance the resonance conjugation of the chemical
structure increase antiprotozoal activity. In contrast, substitution
of an acyl group at the 2 position ablates such conjugation and
reduces antiprotozoal activity (Upcroft et al., 1999).
Metronidazole manifests antibacterial activity against all
anaerobic cocci and both anaerobic gram-negative bacilli, including
Bacteroides spp., and anaerobic spore-forming gram-positive bacilli.
Nonsporulating gram-positive bacilli often are resistant, as are aerobic
and facultatively anaerobic bacteria.
Metronidazole is clinically effective in trichomoniasis, amebiasis,
and giardiasis, as well as in a variety of infections caused by
obligate anaerobic bacteria, including Bacteroides, Clostridium, and