ID: 0900 6592

LSC-30007

Biology Dissertation

Figure 1. Showing a plantation of Artemisia annua, the plant origin of artemisinin (see insert), which
is currently the most effective anti-malarial on the market.
[http://williamkituuka.blogspot.com/2012/01/malaria-drug-makers-see-light.html]

The Potential Medicinal Benefits

of the Artemisia Genus

Word Count: 5460

1
Table of Contents

Abstract__________________________________________________________________pg. 3

Introduction_______________________________________________________________pg. 4-6

Traditional Medicine__________________________________________________pg. 4

The Genus Artemisia__________________________________________________pg. 5-6

Artemisia annua L.__________________________________________________________pg. 7-15

General Facts and Traditional Uses_______________________________________pg. 7

Biological Activity_____________________________________________________pg. 7-12

Clinical Trials_________________________________________________________pg. 12-13

Toxicity_____________________________________________________________pg. 13-14

Prospects____________________________________________________________pg. 14-13

Artemisia herba-alba Asso._____________________________________________________pg. 16-20

General Facts and Traditional Uses________________________________________pg. 16

Biological Activity______________________________________________________pg. 16-19

Clinical Trials__________________________________________________________pg. 19

Toxicity______________________________________________________________pg. 19

Prospects_____________________________________________________________pg. 20

Artemisia afra Jacq.___________________________________________________________pg. 21-24

General Facts and Traditional Uses________________________________________pg. 21

Biological Activity______________________________________________________pg. 21-23

Clinical Trials__________________________________________________________pg. 23

Toxicity______________________________________________________________pg. 24

Prospects____________________________________________________________pg. 24

Conclusion__________________________________________________________________pg. 25-26

Acknowledgements___________________________________________________________pg. 27

References__________________________________________________________________pg. 28-35

2
Abstract:

This report looked at the most medicinally important species in the Artemisia (Asteraceae) genus, to

determine the potential medicinal benefits of the genus as a whole. The aim of the report was to

provide a solid foundation of knowledge, to facilitate and encourage research into this promising

group of organisms. The traditional uses, biological activities, as well as any clinical trials and future

prospects, of Artemisia annua, A. herba-alba and A. afra were outlined by compiling the known

information on these three. The focus was on the anti-malarial and anti-cancer properties of A.

annua, as they have been researched and understood the best, allowing insight into mechanisms

common to the genus. In the end it was determined that the potential of the genus for future plant-

based medication is significant. Potential research into other members of the genus could include

areas such as parasiticidal, fungicidal and bactericidal activity, immune-modulatory effects, and anti-

cancer properties. The promising anti-diabetic effects of A. herba-alba are of interest too, and testing

for similar activity in other species of the genus may be fruitful. The current interest in A. afra and

the new research effort, The International Center for Indigenous Phytotherapy Studies, will result in

more data on these traditional herbs in the near future, promising interesting things to come.

213 Words

3
Introduction

Traditional Medicine

‘Traditional Medicine’ as defined by WHO as ‘ The sum knowledge, skills and practices based on the

theories, beliefs and experiences indigenous to different cultures that are used to maintain health,

as well as to prevent, diagnose, improve, or treat physical and mental illnesses’ (Anon a, 2008)

includes the use of plants to cure a variety of afflictions and is common practice throughout a variety

of cultures which don’t have easy access to western medicine such as in Africa and South America

(Ernst, 2000). Before the advent of contemporary orthodox medicine, the western world was also

reliant on herbal treatment (Ernst, 2000). Archaeologists have found evidence in 65000 year old

Neanderthal burials of medicinal plant pollen in the wounds (Galanti, 2008). Even chimpanzees have

been shown to ingest a variety of medicinal herbs to fight parasites (Wrangham, 1996). Many

contemporary drugs are based on simple extracts from plants such as atropine from the deadly

nightshade, Atropa belladonna (Turkington & Mitchell, 2010). According to WHO, 80% of the world’s

population uses herbal or plant-based medicine as their primary form of healthcare treatment (Anon

a, 2008). Herbal treatment even forms an integral part of the healthcare system in China (Barnes et

al., 2007). Despite these worldwide acknowledged medicinal benefits, herbal treatment is confined

to the realm of alternate and complementary medicine in the western world (Cumming et al., 2007).

The Artemisia genus in particular is used frequently in traditional medicine, even though it has much

promise for proven medicinal benefits.

