Ensuring sustained ACT production and reliable artemisinin supply

Kindermans, Jean-Marie; J, Pilloy; Olliaro, Piero; Gomes, Melba

doi:10.1186/1475-2875-6-125

Cited by 64 publications

(67 citation statements)

References 3 publications

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“…Thus, essential oils as a rich source of flavor molecules are used widely to prevent and treat human diseases (Edris, 2007). The sesquiterpene artemisinin, derived from Artemisia annua, has attracted special attention due to its anti-malarial activity (Kindermans et al, 2007). Alternative sources for the supply of the anti-malarial compound have been proposed due to shortage of the raw material (Chang et al, 2007).…”

Section: Possible Uses Of Flavor Moleculesmentioning

confidence: 99%

Biosynthesis of plant‐derived flavor compounds

Schwab¹,

Davidovich‐Rikanati²,

Lewinsohn³

2008

The Plant Journal

944

704

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SummaryPlants have the capacity to synthesize, accumulate and emit volatiles that may act as aroma and flavor molecules due to interactions with human receptors. These low-molecular-weight substances derived from the fatty acid, amino acid and carbohydrate pools constitute a heterogenous group of molecules with saturated and unsaturated, straight-chain, branched-chain and cyclic structures bearing various functional groups (e.g. alcohols, aldehydes, ketones, esters and ethers) and also nitrogen and sulfur. They are commercially important for the food, pharmaceutical, agricultural and chemical industries as flavorants, drugs, pesticides and industrial feedstocks. Due to the low abundance of the volatiles in their plant sources, many of the natural products had been replaced by their synthetic analogues by the end of the last century. However, the foreseeable shortage of the crude oil that is the source for many of the artifical flavors and fragrances has prompted recent interest in understanding the formation of these compounds and engineering their biosynthesis. Although many of the volatile constituents of flavors and aromas have been identified, many of the enzymes and genes involved in their biosynthesis are still not known. However, modification of flavor by genetic engineering is dependent on the knowledge and availability of genes that encode enzymes of key reactions that influence or divert the biosynthetic pathways of plant-derived volatiles. Major progress has resulted from the use of molecular and biochemical techniques, and a large number of genes encoding enzymes of volatile biosynthesis have recently been reported.

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Section: Possible Uses Of Flavor Moleculesmentioning

confidence: 99%

Biosynthesis of plant‐derived flavor compounds

Schwab¹,

Davidovich‐Rikanati²,

Lewinsohn³

2008

The Plant Journal

944

704

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“…First, they have short in vivo half-lives, and require 3-d treatment regimens in combination with longer-acting antimalarials to maximize cure rates (8,9). 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%

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

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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.

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“…Past experiences in ACT implementation in Sudan [20] and Kenya [21], among others, have demonstrated the unforeseen obstacles that may affect grant progress and Prediction of ACT procurement in two countries [4,22], emphasizing the need to account for the fact that actual disbursement and utilization of Global Fund grants tend to occur behind schedule [23].…”

Section: Predicted Quarterly Disbursementsmentioning

confidence: 99%

“…Production of an ACT requires 12 to 24 months from the planting of Artemisia annua to ACT production [4]. This timeline compares to three to five months for either fully synthetic drugs (e.g., antiretrovirals or tuberculosis drugs) or semi-synthetic drugs requiring fermentation processes (e.g., some antibiotics).…”

Section: Introductionmentioning

confidence: 99%

“…The ensuing sudden upsurge in demand for artemisinin caused large fluctuations in the price and supply of artemisinin. An initially inadequate supply of this key ingredient resulted in a sharp price increase up to $1,200 per kg in [2004][2005], but prices then plunged to as low as $170 per kg in 2007 following subsequent overproduction [4]. Accurate forecasts are needed to stabilize the market by ensuring that production reflects demand [5], but such efforts are complicated by the uncertainty and opacity of global procurement operations.…”

Section: Introductionmentioning

confidence: 99%

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Predicting Global Fund grant disbursements for procurement of artemisinin-based combination therapies

Cohen

Singh

O’Brien

2008

Malar J

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Background: An accurate forecast of global demand is essential to stabilize the market for artemisinin-based combination therapy (ACT) and to ensure access to high-quality, life-saving medications at the lowest sustainable prices by avoiding underproduction and excessive overproduction, each of which can have negative consequences for the availability of affordable drugs. A robust forecast requires an understanding of the resources available to support procurement of these relatively expensive antimalarials, in particular from the Global Fund, at present the single largest source of ACT funding.

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Ensuring sustained ACT production and reliable artemisinin supply

Cited by 64 publications

References 3 publications

Biosynthesis of plant‐derived flavor compounds

Biosynthesis of plant‐derived flavor compounds

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

Predicting Global Fund grant disbursements for procurement of artemisinin-based combination therapies

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