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PubMed1994

Simultaneous determination of chloroquine, proguanil and their metabolites in human biological fluids by high-performance liquid chromatography.

A reversed-phase ion-pair high-performance liquid chromatographic method with ultraviolet detection is described for the simultaneous measurement of chloroquine, proguanil and their major metabolites in human plasma, erythrocytes and urine. After a liquid-solid extraction on a Bond Elut C8 cartridge, the compounds are separated on a C8 Lichrospher 60 RP select B column by isocratic elution; the mobile phase is water-acetonitrile-methanol (78:28:4, v/v/v) with 0.5 M ammonium formate and 0.075 M perchloric acid. The eluent is monitored with an ultraviolet detector at 254 nm. The lower limits of quantification in plasma are near 6.0 ng ml-1 for chloroquine and near 9.0 ng ml-1 for proguanil. No chromatographic interference can be detected from endogenous compounds or from other antimalarial drugs. The method is accurate and precision is good with inter- and intra-assay relative standard deviations lower than 6.8% for plasma samples. N-(2-6 dichlorobenzylidene amino)guanidine is used as an internal standard. The chromatographic procedure takes 35 min and can be used for therapeutic drug monitoring and clinical studies.

Antimalarials↗
PubMed2006

Clinical atovaquone-proguanil resistance of Plasmodium falciparum associated with cytochrome b codon 268 mutations.

Plasmodium falciparum resistance to atovaquone-proguanil has so far been associated with Y268S or Y268N mutations in cytochrome b, although these changes were identified in only seven of the 11 treatment failures. Here, we describe 10 new cases of atovaquone-proguanil treatment failures among which the parasite resistance was confirmed in six cases, either by identifying correct plasma drug concentrations or by observing in vitro atovaquone resistance. Resistance was consistently associated with codon 268 mutations (Y268S or a previously unidentified mutation, Y268C). Notably, mutations were not detected before the treatment but only after the drug exposure.

Adolescent↗
PubMed2005

In vitro recrudescence of Plasmodium falciparum parasites suppressed to dormant state by atovaquone alone and in combination with proguanil.

We studied the viability of Plasmodium falciparum parasites reappearing in long-term cultures after repetitive exposure to atovaquone and proguanil. Parasites (F32 and FCR3) exposed to 100-5000 nM atovaquone for 96 hours were reduced to <5% of initial parasitaemia but recrudesced after 9-15 days. Also, parasites exposed to 1000 nM atovaquone for 48, 72, 96 and 144 hours recrudesced after 9, 14, 21 and 23 days respectively. Immediately after removal of the drug, only 1-3 schizonts per 10000 red blood cells were found consistently, apparently unable to produce trophozoites and thus, possibly, adopting a "dormant state". Parasites (F32 and FCR3) exposed to 500 nM atovaquone for 72 hours reappeared after 14 days. These recrudescing parasites were then re-exposed and suppressed by atovaquone in three consecutive follow-up experiments. They reappeared after 12, 11 and 9 days respectively. No known point mutations in cytochrome b gene (cytb), associated with atovaquone resistance, were detected in any recrudescing parasites. Finally, parasites (F32) exposed to various concentrations of atovaquone and proguanil in combination for 72 hours reappeared after 9-17 days. The baseline susceptibilities of the parasites to individual drugs were similar before and after recrudescence in all experiments.

Animals↗
PubMedDate not supplied

Artesunate-atovaquone-proguanil rescue treatment of multidrug-resistant Plasmodium falciparum malaria in pregnancy: a preliminary report.

Pregnant women are particularly vulnerable to malaria infections. Multidrug resistance in Plasmodium falciparum seriously compromises treatment in some endemic areas. Between April 1999 and October 2001, we treated and prospectively followed 27 Karen pregnant women with multiple recrudescent P. falciparum infections who were resistant to all other antimalarials with a triple combination of artesunate-atovaquone-proguanil. The treatment was well tolerated and we found no evidence of toxicity for the mothers and the fetus. All but 1 woman were cured (cure rate 96%, 95% CI 89-100). The triple combination of artesunate (4 mg/kg/d), atovaquone (20 mg/kg/d), and proguanil (8 mg/kg/d) may provide a much needed, albeit expensive, 3-d rescue treatment for pregnant women exposed to multidrug- resistant P. falciparum malaria.

Adolescent↗
PubMedDate not supplied

Hyperreactive malarial splenomegaly and AIDS: proguanil prevents recurrent pneumonia.