4
Artemisia Genus

Many plants from the Artemisia genus are used throughout different cultures as traditional medicine

(Willcox, 2009). The genus’ name is derived from the

Greek goddess Artemis who gave artemisian plants to

Chiron the Centaur (Wright, 2002). Artemisia is one of

the largest genera in the family of the Asteraceae and

also one of the most widely distributed (El-Sahhar,

2010). There are a total of over 300 species, with the

majority located in China (150 species), ex-USSR (174

species), and Japan (50 species) (Wright, 2002). The

number of species in Europe totals 57 species (Stach et

al., 2007). Artemisia ssp. are often aromatic herbs or

low shrubs (Wright, 2002). The Oxford Dictionary of

Plant Sciences states the following common

Figure 2. Morphology of Artemisia
morphological characteristics of the genus: “Leaves vulgaris, showing the alternate leaves, tiny
flower heads and other common
that are alternate, and much divided pinnately into characteristics. [www.plant-pictures.de]

narrow segments. The flower heads are tiny, usually numerous, often woolly, and gathered into

racemes or panicles. The receptacle is flat and naked, and all the florets are tubular and surrounded

by overlapping, scarious-edged bracts. There is no pappus.”(Allaby, 2006), see Figure 2.

Taxonomically, Artemisia species have been divided into sub-genera and sub-species according to

morphological cues, however molecular studies have revealed inconsistencies which may lead to a

revision of the classification in the future (Wright, 2002). Artemisia species serve a variety of uses

such as as ornamental decoration, flavoring, perfume, and of course as medicinal plants (Wright

2002). The most well-known artemisian species is Artemisia annua, having made headlines a few

years ago as a completely novel treatment for malaria (Anon b, 1998), see Figure 1. The battle

against malaria was getting harder as resistance to new drugs developed at accelerating speeds, but

5
then Artemisia annua was discovered has been used until now, with resistance reports having been

minimal due to it being administered in combination with a different drug (Ringwald, undated). The

main aim of this report is to outline different Artemisia species in order to concentrate all available

medicinal information to facilitate research into this genus which may hold a variety of other herbs

which may prove to be as useful as A. annua. This report will cover the medicinal properties of some

of the more important species in the genus and discuss the implications of these on the potential

medicinal properties of the genus as a whole.

6
Artemisia annua L.

General Facts and Traditional Uses

The first species that will be covered in

this report is Artemisia annua, this

being due to its current status of a

medically very important Artemisia

species. It is a species indigenous to Asia,

specifically from China (Anderson, 1984),

see Figure 3. Traditionally having been

used in Traditional Chinese Medicine

Figure 3. Artemisia annua being grown in a Chinese
(TCM), the conditions that it supposedly garden specifically for its medicinal properties.
[permaculturetokyo.blogspot.com]
cures are ‘heat syndromes’ such as chills

or fevers, with malaria falling into the latter category (Wright, 2002). Other medicinal uses for A.

annua include treatment for hemorrhoids (Ferreira & Janick, 2009), leukemia, melanoma, neonatal

jaundice, for immunosuppression, and as an anti-bacterial, anti-parasitic, antioxidant and as an

antiviral (Anon c, undated).

Biological Activity

The best researched biological activity of A. annua is its malaria action, which is due to A. annua’s

main biological compound ‘artemisinin’(Lackie, 2010). Artemisinin and its various derivatives such as

artemether, dihydroartemisinin, and artesunate, see Figure 5, are all sesquiterpene lactones (Cui &

Su, 2010). They all act in radically different ways to pre-existing malarial drugs, resulting in their

importance in treating Plasmodium strains which are resistant to other drugs, such as quinine

(Meshnick, 2002). It is very fast acting, with clinical responses being visible after minutes, and is

7
effective against virtually all

malaria stages (Cui & Su, 2010)

except for the primary and

dormant liver stages (Seth & Seth,

2009), see figure 4 for the

lifecycle of the malaria parasite.

The main drawback of artemsinin

is its short half-life which

excludes it from being used for

prophylaxis (Cui & Su, 2010).

Even though a lot of research has

gone into elucidating the mode of

action of artemisinin, it is still not
clear, and many controversies
about its action have surfaced
Figure 4. Showing the lifecycle of the Plasmodium parasite. All
stages in the human host are susceptible to artemisinin, except
for hypnozoites (dormant liver stages) and the primary liver
stages which are seen in the hepatic cell above.
[sciencedirect.com/science/article/pii/S0378111910002933]

(Neill, 2011). The mode of action which is most

widely accepted is centered on the reactive

peroxide bridge (Meshnick, 2002), the latter, after

having been removed experimentally, strips

artemisinin of its anti-malarial properties (Krishna

et al., 2004). See Figure 5 for the peroxide bridge

being present in all derivatives. It is thought that

artemisinins after becoming activated, exhibit an

opening of their ring structure, exposing the

Figure 5. Showing the structure of artemisinin
peroxide bridge which generates carbon-centered and some derivatives. Notice the peroxide
bridge present in all of them. [www.scielo.br]
free radicals or reactive oxygen species (ROS)

8
(Zhang et al., 1992). These modulate oxidative stress in the parasite and lower antioxidant and

glutathione levels (Cui & Su, 2010). Two mechanisms for the activation of artemisinin have been

proposed, the first being dependent on haem and the second on carbon centered free radicals

(Krishna et al., 2004). See Figure 6 for a diagram of both mechanisms and their pathways of causing

the ring opening.

