Mefloquine (WR 142,490) in the Treatment of Human Malaria

Trenholme, CM; Williams, Rozanne Lanczak; Desjardins, R.E.; Frischer, Henri; Carson, P. E.; Rieckmann, Karl H.; Canfield, Craig J.

doi:10.1126/science.1105787

Cited by 153 publications

(52 citation statements)

References 7 publications

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“…Human tolerability studies (37) involving 42 volunteers in all showed that single oral doses of WR-142,490 up to and including 1,000.0 mg could be administered without untoward reactions. Single doses of 2,000.0 mg were equally well accepted by four of these volunteers; two other subjects had transient headaches and dizziness for 48 h after receiving such doses.…”

Section: -Quinolinemethanol Antimalarials 1017mentioning

confidence: 99%

“…They sufficed to show: (i) that this compound was equally active against established infections with various drug-susceptible and multidrug-resistant strains of P. falciparum (37); (ii) that single oral doses of 1,000.0 mg were almost always curative and doses of 1,500.0 mg were uniformly curative of such infections (37); (iii) that single doses of 400.0 mg effected prompt clearance of fever and parasitemia, but were rarely curative (37); (iv) that a variety of dosage schedules, ranging from 250.0 mg weekly for eight doses to 1,000.0 mg every 4 weeks for three doses, effected suppressive cure of infections with sporozoites of the multidrug-resistant Vietnam Smith strain (9); and (v) that a single dose of 1,000.0 mg provided complete protection for 2 weeks and partial protection for 4 weeks against challenge with sporozoites of the multidrug-resistant Vietnam Marks strain (27). The results of preliminary studies of the activity of WR-142,490 against infections with the drug-susceptible Chesson and El Salvador strains of P. vivax suggested that trophozoite-induced infections could be cured by a single 400.0-mg dose (10) and showed that sporozoite-induced infections could not be cured by a single dose of 1,000.0 mg (37), but could be suppressed by repetitive weekly doses of 250.0 mg (10).…”

Section: -Quinolinemethanol Antimalarials 1017mentioning

confidence: 99%

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Antimalarial Activities of Various 4-Quinolinemethanols with Special Attention to WR-142,490 (Mefloquine)

Schmidt

Crosby

Rasco

et al. 1978

Antimicrob Agents Chemother

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Pilot appraisals of the activities of a selected group of 4-quinolinemethanols against acute Plasmodium falciparum infections in owl monkeys indicated that compounds of this class are equally active against infections with chloroquine-resistant and chloroquine-susceptible strains and that this efficacy is not compromised by concomitant resistance to pyrimethamine, and in addition, identified three derivatives with outstanding activity (WR-226,253; WR-142,490; and WR-184,806). WR-142,490, the second 4-quinolinemethanol evaluated in the above model, was five times as active as chloroquine against infections with the chloroquine-susceptible, pyrimethamine-resistant strain and had a much larger therapeutic index. Expanded evaluations designed to support projected studies in human volunteers provided full confirmation of the pilot appraisals and in addition showed: (i) that the activity of WR-142,490 was a function of the total dose delivered, single doses being as effective as three or seven fractional doses administered over as many days; (ii) that intravenous administration of this agent was feasible and effective; and (iii) that the compound was at least as active against infections with P. vivax as against infections with P. falciparum . Companion studies in rhesus monkeys infected with P. cynomolgi showed that WR-142,490 lacked prophylactic or radical curative activity, but that it was as effective as chloroquine as a companion to primaquine in a combination curative drug regimen. The results of human volunteer and field trials agree well with comparable segments of these experimental evaluations.

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Section: -Quinolinemethanol Antimalarials 1017mentioning

confidence: 99%

Section: -Quinolinemethanol Antimalarials 1017mentioning

confidence: 99%

Antimalarial Activities of Various 4-Quinolinemethanols with Special Attention to WR-142,490 (Mefloquine)

Schmidt

Crosby

Rasco

et al. 1978

Antimicrob Agents Chemother

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“…Mefloquine, a 4-quinoline methanol, is a new synthetic antimalarial effective against chloroquine and quinine resistant strains of P. falciparum (Trenholme et al, 1975). It has recently been introduced for clinical use in Thailand where the problem of drug resistant falciparum malaria is particularly acute.…”

Section: Introductionmentioning

confidence: 99%

Studies of mefloquine bioavailability and kinetics using a stable isotope technique: a comparison of Thai patients with falciparum malaria and healthy Caucasian volunteers.

