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Plasmodium berghei ANKA: selection of resistance to piperaquine and lumefantrine in a mouse model.

Kiboi DM, Irungu BN, Langat B, Wittlin S, Brun R, Chollet J, Abiodun O, Nganga JK, Nyambati VC, Rukunga GM, Bell A, Nzila A - Exp. Parasitol. (2009)

Bottom Line: We have selected piperaquine (PQ) and lumefantrine (LM) resistant Plasmodium berghei ANKA parasite lines in mice by drug pressure.Cross-resistance studies showed that the PQ-resistant line was highly resistant to LM, while the LM-resistant line remained sensitive to PQ.Thus, if the mechanism of resistance is similar in P. berghei and Plasmodium falciparum, the use of LM (as part of Coartem) should not select for PQ resistance.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Jomo Kenyatta University of Agriculture and Technology, Nairobi, Kenya.

ABSTRACT
We have selected piperaquine (PQ) and lumefantrine (LM) resistant Plasmodium berghei ANKA parasite lines in mice by drug pressure. Effective doses that reduce parasitaemia by 90% (ED(90)) of PQ and LM against the parent line were 3.52 and 3.93 mg/kg, respectively. After drug pressure (more than 27 passages), the selected parasite lines had PQ and LM resistance indexes (I(90)) [ED(90) of resistant line/ED(90) of parent line] of 68.86 and 63.55, respectively. After growing them in the absence of drug for 10 passages and cryo-preserving them at -80 degrees C for at least 2 months, the resistance phenotypes remained stable. Cross-resistance studies showed that the PQ-resistant line was highly resistant to LM, while the LM-resistant line remained sensitive to PQ. Thus, if the mechanism of resistance is similar in P. berghei and Plasmodium falciparum, the use of LM (as part of Coartem) should not select for PQ resistance.

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Related in: MedlinePlus

Development of parasitaemia in the treated (●) and untreated mice (■) at different levels during the selection of piperaquine (A) and lumefantrine (B) resistant Plasmodium berghei GFP (for PQ) and GFP-Luciferase (for LM) ANKA strains in mice. Parasitaemias were assessed after 4 days post-infection (in both control and treated groups) and mice were treated using a 4-day test (4-DT, see Materials and methods).
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fig1: Development of parasitaemia in the treated (●) and untreated mice (■) at different levels during the selection of piperaquine (A) and lumefantrine (B) resistant Plasmodium berghei GFP (for PQ) and GFP-Luciferase (for LM) ANKA strains in mice. Parasitaemias were assessed after 4 days post-infection (in both control and treated groups) and mice were treated using a 4-day test (4-DT, see Materials and methods).

Mentions: When exposed to further 23 passages (27th passage) of selection pressure, parasites regained the resistant phenotype and reached a high level of resistance with I50 and I90 of 129.29 and 68.86, respectively (Table 1). Fig. 1A shows the changing response of the P. berghei ANKA to PQ in the course of PQ drug pressure. After the 5th passage under PQ pressure, a dose of 30 mg/kg (>8 times higher the ED90 of the parent strain) suppressed the bulk of parasitaemia, indeed treated mice had parasitaemia of 0.22% only, compared to almost 9% of the untreated group. Thereafter, PQ resistance arose quite rapidly from the 9th passage. Infected mice treated with 30 mg/kg could yield parasitaemia of 2% at the 9th passage, and at 17th passage, parasitaemia reached 4% after a higher dose, 100 mg/kg. The continuous PQ pressure to 27th passage allowed the selection of parasite lines that reached 7.5% (parasitaemia almost as high as the control [8.26%]), after treated mice with 100 mg/kg, a clear indication of the rise in resistance. This resistant phenotype was stable and these parasite lines were scored as PQ-resistant strains (Table 1 and Fig. 1A).


Plasmodium berghei ANKA: selection of resistance to piperaquine and lumefantrine in a mouse model.

Kiboi DM, Irungu BN, Langat B, Wittlin S, Brun R, Chollet J, Abiodun O, Nganga JK, Nyambati VC, Rukunga GM, Bell A, Nzila A - Exp. Parasitol. (2009)

Development of parasitaemia in the treated (●) and untreated mice (■) at different levels during the selection of piperaquine (A) and lumefantrine (B) resistant Plasmodium berghei GFP (for PQ) and GFP-Luciferase (for LM) ANKA strains in mice. Parasitaemias were assessed after 4 days post-infection (in both control and treated groups) and mice were treated using a 4-day test (4-DT, see Materials and methods).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2691925&req=5

fig1: Development of parasitaemia in the treated (●) and untreated mice (■) at different levels during the selection of piperaquine (A) and lumefantrine (B) resistant Plasmodium berghei GFP (for PQ) and GFP-Luciferase (for LM) ANKA strains in mice. Parasitaemias were assessed after 4 days post-infection (in both control and treated groups) and mice were treated using a 4-day test (4-DT, see Materials and methods).
Mentions: When exposed to further 23 passages (27th passage) of selection pressure, parasites regained the resistant phenotype and reached a high level of resistance with I50 and I90 of 129.29 and 68.86, respectively (Table 1). Fig. 1A shows the changing response of the P. berghei ANKA to PQ in the course of PQ drug pressure. After the 5th passage under PQ pressure, a dose of 30 mg/kg (>8 times higher the ED90 of the parent strain) suppressed the bulk of parasitaemia, indeed treated mice had parasitaemia of 0.22% only, compared to almost 9% of the untreated group. Thereafter, PQ resistance arose quite rapidly from the 9th passage. Infected mice treated with 30 mg/kg could yield parasitaemia of 2% at the 9th passage, and at 17th passage, parasitaemia reached 4% after a higher dose, 100 mg/kg. The continuous PQ pressure to 27th passage allowed the selection of parasite lines that reached 7.5% (parasitaemia almost as high as the control [8.26%]), after treated mice with 100 mg/kg, a clear indication of the rise in resistance. This resistant phenotype was stable and these parasite lines were scored as PQ-resistant strains (Table 1 and Fig. 1A).

Bottom Line: We have selected piperaquine (PQ) and lumefantrine (LM) resistant Plasmodium berghei ANKA parasite lines in mice by drug pressure.Cross-resistance studies showed that the PQ-resistant line was highly resistant to LM, while the LM-resistant line remained sensitive to PQ.Thus, if the mechanism of resistance is similar in P. berghei and Plasmodium falciparum, the use of LM (as part of Coartem) should not select for PQ resistance.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Jomo Kenyatta University of Agriculture and Technology, Nairobi, Kenya.

ABSTRACT
We have selected piperaquine (PQ) and lumefantrine (LM) resistant Plasmodium berghei ANKA parasite lines in mice by drug pressure. Effective doses that reduce parasitaemia by 90% (ED(90)) of PQ and LM against the parent line were 3.52 and 3.93 mg/kg, respectively. After drug pressure (more than 27 passages), the selected parasite lines had PQ and LM resistance indexes (I(90)) [ED(90) of resistant line/ED(90) of parent line] of 68.86 and 63.55, respectively. After growing them in the absence of drug for 10 passages and cryo-preserving them at -80 degrees C for at least 2 months, the resistance phenotypes remained stable. Cross-resistance studies showed that the PQ-resistant line was highly resistant to LM, while the LM-resistant line remained sensitive to PQ. Thus, if the mechanism of resistance is similar in P. berghei and Plasmodium falciparum, the use of LM (as part of Coartem) should not select for PQ resistance.

Show MeSH
Related in: MedlinePlus