Page 103 - 80 guidelines for the treatment of malaria_opt

N
N
CI
2
CH 3
HN
CH 3
H
NH
2
CI
2
F
H 3 C
F
F
N
O
O
O
H
H
H
HO
HN
CH 3
CI
H 3 C
H 3 C
O
O
O H F H 3 C C F F N CH 3 CI ÿ O O HN CH 3 O O H O O O C H C OH CH 3 N CH 3 CH 3 H N H 3 C O O H 3 C O O O S H O O N H C N O CH 3 N CH 3 O CH 3 HO O H N N N O HN O CH 3 H 3 C CH 3 O H O NH H C 2 CH 3
CH 3 CH 3 CI CI N
O O
H H H H
H 3 C H 3 C
HO H 3 C O ANNEX 3. Pharmacology of antimalarial medicines O
H H
CH 3 CH 3 H 3 C N
OH
a3.10 proguanil
Molecular weight: 253.7
CI CI
H H H Proguanil is a biguanide compound that is
N N N CH 3 CI O
H metabolized in the body via the polymorphic
NH
NH
CH 3
cytochrome P450 enzyme CYP2C19 H N S NH 2
2
NH NH CH 3
He, cycloguanil.
CI to the active metabolit H H O
O N N N CH 3
Approximately 3% of Caucasian and
H African populations and 20% of Oriental A3
people are “poor metabolizers” and have
OH
considerably reduced biotransformation of
O
proguanil to cycloguanil (55,56).
Cycloguanil inhibits plasmodial dihydrofolate reductase. The parent compound has
weak intrinsic antimalarial activity through an unknown mechanism. It is possibly
active against pre-erythrocytic forms of the parasite and is a slow blood schizontocide.
H 2 C H H 3 C OH
Proguanil also has sporontocidal activity, rendering the gametocytes non-infective to CH 3 O CI
CH 3
N
O
O
HO
OH
O
CH 3
H
the mosquito vector. Proguanil is given as the hydrochloride salt in combination with N CH 3
OH
OH
atovaquone. It is not used alone for treatment as resistance to proguanil develops very NH N
N quickly. Cycloguanil was formerly administered as an oily suspension of the embonate 2 H 3 C H H
HO H by intramuscular injection. NH 2 H HO O CH 3
OH H H OH S
O OH O OH O O
H 3 C Formulations H 3 C OH N HO OH
• Tablets of 100 mg of proguanil hydrochloride containing 87 mg of proguanil base.
H 3 C
CH 3
N
In coformulation with atovaquone:
• Film-coated tablets containing 250 mg of atovaquone and 100 mg of proguanil
hydrochloride for adults.
• Tablet containing 62.5 mg of atovaquone and 25 mg of proguanil hydrochloride for
paediatric use.
Pharmacokinetics
Proguanil is readily absorbed from the gastrointestinal tract following oral administration.
Peak plasma levels occur at about 4 h, and are reduced in the third trimester of pregnancy.
Around 75% is bound to plasma proteins. Proguanil is metabolized in the liver to the
active antifolate metabolite, cycloguanil, and peak plasma levels of cycloguanil occur
an hour after those of the parent drug. The elimination half-lives of both proguanil
and cycloguanil is approximately 20 h (57, 58). Elimination is about 50% in the urine, of
which 60% is unchanged drug and 30% cycloguanil, and a further amount is excreted
in the faeces. Small amounts are present in breast milk. The elimination of cycloguanil
is determined by that of the parent compound. The biotransformation of proguanil
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