An Ethiopian immigrated to Israel and gave a positive test result for human immunodeficiency virus. Soon after, he was thrice admitted to hospital in 3 months for severe pneumonia. Acquired immunodeficiency syndrome was diagnosed, as was hyperreactive malarial splenomegaly (HMS). Thereafter, during maintained proguanil treatment for HMS, the patient remained well for 16 months. Then, after another pneumonic illness, pneumococcal vaccine was administered. Proguanil was maintained for another 10 months and, despite declining CD4 cell counts, good health continued for a further 18 months.

Antimalarials↗
PubMed1980

High-performance liquid chromatography of proguanil, cycloguanil and 4-chlorophenylbiguanide using hydrophobic pairing ion and its application to serum assay.

A high-performance liquid chromatographic separation of proguanil, cycloguanil and 4-chlorophenylbiguanide is reported using a hydrophobic stationary phase and lauryl sulphate as pairing ion. It is suggested, on the basis of the behaviour of phenylbenzoate as an undissociated solute and the variation of retention with lauryl sulphate and sodium ion concentrations that the mechanism of separation is one of ion exchange. The biguanides can be detected in serum at concentrations in the region of 60 ng ml-1 and preliminary results are presented to show the variation of proguanil in serum over a 24-h peroid following ingestion of 200 mg orally.

Animals↗
PubMed1999

Effects of cimetidine on the pharmacokinetics of proguanil in healthy subjects and in peptic ulcer patients.

The pharmacokinetics of orally administered proguanil and its metabolites were determined in six healthy volunteers and in six peptic ulcer patients, before and after a 3-day course of cimetidine (400 mg given two times daily for 2 days and 400 mg on the third day 1 h before proguanil). Cimetidine significantly increased Cmax (P < 0.05), AUCo-alpha (P < 0.005) and elimination half-life t 1/2b of proquanil in plasma of healthy subjects. In ulcer patients, cimetidine significantly increased, AUCo-alpha (P < 0.05), elimination half life (P < 0.005) and Cmax. Cimetidine significantly reduced (P < 0.05) Total body clearance in both healthy subjects and in peptic ulcer patients. The Cmax and AUCo-alpha of the active metabolite cycloguanil was significantly decreased (P < 0.05) in both the healthy subjects and in the peptic ulcer patients. The Cmax of the inactive metabolite, 4-CPB was significantly decreased in healthy subjects and AUCo-alpha significantly decreased in peptic ulcer patients.

Adult↗
PubMed2001

Subacute clinical forms of Plasmodium falciparum malaria in travelers receiving chloroquine-proguanil prophylaxis.

We have observed 4 French travelers, returning from African countries, who were not immune to malaria and were receiving chloroquine-proguanil prophylaxis, in whom the diagnosis of malaria could easily have been missed because the clinical signs were uncommon. These cases suggest that chloroquine-proguanil prophylaxis is not always effective and that travelers with unexplained symptoms should be monitored closely for malaria.

Adult↗
PubMed2003

Genetic confirmation of atovaquone-proguanil-resistant Plasmodium falciparum malaria acquired by a nonimmune traveler to East Africa.

We report a case of atovaquone-proguanil-resistant Plasmodium falciparum malaria acquired by a nonimmune traveler to Kenya. Recurrent parasitemia occurred 30 days after directly observed therapy with a combination of atovaquone and proguanil. Treatment failure was confirmed by genetic fingerprinting and sequencing. The primary isolate had wild-type sequence of cytochrome b; however, the recrudescent isolate had a single mutation at position 268 (Tyr268Ser).

Adult↗
PubMedDate not supplied

Simultaneous quantitation of the highly lipophilic atovaquone and hydrophilic strong basic proguanil and its metabolites using a new mixed-mode SPE approach and steep-gradient LC.

A bioanalytical method is described for the simultaneous quantitative analysis of the highly lipophilic atovaquone and the strong basic proguanil with metabolites in plasma. The drugs are extracted from protein precipitated plasma samples on a novel mixed-mode solid-phase extraction (SPE) column containing carboxypropyl and octyl silica as functional groups. The analytes are further separated and quantitated using a steep-gradient liquid chromatographic method on a Zorbax SB-CN column with UV detection at 245 nm. Two different internal standards (IS) are used in the method to compensate for both types of analytes. A structurally similar IS to atovaquone is added with acetonitrile to precipitate proteins from plasma. A structurally similar IS to proguanil and its metabolites is added with phosphate buffer before samples are loaded onto the SPE columns. A single elution step is sufficient to elute all analytes. The method is validated according to published guidelines and shows excellent performance. The within-day precisions, expressed as relative standard deviation, are lower than 5% for all analytes at three tested concentrations within the calibration range. The between-day precisions are lower than 13% for all analytes at the same tested concentrations. The limit of quantitation is 25 nM for the basic substances and 50 nM for atovaquone. Several considerations regarding development and optimization of a method for determination of analytes with such a difference in physiochemical properties are discussed.

