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TABLE 8.3 (Continued)
Plant family
Botanical
name
Used
part Type of extract Isolated metabolite In vitro In vivo References
Allocryptopine K1 1.46 μg/mL Nd No
reduction of
parasitemia
Nd
Berberine K1 0.32 μg/mL Nd No
reduction of
parasitemia
Nd
Periplocaceae Cryptolepis
sanguinolenta
Roots Synthesis Cryptolepine triflate K1 0.8 μM 11 43% at Day
5 at 50 mg/
kg per day
Nd
Rocha e
Silva et al.
(2012)
3D7 0.91 μM10
Cryptolepine analog K1 0.1 μM 330 55% at Day
5 at 50 mg/
kg per day
Nd
3D7 0.087 μM 390
Rutaceae Zanthoxylum
zanthoxyloides
Root bark Dichlorome
´
thane Bis-dihydrochelerythrinyl
ether
3D7 6 μMNd
Goodman
et al. (2019)
Buesgenine 3D7 5.7 μMNd
Chelerythrine 3D7 1.1 μMNd
γ-Fagarine 3D7 9.6 μMNd
Skimmianine 3D7 2.7 μMNd
Pellitorine 3D7 8.8 μMNd
Dioncophylaceae family), all presenting very high selectivity index (range 3304891). All
were tested on both sensitive and resistant falciparum strains. Interestingly, P. berghei
ANKA-infected mice treated with dioncophylline C were totally free of parasites 4 days
after infection, while dioconphylline A treatment led to 99% parasite inhibition. In addi-
tion, the root extract of Cryptolepsis sanguinolenta was evaluated for its clinical efficacy for
the treatment of uncomplicated malaria in Ghana and resulted in total parasite elimination
in all patients (n 5 44) by Day 7.
Clinical trials in humans for the evaluation of antimalarial plants and
compounds
Clinical assays in humans: clinical trials evaluating antimalarial efficacy with herbal medi-
cine are scarce, but some have been carried out (
Table 8.4). Clinical trials differ according
to the question raised about tolerability or efficacy, which determines the design of the
study, specifying the primary and secondary endpoints, the duration of the follow-up, and
so on. Then, the study population may be different, children or adults, and the type of
clinical malaria, asymptomatic, uncomplicated, or severe. The number of patients included
is also of high importance; when larger samples are used, the confidence level is increased
and the margin of error decreased. Then, the experimental tools used to follow primary
and secondary endpoints may be different from a lab to another, as the use of PCR to ver-
ify the occurrence of reinfection. Molecular approach is indeed necessary to distinguish
recrudescent parasites from new infections during the follow-up, and/or can be used to
search for submicroscopic parasitemia. Finally, the way to interpret the results is of high
importance. Results can be mostly based on parasite densities during the follow-up, or on
a clinical assessment proposed by the WHO and defined as “adequate clinical response”
(ACR), “early treatment failure” (ETF), or “late treatment failure” (LTF). ACR is defined
by the absence of parasitemia on Day 14 irrespective of axillary temperature, or absence of
fever irrespective of the presence of parasitemia, without previously meeting any of the
criteria of treatment failure. ETF is defined as development of danger signs on Days 1, 2,
or 3 in the presence of parasitemia; fever on Day 2 with parasitemia greater than at base-
line; or fever on Day 3 with parasitemia. LTF is defined as development of any danger
signs or signs of severe malaria in the presence of parasitemia on any day from Days 4 to
14, without previously meeting any of the criteria of ETF; or fever with parasitemia on any
day from Days 4 to 14, without previously meeting any of the criteria of ETF. In addition,
“fever” is usually defined as history of fever in the previous 24 h or axillary temperature
$ 37.5
C.
In general, few herbal preparations have been tested in patients via clinical trials.
Table 8.4 shows that five plants of West African origin have been tested by a clinical
approach in humans by three different teams. The evaluation of the therapeutic efficacy
against malaria of any product raises an obvious ethical problem since malaria is a fatal
disease and effective treatments exist, although the need to complement the therapeutic
arsenal is a reality. As children are the population most affected by severe malaria, most
studies have been done in adults to limit the risks, except for the two studies carried out
in Mali with Argemone mexicana (
Graz et al., 2010; Willcox et al., 2007). Results of efficacy
295Plant extracts and plant compounds validated by in vitro and/or in vivo approach
Medicinal Plants as Anti-infectives
TABLE 8.4 Main West African plants evaluated alone in human clinical trials for their antimalarial activity during P. falciparum uncomplicated
malaria.
Plant family Plant species Preparation
Controlled
intake
Molecular
biology
Treatment
duration
Control
arm
Nb of
participants
Age in
year
Follow-up
duration Efficacy References
Asteraceae Vernonia
amygdalina
Tea from
leaves
No No 7 days No 41 Mean:
28.7
(Range:
1360)
28 ACR/ETF/LTF D14:
67/15/12%; complete
parasite clearance by
D14: 32%
Challand
and
Willcox
(2009)
Cochlospermaceae Cochlospermum
planchonii
Tuberous
roots
decoction
No No 6 days CQ CQ n 5 21;
Cp n 5 46
Mean: 23
(Range:
1245)
6 By D5, 52% had a
PD 5 0 versus 57% for
CQ; PD range: 012,000
versus 0127 for CQ
Benoit-
Vical et al.
