Mathematical model for the spread of drug resistance in Plasmodium falciparum parasite considering transmission conditions

Background: The herbal medicine has been a rich source of new drugs exemplified by quinine and artemisinin. In this study, examined a variety of Japanese traditional herbal medicine (Kampo) for their potential antimalarial activities. Methods: We designed a comprehensive screening to identify novel antimalarial drugs from a library of Kampo herbal extracts (n = 120) and related compounds (n=96). The antimalarial activity was initially evaluated in vitro against chloroquine/mefloquine-sensitive (3D7) and -resistant (Dd2) strains of Plasmodium falciparum . The cytotoxicity was also evaluated using primary Adult Mouse Brain cells. After being selected through the first in vitro assay, positive extracts and compounds were examined for possible in vivo antimalarial activity. Results: Out of 120 herbal extracts, Coptis Rhizome showed the highest antimalarial activity (IC 50 1.9 µg/mL of 3D7 and 4.85 µg/mL of Dd2) with a high selectivity index (SI) > 263 (3D7) and > 103 (Dd2). Three major chlorinated compounds (coptisine, berberine, and palmatine) related to Coptis Rhizome also showed antimalarial activities with IC 50 1.1, 2.6, and 6.0 µM (against 3D7) and 3.1, 6.3, and 11.8 µM (against Dd2), respectively. Among them, coptisine chloride exhibited the highest antimalarial activity (IC 50 1.1 µM against 3D7 and 3.1 µM against Dd2) with SI of 37.8 and 13.2, respectively. . Finally, the herbal extract of Coptis Rhizome and its major active compound coptisine chloride exhibited significant antimalarial activity in mice infected with P. yoelii 17X strain with respect to its activity on parasite suppression consistently from day 3 to day 7 post-challenge. The effect ranged from 50.38 to 72.13% (P <.05) for Coptis Rhizome and from 81 to 89% (P <.01) for coptisine chloride. Conclusion: Coptis Rhizome and its major active compound coptisine chloride showed promising antimalarial activity against chloroquine-sensitive (3D7) and -resistant (Dd2) strains in vitro as well as in vivo mouse malaria model. Thus Kampo herbal medicine is a potential natural resource for novel antipathogenic agents.

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Section: Discussionmentioning

confidence: 99%

Antimalarial activity of traditional Kampo medicine Coptis Rhizome extract and its major active compounds

Teklemichael

Mizukami

Toume

et al. 2020

Preprint

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“…Since P. falciparum has quickly acquired resistance against currently available all antimalarials [45,46,47], it is urgently required to develop novel antimalarial drugs. Here we evaluated the antimalarial activity of 120 Kampo drugs and found that Coptis Rhizome showed low IC 50 and high SI.…”

Section: Discussionmentioning

confidence: 99%

Antimalarial activity of traditional Kampo medicine Coptis Rhizome extract and its major active compounds

Teklemichael

Mizukami

Toume

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: The herbal medicine has been an attractive source of new antimalarial drugs exemplified by quinine and artemisinin, thus we examined a variety of Japanese traditional herbal medicine (Kampo) for their potential antimalarial activities.Methods: We designed a comprehensive screening to identify novel antimalarial drugs from a library of Kampo crude drug extracts (n = 120). The antimalarial activity was initially evaluated in vitro against chloroquine/mefloquine-sensitive (3D7) and -resistant (Dd2) strains of Plasmodium falciparum. The cytotoxicity was also evaluated using primary Adult Mouse Brain cells. Subsequently, major active components of Kampo crude drug extracts showing high antimalarial activities and low cytotoxicity were further evaluated. Finally, the in vivo antimalarial activities of promising Kampo crude drug extract was investigated using P. yoelii infected mouse model in a seven-day suppressive test (treatment start two hours after challenge infection and continue for seven days).Results: Out of 120 extracts, Coptis Rhizome showed the highest antimalarial activity (IC50 1.9 µg/mL of 3D7 and 4.85 µg/mL of Dd2) with a high selectivity index (SI) > 263 (3D7) and > 103 (Dd2). Three major components in Coptis Rhizome also showed antimalarial activities with IC50 ranging from 1.1 to 6.0 µM (against 3D7) and from 3.1 to 11.8 µM (against Dd2). Among them, coptisine chloride exhibited the highest antimalarial activity (IC50 1.1 µM against 3D7 and 3.1 µM against Dd2) with SI of 37.8 and 13.2, respectively. Furthermore, Coptis Rhizome exhibited significant antimalarial activity in mice infected with P. yoelii 17X strain with respect to its activity on parasite suppression consistently throughout the entire test period (P < 0.05).Conclusion: Coptis Rhizome showed a significant in vivo antimalarial activity in mice infected with P. Yoelii, thus it is a potential natural resource for antimalarials and its component coptisine chloride is a promising antimalarial lead compound.