Looareesuwan

White

Warrell

et al. 1987

Brit J Clinical Pharma

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1 A mefloquine hydrochloride tablet (250 mg base equivalent to 4.8 ± 0.6 mg kg-'; mean ± s.d.) and deuterium labelled mefloquine hydrochloride solution (250 mg base) were given to six adult male Thai patients with acute falciparum malaria and six healthy Swiss adult male volunteers (equivalent to 3.5 ± 0.1 mg kg-').2 The relative bioavailability of the tablet formulation derived from comparison of the areas under the plasma concentration-time curves was similar in both groups; 87 ± 11% and 89 ± 10% (mean ± s.d.). 3 The rate of drug absorption appeared to be similar in the two groups but peak plasma mefloquine concentrations were approximately three times higher in the Thai patients (1004 ± 276 ng ml-' for the tablet and 1085 ± 280 ng ml-' for the suspension) compared with the Swiss volunteers (319 ± 73 ng ml-' for the tablet, and 369 ± 121 ng ml-' for the suspension). 4 Estimates of the oral clearance CLpo of unlabelled mefloquine were significantly lower (17.5 ± 4.4 ml h-1 kg-1) in the Thai patients compared with 28.8 ± 3.5 ml h-1 kg-1 in the Swiss volunteers; P < 0.05). Terminal elimination half-lives were significantly shorter in the patients (10.3 ± 2.5 days) than in the volunteers (16.7 ± 1.9 days; P < 0.005). Differences of a similar magnitude were observed when comparing the pharmacokinetic parameters derived from the deuteromefloquine plasma concentrations. 5 Both genetic and disease related factors are likely to account for the large pharmacokinetic differences between the two groups. These findings have implications for the planning of dose finding studies and the use of mefloquine in Thailand.

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“…Consequently, chloroquine resistance in this model may be attributed to reduced exposure of the parasites rather than to ineffectiveness of the drug after it reaches the parasites: This mechanism of resistance provides a basis for explaining how drugs in the same chemotherapeutic class with chloroquine could be effective in the treatment of chloroquine-resistant malaria. For example, amodiaquine, quinine, and mefloquine might have exactly the same, albeit unknown, mechanism of action as chloroquine (2) and yet be more effective in the treatment of chloroquine-resistant malaria (1,13,(16)(17)(18)(19)(20)(21) because they penetrate to the parasites. These four drugs all are quinoline derivatives and have many characteristics in common, but they also possess t Contribution 1521 from the Army Research Program on malaria.…”

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confidence: 99%

“…We now report that mefloquine accumulation is undiminished in erythrocytes infected with P. berghei CR. Mefloquine is a new antimalarial drug (15) that is more effective than chloroquine against P. berghei CR (16) and P. falciparum CR (1,13,(17)(18)(19)21).…”

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confidence: 99%

Chloroquine Resistance in Malaria: Accessibility of Drug Receptors to Mefloquine

Fitch

Chan

Chevli

1979

Antimicrob Agents Chemother

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The process of mefloquine accumulation was studied in mouse erythrocytes infected with either Plasmodium berghei CS (chloroquine susceptible) or P. berghei CR (chloroquine resistant). In both cases, mefloquine was accumulated by a saturable process with an apparent dissociation constant of 2.5 x 106 M and an apparent maximal capacity of 700 ,umol per kg of erythrocyte pellet; uninfected mouse erythrocytes accumulated more than half as much mefloquine as infected erythrocytes. The process of accumulation was not stimulated by providing glucose as a substrate, and it was not inhibited in infected erythrocytes by azide, iodoacetate, or incubation at 2°C. Although mefloquine was accumulated more effectively than chloroquine by uninfected erythrocytes and by erythrocytes infected with P. berghei CR, competition between chloroquine and mefloquine was observed, raising the possibility that the same process of accumulation serves both drugs. Chloroquine competitively inhibits mefloquine accumulation, with an apparent inhibitor constant of 1.7 x 10-3 M, and mefloquine competitively inhibits chloroquine accumulation, with an apparent inhibitor constant of 2 x 10' M.The same process of accumulation and the same group of receptors could serve both drugs if mefloquine has greater access than chloroquine to the receptors.Regardless of whether the same process serves both drugs, undiminished accumulation by erythrocytes infected with P. berghei CR provides an explanation for the superiority of mefloquine in treating chloroquine-resistant malaria.

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Mefloquine (WR 142,490) in the Treatment of Human Malaria

Cited by 153 publications

References 7 publications

Antimalarial Activities of Various 4-Quinolinemethanols with Special Attention to WR-142,490 (Mefloquine)

Antimalarial Activities of Various 4-Quinolinemethanols with Special Attention to WR-142,490 (Mefloquine)

Studies of mefloquine bioavailability and kinetics using a stable isotope technique: a comparison of Thai patients with falciparum malaria and healthy Caucasian volunteers.

Chloroquine Resistance in Malaria: Accessibility of Drug Receptors to Mefloquine

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