Synergismus zwischen Desbutyl-Benflumetol und Retinol bei Plasmodium falciparum in vitro

Samal, Doris; Rojanawatsirivet, Chaiporn; Wernsdorfer, Gunther; Kollaritsch, Herwig; Sirichaisinthop, Jeeraphat; Wernsdorfer, Walther H.

doi:10.1007/s00508-005-0446-4

Cited by 9 publications

(9 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although previously considered only a putative metabolite of lumefantrine because of a lack of supportive pharmacokinetic data (20,24), recent analytical developments have enabled the reliable detection of relatively low concentrations of DBL in samples of plasma from small numbers of patients treated with conventional doses of artemether-lumefantrine combination therapy (11,15,18). The ratio of the maximum plasma concentration (C max ) of the parent compound to that of the metabolite in this situation has varied substantially, from 6 (18) to Ͼ270 (11).…”

mentioning

confidence: 99%

Desbutyl-Lumefantrine Is a Metabolite of Lumefantrine with Potent In Vitro Antimalarial Activity That May Influence Artemether-Lumefantrine Treatment Outcome

Wong

Salman

Ilett

et al. 2011

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Desbutyl-lumefantrine (DBL) is a metabolite of lumefantrine. Preliminary data from Plasmodium falciparum field isolates show greater antimalarial potency than, and synergy with, the parent compound and synergy with artemisinin. In the present study, the in vitro activity and interactions of DBL were assessed from tritiumlabeled hypoxanthine uptake in cultures of the laboratory-adapted strains 3D7 (chloroquine sensitive) and W2mef (chloroquine resistant). The geometric mean 50% inhibitory concentrations (IC 50 s) for DBL against 3D7 and W2mef were 9.0 nM (95% confidence interval, 5.7 to 14.4 nM) and 9.5 nM (95% confidence interval, 7.5 to 11.9 nM), respectively, and those for lumefantrine were 65.2 nM (95% confidence interval, 42.3 to 100.8 nM) and 55.5 nM (95% confidence interval, 40.6 to 75.7 nM), respectively. An isobolographic analysis of DBL and lumefantrine combinations showed no interaction in either laboratory-adapted strain but mild synergy between DBL and dihydroartemisinin (sums of the fractional inhibitory concentrations of 0.92 [95% confidence interval, 0.87 to 0.98] and 0.94 [95% confidence interval, 0.90 to 0.99] for 3D7 and W2mef, respectively). Using a validated ultra-high-performance liquid chromatography-tandem mass spectrometry assay and 94 day 7 samples from a previously reported intervention trial, the mean plasma DBL was 31.9 nM (range, 1.3 to 123.1 nM). Mean plasma DBL concentrations were lower in children who failed artemether-lumefantrine treatment than in those with an adequate clinical and parasitological response (ACPR) (P ‫؍‬ 0.053 versus P > 0.22 for plasma lumefantrine and the plasma lumefantrine-to-DBL ratio, respectively). DBL is more potent than the parent compound and mildly synergistic with dihydroartemisinin. These properties and the relationship between day 7 plasma concentrations and the ACPR suggest that it could be a useful alternative to lumefantrine as a part of artemisinin combination therapy.Desbutyl-lumefantrine (DBL) or desbutyl-benflumetol is a 2,3-benzindene compound with antimalarial activity. Although previously considered only a putative metabolite of lumefantrine because of a lack of supportive pharmacokinetic data (20,24), recent analytical developments have enabled the reliable detection of relatively low concentrations of DBL in samples of plasma from small numbers of patients treated with conventional doses of artemether-lumefantrine combination therapy (11,15,18). The ratio of the maximum plasma concentration (C max ) of the parent compound to that of the metabolite in this situation has varied substantially, from 6 (18) to Ͼ270 (11).DBL is more potent in vitro against chloroquine (CQ)-resistant Plasmodium falciparum and Plasmodium vivax field isolates than lumefantrine (13, 17, 23). There is evidence of in vitro synergy between lumefantrine and DBL against P. falciparum but at ratios (999:1 and 995:5) that were presumably selected at a time when plasma concentrations of DBL were assumed to be very much lower than those of the parent compound (23,24). Int...

show abstract

mentioning

confidence: 99%

Desbutyl-Lumefantrine Is a Metabolite of Lumefantrine with Potent In Vitro Antimalarial Activity That May Influence Artemether-Lumefantrine Treatment Outcome