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“…Since P. falciparum has quickly acquired resistance against currently available all antimalarials [40,41,42], it is urgently required to develop novel antimalarial drugs. Here we found that Coptis Rhizome showed 1.9 µg/ml and 4.9 µg/ml of IC 50 and >263 and >103 SI for Chloroquine sensitive and resistant P. falciparum strains respectively.. We also found that three chemical compounds (coptisine, berberine, and palmatine), which are related to Coptis Rhizome exhibited antimalarial activity with IC 50 less than 12 µMThese compounds belong to the berberine alkaloidal family and share the same isoquinoline skeletons, which is similar to quinoline skeleton found in antimalarial drug quinine.…”

Section: Discussionmentioning

confidence: 99%

Antimalarial activity of traditional Kampo medicine Coptis Rhizome extract and its major active compounds

Teklemichael

Mizukami

Toume

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: The herbal medicine has been a rich source of new drugs exemplified by quinine and artemisinin. In this study, examined a variety of Japanese traditional herbal medicine (Kampo) for their potential antimalarial activities.Methods: We designed a comprehensive screening to identify novel antimalarial drugs from a library of Kampo herbal extracts (n = 120) and related compounds (n=96). The antimalarial activity was initially evaluated in vitro against chloroquine/mefloquine-sensitive (3D7) and -resistant (Dd2) strains of Plasmodium falciparum. The cytotoxicity was also evaluated using primary Adult Mouse Brain cells. After being selected through the first in vitro assay, positive extracts and compounds were examined for possible in vivo antimalarial activity.Results: Out of 120 herbal extracts, Coptis Rhizome showed the highest antimalarial activity (IC50 1.9 µg/mL of 3D7 and 4.85 µg/mL of Dd2) with a high selectivity index (SI) > 263 (3D7) and > 103 (Dd2). Three major chlorinated compounds (coptisine, berberine, and palmatine) related to Coptis Rhizome also showed antimalarial activities with IC50 1.1, 2.6, and 6.0 µM (against 3D7) and 3.1, 6.3, and 11.8 µM (against Dd2), respectively. Among them, coptisine chloride exhibited the highest antimalarial activity (IC50 1.1 µM against 3D7 and 3.1 µM against Dd2) with SI of 37.8 and 13.2, respectively. . Finally, the herbal extract of Coptis Rhizome and its major active compound coptisine chloride exhibited significant antimalarial activity in mice infected with P. yoelii 17X strain with respect to its activity on parasite suppression consistently from day 3 to day 7 post-challenge. The effect ranged from 50.38 to 72.13% (P <.05) for Coptis Rhizome and from 81 to 89% (P <.01) for coptisine chloride.Conclusion: Coptis Rhizome and its major active compound coptisine chloride showed promising antimalarial activity against chloroquine-sensitive (3D7) and -resistant (Dd2) strains in vitro as well as in vivo mouse malaria model. Thus Kampo herbal medicine is a potential natural resource for novel antipathogenic agents.

show abstract

Mathematical model for the spread of drug resistance in Plasmodium falciparum parasite considering transmission conditions

Cited by 6 publications

References 37 publications

Antimalarial activity of traditional Kampo medicine Coptis Rhizome extract and its major active compounds

Antimalarial activity of traditional Kampo medicine Coptis Rhizome extract and its major active compounds

Antimalarial activity of traditional Kampo medicine Coptis Rhizome extract and its major active compounds

Antimalarial activity of traditional Kampo medicine Coptis Rhizome extract and its major active compounds

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