Malaria's Drug Miracle in Danger

Enserink, Martin

doi:10.1126/science.328.5980.844

Cited by 107 publications

(98 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results are in agreement with earlier studies in Nigeria that have shown both combinations to be safe and well tolerated [7,8,17] and are also consistent with the high cure rates that have been reported for ACT in other malaria-endemic areas of Africa [18][19][20]. Artemisinin and related endo-peroxide antimalarials act rapidly by clearing P. falciparum in the blood, thereby providing prompt therapy for severe infections [21]. Moreover, artemisinins are also active against parasites resistant to two major classes of antimalarials, quinolines and antifolates, thereby making them the most potent and effective antimalarials presently used [22].…”

Section: Discussionsupporting

confidence: 82%

Efficacy of artemisinin combination therapy for the treatment of uncomplicated falciparum malaria in Nigerian children

Ojurongbe

Lawal

Abiodun

et al. 2013

J Infect Dev Ctries

View full text Add to dashboard Cite

Introduction: The development and spread of Plasmodium falciparum resistance to most commonly used antimalarials remain a major challenge in the control of malaria. Constant monitoring of drug efficacy is an important tool in establishing rational antimalarial drug policies. Methodology: A randomized comparative study was conducted at the Wesley Guild Hospital, Ilesa, Nigeria between February 2010 and September 2011 comparing the efficacy and safety of artemether-lumefantrine (Coartem) and fixed dose of artesunate plus amodiaquine (Larimal) in the treatment of uncomplicated P. falciparum malaria in children betweem 6 and 144 months of age. P. falciparum malaria parasitemia was assessed by microscopy and rapid diagnostic test. Drugs were administered according to age for three days under supervision. The primary efficacy endpoint was a day 28 PCR-corrected parasitological cure. Results: A total of 182 patients were enrolled in the two treatment groups, Coartem (n = 101) and Larimal (n = 81), and tested after 28 days. In the intention-to-treat population, Coartem (n= 101) and Larimal (n= 81) had a PCR-corrected cure rate of 98% and 100% respectively, while in the per-protocol population, Coartem (n = 89) and Larimal (n = 71) both had a PCR-corrected cure rate of 100% at day 28. Although parasite and fever clearance time was faster in the Larimal group, no significant difference was observed between the two drugs. No serious adverse effects were reported. Conclusion: Five years after being introduced in Nigeria, both Coartem and Larimal have been shown to be safe and highly effective in the treatment of uncomplicated P. falciparum malaria in children.

show abstract

Section: Discussionsupporting

confidence: 82%

Efficacy of artemisinin combination therapy for the treatment of uncomplicated falciparum malaria in Nigerian children

Ojurongbe

Lawal

Abiodun

et al. 2013

J Infect Dev Ctries

View full text Add to dashboard Cite

show abstract

“…Second, isolation from the plant source is still the only practical means of accessing ART as a starting material, and with harvest and extraction costs being highly variable and often subsidy-driven, the supply of ART fluctuates widely (10). Finally, alarming reports of ACT treatment failures along the Thai-Cambodian border, and more recently, increased parasite clearance times with artesunate (AS) monotherapy, have raised significant concerns that resistance to these agents may be emerging (2,3).…”

mentioning

confidence: 99%

“…Herein we describe the exceptional pharmacokinetic and antimalarial properties of OZ439 (Fig. 1C) and the studies that led to its selection as a clinical development candidate (3,5,12).…”

mentioning

confidence: 99%

“…1,2,4-trioxolane | antimalarial drug discovery T he need for new, fast acting, and effective antimalarial drugs has never been greater; drug resistance continues to threaten conventional therapy (1), there are new reports of resistance to the artemisinin derivatives (2,3), and the global aspiration of malaria eradication has been rekindled (4) and is supported by many of the world's most influential organizations (5). The semisynthetic artemisinin (ART) derivatives (Fig.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Synthetic ozonide drug candidate OZ439 offers new hope for a single-dose cure of uncomplicated malaria

Charman

Arbe-Barnes²,

Bathurst

et al. 2011

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

335

365

View full text Add to dashboard Cite

Ozonide OZ439 is a synthetic peroxide antimalarial drug candidate designed to provide a single-dose oral cure in humans. OZ439 has successfully completed Phase I clinical trials, where it was shown to be safe at doses up to 1,600 mg and is currently undergoing Phase IIa trials in malaria patients. Herein, we describe the discovery of OZ439 and the exceptional antimalarial and pharmacokinetic properties that led to its selection as a clinical drug development candidate. In vitro, OZ439 is fast-acting against all asexual erythrocytic Plasmodium falciparum stages with IC 50 values comparable to those for the clinically used artemisinin derivatives. Unlike all other synthetic peroxides and semisynthetic artemisinin derivatives, OZ439 completely cures Plasmodium berghei -infected mice with a single oral dose of 20 mg/kg and exhibits prophylactic activity superior to that of the benchmark chemoprophylactic agent, mefloquine. Compared with other peroxide-containing antimalarial agents, such as the artemisinin derivatives and the first-generation ozonide OZ277, OZ439 exhibits a substantial increase in the pharmacokinetic half-life and blood concentration versus time profile in three preclinical species. The outstanding efficacy and prolonged blood concentrations of OZ439 are the result of a design strategy that stabilizes the intrinsically unstable pharmacophoric peroxide bond, thereby reducing clearance yet maintaining the necessary Fe(II)-reactivity to elicit parasite death.

show abstract

“…Current malaria treatment relies heavily on artemisininbased combination therapies (2). Artemisinin and related endoperoxide antimalarials clear P. falciparum infections rapidly, providing prompt therapy for severe infections (3).…”

mentioning

confidence: 99%

Artemisinin activity againstPlasmodium falciparumrequires hemoglobin uptake and digestion

Klonis

Crespo-Ortiz²,

Bottová³

et al. 2011

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

316

314

View full text Add to dashboard Cite

Combination regimens that include artemisinin derivatives are recommended as first line antimalarials in most countries where malaria is endemic. However, the mechanism of action of artemisinin is not fully understood and the usefulness of this drug class is threatened by reports of decreased parasite sensitivity. We treated Plasmodium falciparum for periods of a few hours to mimic clinical exposure to the short half-life artemisinins. We found that drug treatment retards parasite growth and inhibits uptake of hemoglobin, even at sublethal concentrations. We show that potent artemisinin activity is dependent on hemoglobin digestion by the parasite. Inhibition of hemoglobinase activity with cysteine protease inhibitors, knockout of the cysteine protease falcipain-2 by gene deletion, or direct deprivation of host cell lysate, significantly decreases artemisinin sensitivity. Hemoglobin digestion is also required for artemisinin-induced exacerbation of oxidative stress in the parasite cytoplasm. Arrest of hemoglobin digestion by early stage parasites provides a mechanism for surviving short-term artemisinin exposure. These insights will help in the design of new drugs and new treatment strategies to circumvent drug resistance.erythrocyte | endoperoxide

show abstract

Malaria's Drug Miracle in Danger

Abstract: Like many others before it, the latest generation of malaria drugs is losing its punch. This time, can global disaster be averted?

Cited by 107 publications

References 0 publications

Efficacy of artemisinin combination therapy for the treatment of uncomplicated falciparum malaria in Nigerian children

Efficacy of artemisinin combination therapy for the treatment of uncomplicated falciparum malaria in Nigerian children

Synthetic ozonide drug candidate OZ439 offers new hope for a single-dose cure of uncomplicated malaria

Artemisinin activity againstPlasmodium falciparumrequires hemoglobin uptake and digestion

Contact Info

Product

Resources

About