Adsorption↗
PubMed1993

Proguanil metabolism is determined by the mephenytoin oxidation polymorphism in Vietnamese living in Denmark.

1. A sparteine/mephenytoin phenotyping test was carried out in 37 Vietnamese living in Denmark. By visual inspection the urinary S/R-mephenytoin ratio appeared to show a bimodal frequency distribution. Eight putative poor metabolizers of mephenytoin, PMm (22%), had S/R-mephenytoin ratios from 0.79 to 1.12 and 29 putative extensive metabolizers of mephenytoin, EMm, had S/R-mephenytoin ratios < or = 0.55. All of the subjects were extensive metabolizers of sparteine with urinary metabolic ratios from 0.15 to 2.4. 2. The metabolism of the antimalarial prodrug proguanil was studied in 34 of the subjects after a single oral dose of 100 mg. The median 12 h urinary recoveries of the active metabolite cycloguanil and the minor metabolite 4-chlorphenylbiguanide were 5.8 and 1.9% of the dose, respectively, in 26 EMm compared with 1.6 and 0.4%, respectively, in 8 PMm (P < 0.001, Mann-Whitney U-test). 3. There was no statistically significant correlation (Spearmans rs) between any index of proguanil metabolism and the sparteine metabolic ratio.

Administration, Oral↗
PubMed2006

A randomised, double-blind, placebo-controlled trial of atovaquone-proguanil vs. sulphadoxine-pyrimethamine in the treatment of malarial anaemia in Zambian children.

OBJECTIVE: To compare the efficacy of atovaquone-proguanil (AP) and sulphadoxine-pyrimethamine (SP) in the treatment of malarial anaemia in Zambian children. METHODS: An individually randomised, double-blind, controlled trial was undertaken in Zambian children with moderately severe anaemia and Plasmodium falciparum parasitaemia. The main trial endpoint was treatment failure defined as a need for blood transfusion or treatment with quinine, persistent anaemia or death within 14 days from the start of treatment. Secondary endpoints were parasitological and haematological findings 14 or 28 days after the start of treatment. RESULTS: A total of 128 children with a packed cell volume of <21% and >9% and P. falciparum parasitaemia received treatment with AP and 127 treatment with SP. Treatment failure occurred in 28 children (22%) who received SP and in 10 (8%) who received AP (OR: 3.34, 95% CI: 1.54, 7.21). Ten children required blood transfusion, all of whom were in the SP treatment group. Six children died, five of whom were in the AP group; none of the deaths were considered to be related directly to treatment. CONCLUSIONS: Atovaquone-proguanil proved more effective than SP in the treatment of malarial anaemia in an area with a modest level of SP resistance. AP is no longer available through the Malarone Donation Programme and is too expensive for routine use in Africa. However, this study has shown that in an area with a modest level of resistance to SP, use of a more effective antimalaria reduces the need for blood transfusion in children with malarial anaemia.

Anemia↗
PubMed1987

A preliminary pharmacokinetic study of the antimalarial drugs, proguanil and chlorproguanil.

Pharmacokinetic parameters for cycloguanil and chlorcycloguanil, the active metabolites of proguanil (Paludrine] and chlorproguanil (Lapudrine) have been measured in a bioassay which assesses the in-vitro growth inhibition of a cycloguanil- and chlorcycloguanil-sensitive strain of Plasmodium falciparum produced by dilutions of plasma collected after oral administration of the pro-drugs. A single compartment model is applicable for cycloguanil with mean rate constants of elimination of 0.0624 h-1 and availability of 0.2398 h-1. The elimination profile for chlorcycloguanil indicates partition of drug into more than one compartment. In 2 of 10 subjects dosed with proguanil and 1 of 11 subjects dosed with chlorproguanil, the active metabolite levels were significantly lower than the mean for the other subjects. Abnormally low cycloguanil or chlorcycloguanil plasma levels may be of importance in relation to effective prophylaxis against malaria.

Adult↗
PubMed1998

Cycloguanil and its parent compound proguanil demonstrate distinct activities against Plasmodium falciparum malaria parasites transformed with human dihydrofolate reductase.

