A comparison of the stage-specific efficacy of chloroquine, artemether and dioncophylline B against the rodent malaria parasite Plasmodium chabaudi chabaudi in vivo

Chimanuka, Bantuzeko; François, Guido; Timperman, G.; Heyden, Vander Y.; Holenz, Jörg; Plaizier-Vercammen, Jacqueline; Bringmann, Gerhard

doi:10.1007/s004360000358

Cited by 16 publications

(3 citation statements)

References 30 publications

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“…Artemether is an excellent antimalarial agent and belongs to a group reputed to be the most rapidly acting schizontocidal agents [43] reducing parasite burden by a factor of 10 4 /cycle of schizogony [44]. Clinical cure rates of ninety percent (90%) and above have been recorded in previous studies with artemethermonotherapy.…”

Section: Discussionmentioning

confidence: 99%

Effect of Artemether Treatment on Plasma Lipid Profile in Malaria

Edikpo¹,

Okonkwo²,

Adikwu³

2014

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This study was undertaken to assess the effect of artemether treatment on plasma lipid profile in malaria infection. While the importance of lipid to plasmodial infective processes and metabolism is being increasingly appreciated, little is known about the attendant effect of chemotherapy on plasma lipid profile. Thirty patients with uncomplicated malaria were chosen from two secondary health-care facilities in Yobe State, Nigeria with informed consents and ethical clearance. Based on predetermined inclusion criteria patients were given 3.2 mg/kg of artemether with 1.6 mg/kg on subsequent days for a total of five days. This was done after the collection of urine and blood samples for urinalysis, malaria parasite density count and serum lipid analysis. A follow-up was planned seven (7) days from first dose during when clinical assessment and repeat malaria parasite density count and serum lipid analysis were done. Data were analyzed with statistical package for social scientist and Microsoft Excel spread sheet while level of significance at p ≤ 0.05 was calculated using paired t-test. Serum HDL cholesterol concentration recorded a significant decline of 0.13 mmol/L from a pre-treatment mean concentration of 1.17 mmol/L (p < 0.04). Triglyceride, total cholesterol, LDL-cholesterol, VLDL-cholesterol showed increment or reductions that were not significant. The clinical cure rate was 50% and mean percentage reduction in parasitaemia was 52%. A possible explanation for this low cure rate could be resistance, unfavorable pharmacokinetic disposition or lack of full adherence. A trial with complete parasite clearance, possibly using artemisinin-based combinational therapy would provide a more compelling result.

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Section: Discussionmentioning

confidence: 99%

Effect of Artemether Treatment on Plasma Lipid Profile in Malaria

Edikpo¹,

Okonkwo²,

Adikwu³

2014

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“…This is a particularly unexpected observation as relatively few antimalarial agents, notably artemisinin [63], triclosan [64], and the choline analog T3 [65], show rapid onset of inhibition of ring stage parasites. Most antimalarials, including chloroquine and the antifolates, are usually more effective during late erythrocytic stages [63], [66], [67]. However, the reason why rings are more rapidly inhibited than the other stages is presently not known.…”

Section: Discussionmentioning

confidence: 99%

Oleic Acid Biosynthesis in Plasmodium falciparum: Characterization of the Stearoyl-CoA Desaturase and Investigation as a Potential Therapeutic Target

