2,4,7-Triamino-6-<i>ortho</i>-substituted Arylpteridines. A New Series of Potent Antimalarial Agents

Osdene, T. S.; Russell, Peter B.; Rane, Leo

doi:10.1021/jm00315a031

Cited by 188 publications

(81 citation statements)

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“…These older phenanthrenemethanols were systematically evaluated in the Rane Laboratory for activity in mice infected with P. berghei, utilizing a model system (18) that places emphasis on capacity of test agents to cure established infections rather than to achieve suppression of parasitemia to an arbitrarily selected level as in the avian models (6). WR-33,063, previously designated SN-13,465, the bromo-analog of SN-9160 referred to above, emerged as the most active of the group, exhibiting significant curative activity at a dose that was well tolerated, CD50 -450.0 mg/kg (personal communication, W. E. Rothe and D. P. Jacobus, WRAIR).…”

Section: Methodsmentioning

confidence: 99%

Antimalarial Activities of Various 9-Phenanthrenemethanols with Special Attention to WR-122,455 and WR-171,669

Schmidt

Crosby

Rasco

et al. 1978

Antimicrob Agents Chemother

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Pilot appraisals of the activities of 16 specially selected 9-phenanthrenemethanols against acute infections with Plasmodium falciparum in owl monkeys showed that all were more active than the reference compound, 455, the most active derivative, and WR-171,669, ranked sixth, were selected for study in human volunteers. To assist this undertaking, appraisals of both compounds in owl monkeys infected with various strains of P. falciparum were expanded. These assessments showed: (i) that 455 of activities against infections with chloroquineresistant and pyrimethamine-resistant strains of P. falciparum in owl monkeys. These examinations showed that, as a class, the 9-phenanthrenemethanols were fully effective in the face of resistance to the above drugs and identified six derivatives which, as measured by curative doses, were at least as active as chloroquine against infections with a chloroquine-susceptible strain of P. falciparum.The current report records the results of the pilot evaluations referred to above. It also presents the results of broader assessments of the antmalarial properties of two members of the pilot group, WR-122,455 and WR-171,669, the most active of the 9-phenanthrenemethanols with, respectively, 2-piperidyl and alkylaminoalkyl substituents on the 9-methanol (see Table 1 for structures). These assessments were undertaken to support and guide projected trials of WR-122,455 and WR-171,669 in human volunteers. They were aimed at strengthening the pilot appraisals, determining the influence of the dosage regimen on the activities of both compounds, and ascertaining whether 455 had tissue schizonticidal as well as blood schizonticidal activity.

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Section: Methodsmentioning

confidence: 99%

Antimalarial Activities of Various 9-Phenanthrenemethanols with Special Attention to WR-122,455 and WR-171,669

Schmidt

Crosby

Rasco

et al. 1978

Antimicrob Agents Chemother

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“…For the dose-response study, severely infected mice were used in a protocol adapted from that described by Osdene et al (17). One million P. berghei-parasitized RBC (prepared as described above) were injected intraperitoneally.…”

mentioning

confidence: 99%

“…The study of the correlation between efficacy and halofantrine pharmacokinetics also used the protocol of Osdene et al (17). One million P. berghei-parasitized RBC from a previously infected donor mouse with rising parasitemia (20%) were diluted in 0.2 ml of phosphate-buffered saline and injected intraperitoneally.…”

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confidence: 99%

Efficacy and Pharmacokinetics of Intravenous Nanocapsule Formulations of Halofantrine in Plasmodium berghei -Infected Mice

Mosqueira

Loiseau

Bories

et al. 2004

Antimicrob Agents Chemother

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The efficacy and pharmacokinetics of a new parenteral formulation of halofantrine were studied in mice infected with Plasmodium berghei. The formulation consisted of nanocapsules with an oily core, prepared from either poly(D,L-lactide) (PLA) homopolymer or PLA that was surface modified with grafted polyethylene glycol chains. They were compared with a previously described intravenous halofantrine preparation. No toxic effects were observed with halofantrine in form of nanocapsules after intravenous administration for doses of up to 100 mg/kg, whereas the solubilized form in polyethylene glycol-dimethylacetamide was toxic at this dose. The halofantrine-loaded nanocapsules showed activity that was similar to or better than that of the solution in the 4-day test and as a single dose in severely infected mice, with only minimal differences between the two nanocapsule formulations. Halofantrine pharmacokinetics were determined in parallel with parasite development in severely infected mice. Nanocapsules increased the area under the curve for halofantrine in plasma more than sixfold compared with the solution throughout the experimental period of 70 h. Furthermore, nanocapsules induced a significantly faster control of parasite development than the solution in the first 48 h posttreatment. While the parasitemia fell more rapidly with PLA nanocapsules, the effect was more sustained with the surface-modified ones. This is consistent with surface-modified nanocapsules remaining longer in the circulation. These results suggest that nanocapsule formulations could provide a more favorable halofantrine profile in the plasma and reduce the intravenous dose necessary and therefore the toxicity, thus suggesting the use of halofantrine by a parenteral route in severe malaria.

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“…When this compound was given intraperitoneally at the same dose level (3.16 mg/kg per day), one of two monkeys died of drug toxicity; the monkey that survived the drug toxicity showed no beneficial effects of the compound given. Intravenous administration at 10 mg/kg per day produced toxic deaths in two of three monkeys; intraperitoneal administration at 10 mg/kg per day produced peritonitis and/or drug toxicity so severe that 4/4 monkeys died by day 15. This compound was completely ineffective by the oral route of administration at 31.6 mg/kg and 10 mg/kg.…”

Section: Organic Synthesesmentioning

confidence: 92%

“…Procedures and data on curative and prophylactic antimalarial activities Representative compounds were tested for antimalarial activity against Plasmodium berghei (blood-induced) in mice (15) (Table 1), and for prophylactic activity against P. gallinaceum (sporozoite-induced) in chicks (13) (Table 2). Quinones 1, 2, 4, and 5 were tested against P. berghei.…”

Section: Organic Synthesesmentioning

confidence: 99%

Antimalarial Quinones for Prophylaxis Based on a Rationale of Inhibition of Electron Transfer in Plasmodium

Wan

Porter

Folkers

1974

Proc. Natl. Acad. Sci. U.S.A.

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2,4,7-Triamino-6-ortho-substituted Arylpteridines. A New Series of Potent Antimalarial Agents

Cited by 188 publications

References 0 publications

Antimalarial Activities of Various 9-Phenanthrenemethanols with Special Attention to WR-122,455 and WR-171,669

Antimalarial Activities of Various 9-Phenanthrenemethanols with Special Attention to WR-122,455 and WR-171,669

Efficacy and Pharmacokinetics of Intravenous Nanocapsule Formulations of Halofantrine in Plasmodium berghei -Infected Mice

Antimalarial Quinones for Prophylaxis Based on a Rationale of Inhibition of Electron Transfer in Plasmodium

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