Treatment of Falciparum Malaria from Vietnam with a Phenanthrene Methanol (WR 33063) and a Quinoline Methanol (WR 30090)

Canfield, Craig J.; Hall, Anthony; MacDonald, Bruce S.; Neuman, David A.; Shaw, James A.

doi:10.1128/aac.3.2.224

Cited by 29 publications

(11 citation statements)

References 6 publications

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“…Mefloquine exhibited a long half-life in humans, and this desirable property facilitated its administration as a single dose for malaria treatment and as a once-weekly dosing for prophylaxis (50). In contrast, WR030090 was only partially effective as a prophylactic agent, required a dosing regimen similar to that of quinine to effect cures, and was subsequently abandoned (6,9,21,30). However, it is important to recognize that this occurred because of unfavorable pharmacokinetic characteristics, not as a consequence of unacceptable toxicity.…”

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confidence: 99%

“…In the late 1960s to early 1970s, Plasmodium falciparum malaria in Southeast Asia had begun to develop resistance to all of the available antimalarial drugs (6). Cure rates were 11 to 20% and 26 to 50% for chloroquine and quinine, respectively, and had declined to only 90% for the triple combination of quinine/pyrimethamine/dapsone (6).…”

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confidence: 99%

“…As a consequence, the U.S. Army began routinely employing two experimental antimalarial drugs, WR030090 and WR033063, for the treatment of recrudescent malaria infections at the Walter Reed Army Medical Center (6). Subsequent field trials demonstrated that WR030090, a quinolinyl methanol, exhibited cure rates of at least 88% and was better tolerated than quinine (6,21).…”

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confidence: 99%

“…Cure rates were 11 to 20% and 26 to 50% for chloroquine and quinine, respectively, and had declined to only 90% for the triple combination of quinine/pyrimethamine/dapsone (6). All of these regimens were associated with adverse side effects (6). As a consequence, the U.S. Army began routinely employing two experimental antimalarial drugs, WR030090 and WR033063, for the treatment of recrudescent malaria infections at the Walter Reed Army Medical Center (6).…”

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Utility of Alkylaminoquinolinyl Methanols as New Antimalarial Drugs

Dow

Heady

Bhattacharjee

et al. 2006

Antimicrob Agents Chemother

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Mefloquine has been one of the more valuable antimalarial drugs but has never reached its full clinical potential due to concerns about its neurologic side effects, its greater expense than that of other antimalarials, and the emergence of resistance. The commercial development of mefloquine superseded that of another quinolinyl methanol, WR030090, which was used as an experimental antimalarial drug by the U.S. Army in the 1970s. We evaluated a series of related 2-phenyl-substituted alkylaminoquinolinyl methanols (AAQMs) for their potential as mefloquine replacement drugs based on a series of appropriate in vitro and in vivo efficacy and toxicology screens and the theoretical cost of goods. Generally, the AAQMs were less neurotoxic and exhibited greater antimalarial potency, and they are potentially cheaper than mefloquine, but they showed poorer metabolic stability and pharmacokinetics and the potential for phototoxicity. These differences in physiochemical and biological properties are attributable to the "opening" of the piperidine ring of the 4-position side chain. Modification of the most promising compound, WR069878, by substitution of an appropriate N functionality at the 4 position, optimization of quinoline ring substituents at the 6 and 7 positions, and deconjugation of quinoline and phenyl ring systems is anticipated to yield a valuable new antimalarial drug.In the late 1960s to early 1970s, Plasmodium falciparum malaria in Southeast Asia had begun to develop resistance to all of the available antimalarial drugs (6). Cure rates were 11 to 20% and 26 to 50% for chloroquine and quinine, respectively, and had declined to only 90% for the triple combination of quinine/pyrimethamine/dapsone (6). All of these regimens were associated with adverse side effects (6). As a consequence, the U.S. Army began routinely employing two experimental antimalarial drugs, WR030090 and WR033063, for the treatment of recrudescent malaria infections at the Walter Reed Army Medical Center (6). Subsequent field trials demonstrated that WR030090, a quinolinyl methanol, exhibited cure rates of at least 88% and was better tolerated than quinine (6, 21).Shortly thereafter, mefloquine was discovered and was developed commercially by Hoffman La Roche and the U.S. Army. Mefloquine exhibited a long half-life in humans, and this desirable property facilitated its administration as a single dose for malaria treatment and as a once-weekly dosing for prophylaxis (50). In contrast, WR030090 was only partially effective as a prophylactic agent, required a dosing regimen similar to that of quinine to effect cures, and was subsequently abandoned (6,9,21,30). However, it is important to recognize that this occurred because of unfavorable pharmacokinetic characteristics, not as a consequence of unacceptable toxicity.Mefloquine combined with artesunate constitutes one of the most effective combination agents for treatment of malaria (41). Mefloquine is also the only once-weekly drug approved for malaria chemoprophylaxis in the United States that...

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