The lack of suitable antimalarial agents to replace chloroquine and pyrimethamine/sulfadoxine threatens efforts to control the spread of drug-resistant strains of the malaria parasite Plasmodium falciparum. Here we describe a transformation system, involving WR99210 selection of parasites transformed with either wild-type or methotrexate-resistant human dihydrofolate reductase (DHFR), that has application for the screening of P. falciparum-specific DHFR inhibitors that are active against drug-resistant parasites. Using this system, we have found that the prophylactic drug cycloguanil has a mode of pharmacological action distinct from the activity of its parent compound proguanil. Complementation assays demonstrate that cycloguanil acts specifically on P. falciparum DHFR and has no other significant target. The target of proguanil itself is separate from DHFR. We propose a strategy of combination chemotherapy incorporating the use of multiple parasite-specific inhibitors that act at the same molecular target and thereby maintain, in combination, their effectiveness against alternative forms of resistance that arise from different sets of point mutations in the target. This approach could be combined with traditional forms of combination chemotherapy in which two or more compounds are used against separate targets.

Animals↗
PubMed1971

Tropical splenomegaly syndrome in Zambia: further observations and effects of cycloguanil and proguanil.

Nineteen Zambian patients with the tropical splenomegaly syndrome and sinusoidal lymphocytosis on liver biopsy were studied. The association of macrobulinaemia with the tropical splenomegaly syndrome has again been confirmed. Sixteen patients were treated with antimalarials-12 with cycloguanil pamoate alone, 3 with cycloguanil and proguanil, and 1 with proguanil alone. Twelve patients were observed for periods of sufficient length for the drug effect to be assessed, and in 11 there was a good response in terms of decrease in spleen size.Cycloguanil pamoate may be of value both for prophylaxis and treatment in areas where tropical splenomegaly syndrome is endemic.

Adolescent↗
PubMed1990

Multiple-dose kinetics in healthy volunteers and in vitro antimalarial activity of proguanil plus dapsone.

The multiple-dose kinetics of a daily dose of proguanil (200 mg) coadministered with dapsone (10 mg) was investigated in 6 healthy adult male volunteers. The kinetics of dapsone (DDS), monoacetyldapsone (MADDS), proguanil (PROG) and its active metabolite cycloguanil (CYCLO) were derived from plasma drug concentrations after the last maintenance dose. The following kinetic parameters (mean values) were estimated for DDS and PROG, respectively: maximum concentration (Cmax) = 285 and 151 ng/ml, minimum concentration (Cmin) = 125 and 31 ng/ml, elimination half-life (t1/2) = 23.3 and 18.3 h, plasma clearance (Cl) = 0.032 and 1.27 l/h/kg and apparent volume of distribution (Vss) = 1.05 and 33.32 l/kg. The Cmax, Cmin and t1/2 of CYCLO were 56 ng/ml, 17 ng/ml and 15.0 h, respectively. The antimalarial activity of the proguanil/dapsone combination was assessed in vitro by measuring the inhibition of re-invasion of two Plasmodium falciparum isolates grown in the presence of volunteers' sera. Both FC-27 [chloroquine (CQ)- and pyrimethamine (PYR)-sensitive] and K1 (CQ- and PYR-resistant) isolates were completely inhibited by the drug combination at steady-state concentrations. These findings suggest that the drug regimen may be effective against drug-resistant falciparum malaria.

Adult↗
PubMed2003

Atovaquone-proguanil for recrudescent Plasmodium falciparum in Vietnam.

Malarone, a fixed combination of atovaquone with proguanil (AP), has recently been recognized as a promising treatment against multidrug-resistant Plasmodium falciparum. In Vietnam, the first-line treatment for P. falciparum malaria is currently a combination of mefloquine and an artemisinin derivative, and the use of AP has not been explored. The aim of the present study, based in Vietnam, was to assess the efficacy of AP when used to treat P. falciparum recrudescences that had occurred after primary treatment with mefloquine-artesunate. All but two of the 39 patients investigated completed follow-up. The mean parasite- and fever-clearance times [and 95% confidence intervals (CI)] after AP treatment were 36 (30-42) and 21 (18-24) h, respectively. Most (32) of the 37 infections that were followed adequately appeared to be eradicated by the AP, the other five recrudescing once more. The overall cure 'rate' and (CI) was 86% (76%-98%). All of the patients tolerated the AP well. Atovaquone-proguanil appears to be a safe and promising alternative treatment for P. falciparum infections in South-east Asia, although the combination is relatively expensive and may not clear some infections with multidrug-resistant parasites.

Adolescent↗