(2003)
N. D. N. D. Tea from
leaves
No No Mean 8.4
days (135
days)
No 19 Mean: 17
(Range:
0.950)
14 Parasites were not
cleared, except for 1
patient by D7.
Willcox
(1999)
D14: 95% CI for
PD 5 255330/μL
Papaveraceae Argemone
mexicana
Decoction
with aerial
parts
No Yes for
positive
cases at
D28
A: 3; B:7;
C: 8 days
No A n 5 23; B
n 5 40; C
n 5 17
Medians
A: 2.3;
B: 1.9;
C: 2.0
28 ACR/ETF/LTF D14: A:
35/26/35%, B: 73/15/
13%, C: 65/12/24
Willcox
et al.
(2007)
ACR/ETF/LTF D28: A:
22/26/39%, B: 63/15/
23%, C: 59/12/23%
Decoction
with aerial
parts
No No 7 days Art-AQ Am: 199 Medians 28 ACR D14: Am 65.7%,
Art-AQ: 100%
Graz et al.
(2010)
Art-AQ: 102 Am: 5;
Art-AQ:
5
Periplocaceae Cryptolepsis
sanguinolenta
Tea from
roots
No No 5 days No 44 Mean:
9.2
28 By Day 4, 50% had a
PD 5 0; By Day 7, 100%
had a PD 5 0
Bugyei,
Boye, and
Andy
(2010)
Rubiaceae Nauclea
pobeguinii
Capsules of
80%
ethanolic
quantified
extract
from NP
stem bark
Yes for the
first 3 days
No 7 days No 11 Mean:
25.7
(Range:
2033)
14 ACR/ETF/LTF D14:
91/0/9%
Mesia
et al.
(2012a)
Capsules of
80%
ethanolic
quantified
extract
from NP
stem bark
Yes for the
first 3 days
No 7 days Art-AQ Np: 33; Art-
AQ: 32
Means:
Np: 22.8;
Art-AQ:
25.7
14 APCR D14: Np: 87.9,
Art-AQ: 96.9%
Mesia
et al.
(2012)
were interesting for A. mexicana, Vernonia amygdalina, and Nauclea pobeguinii with ACRs
ranging from 67% for V. amygdalina to 87.9% for N. pobeguinii, although well below the
rate of artesunate-amodiaquine, the reference association used in two of the studies.
However, these studies suffer from design weaknesses. The lack of supervision for treat-
ment administration in most of the studies is a source of bias in the analysis of the results.
Follow-up of 14 days (or less) does not comply with WHO recommended protocols and
the lack of molecular methods does not allow to distinguish true failures due to parasite
recrudescences from failures due to new infections. In addition, WHO guidelines for the
treatment of malaria recommend that first-line treatment should be changed if the total
failure rate exceeds 10%
(WHO, 2009). Finally, none of these studies presented a chemical
analysis of the administered preparation. Knowing the chemical composition, especially
the amount of the main active metabolites, would give an idea of the composition needed
for a certain activity, or provide a basis for comparison when evaluating the efficacy of the
same preparation in other contexts.
Surprisingly, the problem of malaria prevention with plant preparations has been little
studied so far, except with Artemisia which will be discussed in the next paragraph. Yet,
preventive use, as opposed to curative use, is less subject to ethical questions and could
help reduce malaria transmission.
The case of Artemisia in West Africa
Artemisia annua and A. afra are two plant species described for their antimalarial activ-
ities. Both plants are not endemic in West Africa. A. annua originates from China and
grows all over Europe and in Asia. It is also found in Canada and the United States, fol-
lowing its settlement in North America from northern Asia. A. annua is well known for
its historic use in China to treat or prevent malaria an d for the research work of Chinese
researchers that led to the identification of artemisinin as a bioactive antimalarial mole-
cule, work that was awarded by the 2015 Nobel Prize in Medicine (
Tu, 2011).
