Table 1.

Natural Products and extracts with confirmed or presumed activities in human

Natural product	Source	Mechanism of action	Highest level demonstration of activity
Quinine	Cinchona genus	Assumed to be similar to chloroquine – and prevent heme polymerisation.	Early reports of activity with Cinchona bark showed partial activity with 60g bark over up to 21 days. This represents a total dose of 350 -700 mg, compared to a current clinical dose of 500 mg (10 mg/kg salt) given three times a day for seven days currently - suggesting the bark treatment was unlikely to be completely effective [31]
Lapachol Lapinone Atovaquone	Bignoniaceae	Electron transport inhibition	Lapachol is a naphthoquinone used to treat malaria and fevers [41] reported in the 19th century; it showed weak activity against P. zophurae infected ducks, when tested in 1943. Lapinone (a close derivative) was confirmed active in patients with P vivax[42]by intravenous administration for four days (N=9). Chemical optimisation of the scaffold led to atovaquone
Artemisinin	Artemisia annua	Free radical activation in the presence of free ferrous iron – liberated in erythrocytes by parasite digestion of haemaglobin	Traditional Chinese Medicine. Tea made from 5 g/l leaves gave 12 mg artemisinin, and clears parasite in 3-4 days [43]. (Partial protection, since this is much lower than the WHO recommended dose). More recent studies [44] achieved doses of 95 mg, with 70% cure on day 7, but still with high recrudesence and only 30% cure at day 28 [45]. Chemical optimization has led to longer acting synthetic endoperoxides, currently in development.
Yingzhaosu A	Artabotrys uncinatus (Ying Zhao)	Presumed to be free radical activation in the presence of free ferrous iron – liberated in erythrocytes by parasite digestion of haemoglobin.	Traditional Chinese medicine. The active ingredient was modified to make Ro-41-3823 which was: Single tested in patients (N=30) aged 12 -42 years, with parasitaemia > 5000/ml and temperature 37.7 -39.8 oC. 80% patients were parasite free at day 7 with a single dose of 25 mg/kg.[46] Discontinued because of lack of superiority over mefloquine or artemisinin, and because of safety concerns.
Cryptolepine	Cryptolepis sanguinolenta	DNA intercalation [47]	Patients between 16 and 60, (N=12) with parasitaemia between 1000 and 10000/ul given 25 mg/kg extract tid for seven days. No recrudescence at day 28. Cryptolepine administered orally to P. berghei-infected mice in doses of 50mg/kg/day for four days reduced parasitaemia by 80% but the mice were not cured of malaria (Wright et al., 1996) [48]. Decoction has been standardized by the Faculty of Pharmacy, Kwame Nkrumah University of Science and Technology, Ghana and is marketed as PHYTO-LARIA®.
Curcumin	Curcuma longa	Antioxidant activity?	45 patients have been treated with a nanomilled curcumin, both vivax and falciparum malaria. Nanomilling is used to improves bioavailability. No clinical data on parasitaemia or fever available S Kumesh Kar pers. comm
Strictosamide	Nauclea pobeguinii		Traditional treatment from DR Congo, Herbal medicinal Product PR 259 CT1 – completed a phase I trial – 1000 mg t.i.d for 7 days [49] Phase IIb (N=65 patients) treated with 1000 mg tid for three days, followed by 500 mg tid per day for four days. Parasitaemia fulfilled the WHO research criteria for malaria. ACPR at day 14 was 90.3% compared with ASAQ at 96.9%.[50]. Shown to be orally active in murine models but not in vitro suggesting that deglycosylation may be required for activity.
Protopine Allocryptopine Berberine	Argemone mexicana		Initial study (N=80) with 80% patients < 5 years old. Showed need for high dose regimen [51]. Follow up study (N=199) vs amodiaquine artesunate (N=102) [52] median age 5 years given for 7-14 days twice per day 89% successful at day 28, compared with a 95% success rate for ASAQ. P atients had low parasitaemia (<1000/μL), with only 17.8% of patients fulfilled the WHO research criteria for clinical malaria.
Vernodalin	Vernonia amygdalina		Known as omubirizi in southwestern Uganda and used for pain relief and malaria attack, obtained from The Medical Traditional Healer Association in Rukararwe, Bushenyi District, Uganda [53] Clinical study for decoction (N=33) infusion given four times per day for 7 days [54] 67% response, inclusion criteria allowed patients with <2000/uL and temperature <37.5 oC. All patients over 12 years old
Febrifugine	Dichroa febrifuga		Ch’ang shan, is a traditional Chinese anti-malarial herb. Reports from 1942 suggest a dose of 60 mg was clinically effective [55]. Adverse reaction prevented widespread use of febrifugine. Halofuginone, a halogenated derivative is used against coccidiosis, and other derivatives have been tested against Plasmodium [56]
Gedunin	Azadirachta indica	HSP90 inhibitor ?[57]	Neem extracts are known to be active based on traditional and observations from India in the early 20th century [58]. No published recent clinical studies on malaria, although the aqueous/acetone extract is safe [59] and is registered in Nigeria in 250mg capsules as IRACARP®, adult treatment costs of around $6.00. Most potent ingredient is gedunin [60]. Murine activity is variable and requires cytochrome 3A4 inhibitor.[61]

There are two well documented commercial uses of herbal medicinal products. The first by the Department of Medicaments traditionnels améliorés, (DMT) in Mali which uses a mixture of three herbs Cassia occidentalis (leaves), Lippia chevalieri Moldenke (leaves), and Spilanthes oleracea, Jacq (flowers). Sidibe OM, (2006) Pharmacy Thesis, University of Bamako, Mali http://www.keneya.net/fmpos/theses/2006/pharma/pdf/06P18.pdf.

Ayush-64 is a combination of four Ayurvedic drugs used in India registered by the Central Council for Research in Ayurveda and Siddha (CCRAS). It is formulated into tablets, and dosed at 1g per day over 5-7 days, at a treatment cost of 14 rupees ($0.28) [62]. Effectiveness, measured as ACPR at day 28 was only 48.9% compared with 100% for chloroquine, and it is not recommended for use in treatment. However, the activity in man suggests that there is a need for identification and optimisation of the active ingredients or their metabolites. This figure builds from Table 3 from Willcox and Bodeker 2004 [63]