Wong

Salman

Ilett

et al. 2011

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…There are also recent reports of a beneficial effect of supplementing specific antimalarial treatment with retinol [13][14][15][16][17], an observation also supported by observations in the murine Plasmodium berghei model [18]. Contrary to reports on the absence of an effect of retinol on the development of P. falciparum [19,20], recent studies with fresh isolates of P. falciparum have produced evidence of an intrinsic antimalarial activity of retinol and of an enhancement of the activities of artemisinin and monodesbutyl-benflumetol [21,22].…”

Section: Introductionmentioning

confidence: 82%

Spezifische pharmakodynamische Interaktion zwischen Atovaquon und Retinol bei Plasmodium falciparum

Exner

Wernsdorfer

Sirichaisinthop

et al. 2007

Wien Klin Wochenschr

Self Cite

View full text Add to dashboard Cite

The study has been conducted with the objective of assessing the blood schizontocidal activities of atovaquone (ATO), retinol (RET) and combinations of both (ATO-RET) at set retinol concentrations corresponding to the 50th, 65th and 80th percentile of the physiological serum retinol levels. The in vitro tests followed the WHO standard protocol Mark II for measuring the inhibition of schizont maturation in Plasmodium falciparum. Valid results for all 5 test lines were obtained with 26 fresh parasite isolates from northwestern Thailand, an area affected by multidrug-resistance. The EC(50) values for atovaquone, retinol and for ATO in ATO-RET low, medium and high were 3.1 nM, 561.8nM, 0.85 nM, 0.73 nM and 0.45 nM, respectively, the EC(90) values 33.7 nM, 9338.6 nM, 25.31 nM, 8.89 nM, and 5.42 nM. The geometric mean cut-off concentrations of schizont maturation of atovaquone alone and for atovaquone in ATO-RET low, medium and high were 282.5 nM, 79.0 nM, 38.7 nM and 23.7 nM, respectively. These results and those of the Berenbaum analysis based on the fractional inhibitory concentrations indicate synergistic pharmacodynamic interaction between atovaquone and retinol, a phenomenon suggesting that the antimalarial activity of atovaquone could be enhanced by supplementation with retinol.

show abstract

“…As earlier studies have yielded evidence of activity of retinol against P. falciparum in vitro [7] as well as synergistic interaction be tween retinol (Fig. 2) and various blood schizontocidal compounds such as monodesbutylbenflumetol, atova quone as well as artemisinin [8][9][10][11], it was of interest to investigate whether this phenomenon extends also to 4quinolinemethanols such as quinine -the secondary objective of the study.…”

Section: Introductionmentioning

confidence: 97%

Synergism between quinine and retinol in fresh isolates of Plasmodium falciparum

Knauer

Congpuong

Wernsdorfer

et al. 2008

Wien Klin Wochenschr

Self Cite

View full text Add to dashboard Cite

Following earlier reports of synergism between retinol and various antimalarial compounds, the pharmacodynamic interaction between retinol and quinine was investigated in 38 fresh isolates of Plasmodium falciparum. The study was carried out in western Thailand, an area with quinine-resistant P. falciparum. The combination of quinine with retinol in concentrations corresponding to the 50(th), 65(th) and 80(th) percentile of the physiological values in healthy subjects, significantly reduced the EC(50), EC(90), EC(99) and GMCOC for quinine. The FIC values at EC(90) and EC(99) indicate increasing synergism with rising EC and retinol concentration. The mean SFIC value dropped to a level as low as 0.2420, indicating strong synergism.

show abstract

Synergismus zwischen Desbutyl-Benflumetol und Retinol bei Plasmodium falciparum in vitro

Cited by 9 publications

References 17 publications

Desbutyl-Lumefantrine Is a Metabolite of Lumefantrine with Potent In Vitro Antimalarial Activity That May Influence Artemether-Lumefantrine Treatment Outcome

Desbutyl-Lumefantrine Is a Metabolite of Lumefantrine with Potent In Vitro Antimalarial Activity That May Influence Artemether-Lumefantrine Treatment Outcome

Spezifische pharmakodynamische Interaktion zwischen Atovaquon und Retinol bei Plasmodium falciparum

Synergism between quinine and retinol in fresh isolates of Plasmodium falciparum

Contact Info

Product

Resources

About