Dried-leaf Artemisia annua: A practical malaria therapeutic for developing countries?

Table 1 Antimalarial compounds in Artemisia annua vs falciparum malaria

Compound	Compound IC50 (μmol/L)	Compound + artemisinin IC50 (nmol/L)	Ref.
Terpenes
Artemisinin	0.033 0.022, 0.0231	Not applicable	Liu et al[52]
Artemisinic acid	77.8, 61.61	No numerical value provided; response depended on concentration of compound tested with artemisinin	Suberu et al[19]
Arteannuin B	3.2, 4.81
Dihydroartemisinic acid	21.1, 17.71
Nerolidol	94	Interaction with artemisinin not yet tested	van Zyl et al[55]
α-pinene	14
1,8-cineole (eucalyptol)	704
Limonene	5334
Phenolic acids
Chlorogenic acid	69.4, 61.41	No numerical value provided; response depended on concentration of compound tested with artemisinin	Suberu et al[19]
Rosmarinic acid	65.1, 65.01
Flavonoids
Artemetin	26	26	Liu et al[52]
Casticin	24	26
Cirsilineol	23	22.5
Chrysoplenol-D	32	15
Chrysoplenetin	36	16
Eupatorin	65	30
Isovitexin	72.5, 48.11	Interaction with artemisinin not yet tested	Suberu et al[19]
Luteolin	11, 122		Lehane et al[54]
Kaempferol	33, 252
Myricetin	40, 762
Quercetin	15, 142, 14.7, 4.11, 2.943
			Ganesh et al[58]
Rutin	7.1, 3.5, 10.383

¹Against CQ-sensitive HB3 and CQ-resistant Dd2 strains, respectively;

²Against CQ-sensitive 3D7 and CQ-resistant 7G8 strains, respectively;

³Against fresh Bangladeshi isolates, CQ-sensitive 3D7, and CQ-resistant K1 strains, respectively;

⁴Against CQ-resistant FCR-3. CQ: Chloroquine.

Table 2 Kenyan human trial data[20] for orally delivered dried leaf Artemisia annua (plant-based artemisinin combination therapy)

pACT (dried leaf A. annua tablets, ea 500 mg, 3.7 mg artemisinin/tablet)
Artemisinin dose (mg)		No. ofpatients	Leaf DW (g)		%Recrudescence
Day 1	Days 2-6		Day 1	Days 2-6
7.4 × 2	3.7 × 2	12	2	1	25
11.1 × 2	7.4 × 2	12	3	2	9.1
14.8 × 2	11.1 × 2	12	4	3	16.7
18.5 × 2	14.8 × 2	12	5	4	9.1
Compare to orally delivered pure artemisinin[39]
Day 1	Day 2-7
500 × 2	500	227	NA		24

A. annua: Artemisia annua; pACT: Plant-based artemisinin combination therapy; NA: Not available.

Table 3 Estimated numbers of adult patients treatable from plant-based artemisinin combination therapy¹

For A. annua cultivar containing	Number of patients treated at various dry leaf tonnage
	2 T/ha2	3 T/ha	4 T/ha3	5 T/ha
0.7% artemisinin/g DW (Kenyan cultivar)	127260	190890	254520	318150
1.4% artemisinin/g DW (WPI cultivar)	254520	381780	509040	636300

¹Assumptions: each adult needs 100 mg artemisinin (AN) over 6 d for a cure; at 0.7% and 1.4% AN that is approximately 15 and 7.5 g DW leaves, respectively, for a single adult total malaria treatment;

²Below the average of 2.5 T/ha reported for all of East Africa;

³Equal to the maximum obtained growing A. annua SAM in the Stow, MA, United States field trials. A. annua: Artemisia annua.

Table 4 Estimated number of patient treatments by current artemisinin combination therapy vs plant-based artemisinin combination therapy

Combination therapy drug	Adult treatments per ton of artemisinin
AL1	1.76 million
AS/AQ1	2.5 million
pACT leaves with 0.7% artemisinin2	8.6 million

¹http://www.rollbackmalaria.org/partnership/wg/wgprocurementsupply/docs/psmwg_ppACT-API.pdf, p.2 [cited May 27, 2014];

²Assumes a 6 day treatment with pACT, with each patient receiving 15 g dried leaves per full malaria treatment for leaves with 0.7% artemisinin. To obtain an amount of artemisinin equal to 1 T of the extracted drug, one would have to harvest 142.8 tons of dried A. annua leaves containing 0.7% artemisinin. AL: Artemether/lumefantrine; AS/AQ: Artesunate/amodiaquine; pACT: Plant-based artemisinin combination therapy.

Table 5 Comparison of emerging antimalarial therapeutic technologies with plant-based artemisinin combination therapy

Technology	Advantages	Disadvantages
Synthetic AN[116]	Fully synthetic method giving AN = compound	Requires co-drug to obviate emergence of AN drug resistance
	Lowers AN cost compared to extraction	Not yet in production
		Needs sophisticated process
		Likely all under Western control
		Challenging patient compliance due to multiday dosing
Semi-synthetic AN[117]	Semi-synthetic method giving authentic AN	Requires co-drug to obviate emergence of AN drug resistance
	Lowers AN cost compared to extraction	Production began via Sanofi
		Needs sophisticated process
		Likely all under Western control
		Challenging patient compliance due to multiday dosing
OZ439[118]	Single dose cure insures patient compliance	Requires co-drug to obviate emergence of AN drug resistance
	In successful Phase 2 trials	Not yet in production
	Mechanism of action not the same as AN	Needs sophisticated process
	Probably low cost due to full synthesis	Likely all under Western control
pACT[20-24]	Has its own in planta co-drug to obviate emergence of AN drug resistance	Not yet in production
	Very low cost	Likely to meet push back from pharmaceutical industry
	Very consistent product	Challenging patient compliance due to multiday dosing
	Can be used to treat other diseases
	Can be locally owned, produced, managed, and distributed

AN: Artemisinin.