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PubMed2000

In vitro proguanil activation to cycloguanil is mediated by CYP2C19 and CYP3A4 in adult Chinese liver microsomes.

AIM: To identify the cytochrome P450 isoforms involved in proguanil (PG) activation to cycloguanil (CG) in Chinese liver microsomes. METHODS: The kinetics of the CG formation from PG was determined in the liver microsomes of 6 Chinese subjects. Selective chemical inhibitors to various cytochrome P450 isoforms were employed to conduct inhibition experiments. The relationship between the CG formation and S-mephenytoin 4'-hydroxylation was analyzed. RESULTS: The kinetic behaviors of CG formation were described well by a single-enzyme Michaelis-Menten equation in five livers. The apparent Km and Vmax were (82 +/- 47) mumol.L-1 and (8 +/- 6) pmol.min-1.mg-1 protein, respectively. However, the remaining one displayed a two-enzyme kinetic behavior. Inhibition experiments showed that troleandomycin (100 mumol.L-1) and diethyldithiocarbamate (100 mumol.L-1), as potent CYP3A4 and CYP2E1 inhibitors, respectively, reduced the formation rate of CG by 81.1% and 47.23%, while quinidine (10 mumol.L-1), furafylline (20 mumol.L-1), and sulfaphenazole (10 mumol.L-1), which were inhibitors towards CYP2D6, 1A2 and 2C9/10, respectively, did not display significant inhibition. At a low PG concentration of 5 mumol.L-1, the CG formation correlated well with S-mephenytoin 4'-hydroxylation (r = 0.805, P < 0.05). Nevertheless, when a high substrate concentration (500 mumol.L-1) was used, the correlation coefficient decreased (r = 0.581, P < 0.05). CONCLUSION: The present study indicates that CYP3A4 and CYP2C19 are involved in PG activation to CG in adult Chinese liver microsomes. CYP2C19 played an important role in the clearance of PG at a substrate concentration close to in vivo therapeutic concentrations, while CYP3A4 gradually made a dominant contribution with the increase of PG concentration.

Adult↗
PubMed2002

[What is the value of the combination atovaquone-proguanil for the clinician?].

Malarone (atovaquone-proguanil) is a new option now available to French clinicians for prophylaxis and treatment of malaria. Administered by the oral route, malarone is almost 100% effective with few side effects. It is indicated for chemoprophylaxis in travelers entering areas with chloraquine-resistant Plasmodium falciparum. Compliance with prophylactic treatment is enhanced by the low frequency of adverse effects and the need to continue chemoprophylaxis for only 7 days after leaving the endemic area. For curative treatment of malaria, malarone is especially useful in patients with uncomplicated forms of Plasmodium falciparum malaria. This drug combination is also suitable as a stand-by treatment.

Animals↗
PubMedDate not supplied

[Pharmaceutical care for international voyagers: prophylaxis including chloroquine plus proguanil].

A pharmacotherapeutic follow-up of 42 voyagers prescribed with antimalarial chemoprophylaxis including chloroquine plus proguanil was performed. A report-based retrospective study showed 69% of chemoprophylaxis compliance. Adverse effects related to this type of medication would develop in 33% of voyagers. Adverse effects most commonly detected were mainly mild to moderate gastrointestinal (28.5% of voyagers) events. Resulting data are consistent with the safety profile of the chloroquine/proguanil combination as established in the international literature. It is concluded that antimalarial chemoprophylaxis should be initiated at 15 days before departure when prolonged stays are expected, so that potential adverse effects may be detected beforehand.

Adult↗
PubMed2005

Emergence of atovaquone-proguanil resistance during treatment of Plasmodium falciparum malaria acquired by a non-immune north American traveller to west Africa.

The importation of drug-resistant malaria is a growing public health problem in non-endemic countries. The combination of atovaquone and proguanil (Malarone) has become established as an agent of choice to prevent and treat chloroquine-resistant Plasmodium falciparum malaria in travelers. We describe the first reported case in North America of genetically confirmed atovaquone/proguanil-resistant P. falciparum malaria. Polymerase chain reaction and sequence analysis of the primary and recrudescent isolates confirmed the acquisition of a point mutation (Tyr268Ser) in the cytochrome b gene of the recrudescent isolate known to confer high-level resistance to atovaquone. Suboptimal therapy may have played a contributory role in the emergence of resistance.

Adult↗
PubMed1988

Observations on early and late post-sporozoite tissue stages in primate malaria. V. The effect of pyrimethamine and proguanil upon tissue hypnozoites and schizonts of Plasmodium cynomolgi bastianellii.

Two rhesus monkeys were each infected with 2.1 x 10(6) sporozoites of Plasmodium cynomolgi bastianellii; one was treated with 1.0 mg of pyrimethamine base per kg body weight for 5 d after sporozoite inoculation. A further 2 monkeys were each infected with 9.75 x 10(6) sporozoites of the same parasite; one was treated with 10 mg of proguanil per kg body weight for 4 out of 5 d after inoculation. The treated monkeys showed a delayed primary parasitaemia and relapses. In sections of liver biopsies taken 7.5 d after sporozoite inoculation, all monkeys showed numerous hypnozoites. However, there were no full grown schizonts and only rare retarded schizonts in the treated monkeys, in contrast to the untreated monkeys which had many mature or nearly mature schizonts. Later biopsies confirmed the continued presence of hypnozoites in all monkeys.

Animals↗