Semisynthetic artemisinin derivatives (artesunate, artemether, arteether, etc.) are also
highly active agai nst Plasmodium. Most often used in combination with another antima-
larial molecule with a different mechanism of action and half-life, these molecules consti-
tute the last effective bulwark against malaria. The antimalarial activity of the traditional
remedy, an infusion prepared with the fresh leaves, has been validated in vitro on both
asexual (
De Donno et al., 2012; Liu et al., 2010; Rocha e Silva et al., 2012)andsexual
forms of P. falciparum (
Snider & Weathers, 2021). In vitro, the antiparasite activity of the
infusion preparation on chloroquine-sensitive and resistant falciparum strains, but also on
field isolates, is characterized by IC
50
s values between 0.11 and 1.11 μg/mL, very good
values for crude extracts. Concerning its clinical activity in humans, A. annua tea in a
curative scheme has not shown sufficient efficacy to be recommended (
Mueller et al.,
2004
). But some efficacy in the prevention of malaria has been demonstrated through a
clinical trial which reported 40% of more than one clinical malaria attacks during the 9-
months follow-up in the control group, compared to 17.9% in the A. annua group
(
Ogwang et al., 2012). A. afra, a plant of the same genus, is found naturally in South and
East Africa; it is one of the most popular and commonly used herbal medicines in
298 8. Medicinal plants from West Africa used as antimalarial agents: an overview
Medicinal Plants as Anti-infectives
Southern Africa. This plant is used in decoction or infusion of fresh leaves, to treat a
wide range of diseases, including malaria. Interestingly, its antimalarial activity in vitro
was confirmed despite the absence of artemisinin, both on asexual and sexual stages of
P. falciparum (
Moyo et al., 2019; Snider & Weathers, 2021). However, IC
50
sofasexual
stages are much lower than those of A. annua with IC
50
svaluesbetween8.9and15.3μg/
mL (
Kraftetal.,2003).
At this time, A. annua tea is at the heart of a political-scientific debate whose objec-
tive is to promote or not its use in malaria-endemic areas. As herbal teas derived from
traditional medicine to prevent or treat fevers are widely used by local populations in
malaria-endemic areas, it is a potentially powerful public health tool. The WHO reports
very poor indicators of access to care in malaria-endemic countries, particularly in
Africa where only 20% of pregnant women have access to malaria preventive treatment
during pregnancy. Traditional and/or c omplementary medicine may constitute a way
to improve access to care. The WHO Strategy for Traditional Medicine 201423 high-
lights that herbal medicines and traditional treatments are the main health care for mil-
lions of people around the world. It is also argued that this care is close to the people,
easily accessible, and affordable
(WHO, 2013) . However, the WHO’s main warnings
regarding the use of this tea are the variable quality of homemade remedies and the
promotion of parasite resistance to artemisinin, an extremely serious threat in the fight
against malaria
(WHO, 2019). However, the multiplicity of antiplasmodial molecules in
the leaves of A. annua may limit the risk of resistance promotion, as previously shown
in a murine model (
Elfawal, Towler, Reich, Weathers, & Rich, 2015 ). Although addi-
tional scientific data are needed to confirm or not the relevance and the absence of risk
regarding artemisinin resistance of using such a tea, a small group of people have been
very active in promoting the us e of A. annua teas since 2017, by, for example, writing a
note for the WHO (
Weathers, Cornet-V ernet, Hassanali, & Schul, 2017), producing the
film “malaria business” promoting the benefits of the tea for eradicating malaria and
accusing the pharmaceutical industry of h iding information, and creating an associa-
tion to promote the production, sale, and use of this plant against malaria (“La Maison
de l’Artemisia”). This association already has 91 sites in 24 countries, including 39 sites
in West African countries. In France, a group of scientists and clinical doctors
expressed their concern about the use of A. annua tea in various media and reported
cases of imported severe malaria following the use of the tea for prophylaxis during a
stay in sub-Saharan Africa (
Argemi et al., 2019; Lagarce et al., 2016). The French journal
“Prescrire,” intended for doctors, also published a warning in 2021 about the consump-
tion of this plant, which is associated with a prolongation of the QT interval of the elec-
trocardiogram (
Anonymous, 2021).
Meanwhile, the use of A. annua teas seems to have become very popular in West Africa,
although, to date, no ethnopharmacological studies have established such facts. Since
March 2020, the Covid-19 pandemic seems to have increased the popularity of antim alarial
treatments, including A. annua-based teas, partly due to the controversy surrounding chlo-
roquine. In Madagascar in particular, the use of a preparation containing several plants,
the Covid Organics, including A. annua, is recommended by the government as a preven-
tive treatment for COVID-19. Again, ethnopharmacological studies are needed to confirm
and understand this increasing use of A. annua in West Africa.
299The case of Artemisia in West Africa
Medicinal Plants as Anti-infectives
Conclusion
The use of plants against malaria remains an important way of treatment for local
populations in West Africa. Ethnopharmacological studies depicting local uses of specific
plants have enabled the identification of active plant species against malaria and of iso-
lated compounds that still need research and development to be used as a medicine.
Numerous West African plants and compounds are thus promising candidates for drug
development, but this requires a significant investment of time and money. So far, only
quinine and artemisinin are natural molecules from plants that have led to antimalarial
drugs. Another antimalarial drug, atovaquone, is also a molecule derived from a plant
compound. The use of whole plants or parts of plants as in traditional use can also be of
significant interest in Public Health, due to its accessibility to the most vulnerable popula-
tions. Scientific validation of the preventive or curative activity and safety of these pro-
ducts remains an essential step.
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