et al. 2009

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Background Plasmodium falciparum parasitization of erythrocytes causes a substantial increase in the levels of intracellular fatty acids, notably oleic acid. How parasites acquire this monounsaturated fatty acid has remained enigmatic. Here, we report on the biochemical and enzymatic characterization of stearoyl-CoA desaturase (SCD) in P. falciparum.Methodology/Principal FindingsMetabolic labeling experiments allowed us to demonstrate the production of oleic acid from stearic acid both in lysates of parasites incubated with [14C]-stearoyl-CoA and in parasite-infected erythrocytes labeled with [14C]-stearic acid. Optimal SCD activity was detected in schizonts, the stage of maximal membrane synthesis. This activity correlated with a late trophozoite stage-specific induction of PFE0555w transcripts. PFE0555w harbors a typical SCD signature. Similar to mammalian SCDs, this protein was found to be associated with the endoplasmic reticulum, as determined with PFE0555w-GFP tagged transgenic P. falciparum. Importantly, these parasites exhibited increased rates of stearic to oleic acid conversion, providing additional evidence that PFE0555w encodes the plasmodial SCD (PfSCD). These findings prompted us to assess the activity of sterculic acid analogues, known to be specific Δ9-desaturase inhibitors. Methyl sterculate inhibited the synthesis of oleic acid both with parasite lysates and infected erythrocytes, most likely by targeting PfSCD. This compound exhibited significant, rapid and irreversible antimalarial activity against asexual blood stages. This parasiticidal effect was antagonized by oleic acid.Conclusion/SignificanceOur study provides evidence that parasite-mediated fatty acid modification is important for blood-stage survival and provides a new strategy to develop a novel antimalarial therapeutic based on the inhibition of PfSCD.

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“…The IDC comprises sequential morphologically, transcriptionally and metabolically divergent developmental stages, and multiple antimalarials show stage-specific efficacy (e.g. [ 11 , 12 ]). Determining which IDC stage is most vulnerable to treatment is especially useful for drugs with short half-lives [ 13 ], such as artemisinin derivatives [ 14 , 15 ], which are currently used in combination therapy as first-line treatment for malaria.…”

Section: Introductionmentioning

confidence: 99%

Daily rhythms of both host and parasite affect antimalarial drug efficacy

Owolabi

Reece

Schneider

2021

Evolution, Medicine, and Public Health

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Background and objectives Circadian rhythms contribute to treatment efficacy in several non-communicable diseases. However, chronotherapy (administering drugs at a particular time-of-day) against infectious diseases has been overlooked. Yet, the daily rhythms of both hosts and disease-causing agents can impact the efficacy of drug treatment. We use the rodent malaria parasite Plasmodium chabaudi, to test if the daily rhythms of hosts, parasites, and their interactions, affect sensitivity to the key antimalarial, artemisinin. Methodology Asexual malaria parasites develop rhythmically in the host’s blood, in a manner timed to coordinate with host daily rhythms. Our experiments coupled or decoupled the timing of parasite and host rhythms, and we administered artemisinin at different times of day to coincide with when parasites were either at an early (ring) or later (trophozoite) developmental stage. We quantified the impacts of parasite developmental stage, and alignment of parasite and host rhythms, on drug sensitivity. Results We find that rings were less sensitive to artemisinin than trophozoites, and this difference was exacerbated when parasite and host rhythms were misaligned, with little direct contribution of host time-of-day on its own. Furthermore, the blood concentration of haem at the point of treatment correlated positively with artemisinin efficacy but only when parasite and host rhythms were aligned. Conclusions and implications Parasite rhythms influence drug sensitivity in vivo. The hitherto unknown modulation by alignment between parasite and host daily rhythms suggests that disrupting the timing of parasite development could be a novel chronotherapeutic approach. Lay Summary We reveal that chronotherapy (providing medicines at a particular time-of-day) could improve treatment for malaria infections. Specifically, parasites’ developmental stage at the time of treatment and the coordination of timing between parasite and host both affect how well antimalarial drug treatment works.

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A comparison of the stage-specific efficacy of chloroquine, artemether and dioncophylline B against the rodent malaria parasite Plasmodium chabaudi chabaudi in vivo

Cited by 16 publications

References 30 publications

Effect of Artemether Treatment on Plasma Lipid Profile in Malaria

Effect of Artemether Treatment on Plasma Lipid Profile in Malaria

Oleic Acid Biosynthesis in Plasmodium falciparum: Characterization of the Stearoyl-CoA Desaturase and Investigation as a Potential Therapeutic Target

Daily rhythms of both host and parasite affect antimalarial drug efficacy

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