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

1564 Anti-parasitic. Dapsone is also highly effective against Plasmodium
falciparum with IC 50
of 0.006-0.013 mg/mL (0.6-1.3 mg/L) even in
sulfadoxine-pyrimethamine–resistant strains. Dapsone has an IC 50
of 0.55 mg/L against Toxoplasma gondii tachyzoites.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Antifungal. Dapsone is effective at concentrations of 0.1/mg/L against
the fungus Pneumocystic jiroveci.
Drug Resistance. Resistance to dapsone in P. falciparum, P. jiroveci,
and M. leprae results primarily from mutations in genes encoding
dihydropteroate synthase (Figure 56–5). In P. falciparum mutations
occur at several positions such as 436, 437, 540, 58, and 613. In
P. jiroveci isolates, mutations are often amino acid substitutions at
positions 55 and 57. In M. leprae, mutations are encountered at
codons 53 and 55.
Absorption, Distribution, and Excretion. After oral administration,
absorption is complete; the elimination t 1/2
is 20-30 hours. The
population pharmacokinetics of dapsone are shown in Table 56–2
(Simpson et al., 2006). CL increases 0.03 L/hour and V d
0.7 L
increases for each 1-kg increase in body weight above 62.3 kg.
Dapsone undergoes N-acetylation by NAT2. N-oxidation to dapsone
hydroxylamine is via CYP2E1, and to a lesser extent by
CYP2C. Dapsone hydroxylamine enters red blood cells, leading to
methemoglobin formation. Sulfones tend to be retained for up to
3 weeks in skin and muscle and especially in liver and kidney.
Intestinal reabsorption of sulfones excreted in the bile contributes to
long-term retention in the bloodstream; periodic interruption of
treatment is advisable for this reason. Epithelial lining fluid to
plasma ratio is between 0.76 and 2.91; CSF-to-plasma ratio is
0.21-2.01 (Gatti et al., 1997). Approximately 70-80% of a dose
of dapsone is excreted in the urine as an acid-labile mono-Nglucuronide
and mono-N-sulfamate.
Therapeutic Uses. Dapsone is administered as an oral agent.
Therapeutic uses of dapsone in the treatment of leprosy are described
later. Dapsone is combined with chlorproguanil for the treatment of
malaria. Dapsone is also used for P. jiroveci infection and prophylaxis,
and for the prophylaxis for T. gondii, as discussed in chapters
devoted to these infections. The anti-inflammatory effects are the
basis for therapy for pemphigoid, dermatitis herpetiformis, linear
IgA bullous disease, relapsing chondritis, and ulcers caused by the
brown recluse spider (Wolf et al., 2002).
Dapsone and Glucose-6-Phosphate Dehydrogenase Deficiency.
Glucose-6-phosphate dehydrogenase (G6PD) protects red cells against
oxidative damage. However, G6PD deficiency is encountered in nearly
half a billion people worldwide, the most common of 100 variants
being G6PD-A - . Dapsone, an oxidant, causes severe hemolysis in
patients with G6PD deficiency. Thus, G6PD deficiency testing should
be performed prior to use of dapsone wherever possible.
Other Untoward Effects. Hemolysis develops in almost every individual
treated with 200-300 mg of dapsone per day. Doses of ≤100 mg in
healthy persons and ≤50 mg in healthy individuals with a G6PD deficiency
do not cause hemolysis. Methemoglobinemia also is common.
A genetic deficiency in the NADH-dependent methemoglobin
reductase can result in severe methemoglobinemia after administration
of dapsone. Isolated instances of headache, nervousness, insomnia,
blurred vision, paresthesias, reversible peripheral neuropathy
(thought to be due to axonal degeneration), drug fever, hematuria,
pruritus, psychosis, and a variety of skin rashes have been reported. An
infectious mononucleosis-like syndrome, which may be fatal, occurs
occasionally.
PRINCIPLES OF ANTITUBERCULOSIS
CHEMOTHERAPY
Evolution and Pharmacology. Mycobacterium tuberculosis
is not a single species, but a complex of species
with 99.9% similarity at nucleotide level. The complex
includes M. tuberculosis (typus humanus), M. canettii,
M. africanum, M. bovis, and M. microti. They all cause
tuberculosis (TB), with M. microti responsible for only
a handful of human cases.
Antituberculosis Therapy. Isoniazid, pyrazinamide,
rifampin, ethambutol, and streptomycin are currently
considered first-line anti-TB agents. Moxifloxacin is
being studied as a first-line agent. First-line agents are
more efficacious and better tolerated, relative to secondline
agents. Second-line agents are used in case of poor
tolerance or resistance to first-line agents. Second-line
drugs include ethionamide, PAS, cycloserine, amikacin,
kanamycin, and capreomycin.
When anti-TB drug monotherapy was administered
to TB patients, resistance emergence terminated
the effectiveness of these drugs. The mutation rates to
first-line anti-TB drugs are between 10 -7 and10 -10 , so
that the likelihood of resistance is high to any single
anti-TB drugs in patients with cavitary TB who have
~10 9 CFU of bacilli in a 3-cm pulmonary lesion.
However, the likelihood that bacilli would develop
mutations to two or more different drugs is the product
of two mutation rates (between 1 in 10 14 and 1 in 10 20 ),
which makes the probability of resistance emergence
to more than two drugs acceptably small. Thus, only
combination therapy anti-TB therapy is currently recommended
for treatment of TB. Multidrug therapy has
led to a reduction in length of therapy.
Types of Antituberculosis Therapy
Prophylaxis. After infection with M. tuberculosis, ~10% of people
will develop active disease over a lifetime. The highest risk of reactivation
TB is in patients with Mantoux tuberculin skin test reaction
≥5 mm who also fall into one of the following categories:
recently exposed to TB, have HIV co-infection, have fibrotic changes
on chest radiograms, or are immunosuppressed due to HIV infection,
post-transplantation, or are taking immunosuppressive medications
for any reason. If the tuberculin skin test is ≥10 mm, high risk
of TB is encountered in recent (≤5 years) immigrants from areas of
high TB prevalence, children <4 years of age, children exposed to
adults with TB, intravenous drug users, as well as residents and