Figure 6. Showing two proposed pathways of how artemisinin becomes

activated: a) through ferrous haem, b) through the heam losing the second C-
4 radical 16 (Krishna et al., 2004).
[http://archives.who.int/eml/expcom/children/Applications/REF8.pdf]

The free radicals formed then proceed to alkylate close-by cells, such as the parasitized red blood

cells (Krishna et al., 2004). This alkylation when done in vitro with synthetic alkyl agents was shown

to need higher concentrations compared to those generated in normal medication with artemisinin

(Cui & Su, 2010). This indicates that the free radicals released during in vivo administration must act

in a selective way, but where this selectivity stems from is as yet poorly understood (Wu & Liu, 2003).

Currently there have been no major reports of resistance to artemisinin, but individual cases of

ineffective treatment are surfacing in India (Anon d, 2011) and Cambodia (Denis et al., 2006), having

9
prompted research into possible mechanisms of resistance in mosquitoes (Cui & Su, 2010).

Artemisinin is only administered as ACT (Artemisinin Combination Therapy) which is artemisinin in

combination with a different anti-malarial which has a longer half-life and is sometimes, in P. vivax

infections, complemented with primaquine which is effective against hypnozoites, the dormant liver

stages (Bassat, 2011); overall greatly reducing the risk of resistance developing.

Beside the anti-malarial properties described above, A. annua also exhibits a variety of other

medicinal benefits which have been discovered and elucidated in part thanks to its use as an anti-

malarial. The most important and promising is its induction of apoptosis in human cancer cells (Singh

& Lai, 2004). Artesunate, a derivative of artemisinin, was tested against 55 cancer cell lines of the

Developmental Therapeutics Program of the National Cancer Institute, US, which showed that

artesunate was effective at comparable concentrations to commercially available cancer drugs

(Efferth et al., 2001). The anti-tumor action stems from the endoperoxide bridge, similar to the

parasiticidal action, with experiments having shown that the anti-tumor action is one-fiftieth or less

of its natural action after the endoperoxide bridge had been removed (Mercer et al., 2007). The

remaining action must be due to an alternative mechanism (Beekman, 1998), but it is as of yet poorly

understood. The anti-tumor action is dependent on iron, apparent in iron-preloaded cells

experiencing a 100-fold increase in artemisinin cytotoxicity (Lai et al., 2005). This also explains the

high specificity for tumor cells: these express significantly higher amounts of transferrin receptors

compared to non-cancerous cells to sustain the increased metabolic activities, resulting in high iron

concentrations and hence high susceptibility to artemisinin and its derivatives (Crespo-Ortiz & Wei,

2012). The specific mechanism by which it actually damages the tumor cells is still being debated on,

a variety of mechanisms having been proposed, see Figure 7. Oxidative stress induced in cancer cells

through ROS is a common anti-cancer mechanism due to cancer cells’ low concentrations of

antioxidants, causing artemisinin-generated ROSs to generally be seen as the main anti-cancer agents

(Crespo-Ortiz & Wei, 2012). It is possible that it is not just one of the mechanisms in Figure 6 but

rather a combination of them which is responsible for the anti-cancer properties of the artemisinin

10
family. This in turn enhances their prospects for treating drug-resistant tumors and lowers the

chance of the tumors developing resistance to them through mutations (Efferth, 2005).

Figure 7. Showing possible anti-cancer mechanisms postulated for artemisinin derivatives:

(a) Activation of artemsinin in endosome through transferrin-released-iron causes
lysosomal disruption and ROS release resulting in cell death (Crespo-Ortiz & Wei, 2012).
(b) Specific binding of heme to artemisinin inside the mitochondrion may generate carbon-
centered radicals which interfere with the electron transport chain causing apoptosis.
(c) The ROS may cause endoplasmic reticulum stress leading to calcium deficiency and
following that to apoptosis (Li et al., 2009).
(d) Alternatively, the ROSs may cause DNA damage leading to cell death.
[http://www.hindawi.com/journals/jbb/2012/247597/fig2/]

Beside its anti-cancer and antimalarial activity, A. annua has also been demonstrated to have a

variety of other medicinal benefits, such as to treat a Schistosoma infection (Utzinger et al., 2010).

Oral ingestion of artemisinin has also been found to act as a potent anti-inflammatory in severe

inflammatory conditions (Shakir et al., 2011). Artemisinin and its derivatives have also demonstrated

antibacterial activity against gonococci and anaerobic bacteria (Shoeb et al., 1990). A study which

induced sepsis in mice found artemisinin to provide protection by reducing serum concentration

11
levels of tumor necrosis factor alpha and when given in conjunction with unasyn, an antibacterial

consisting of ampicillin sodium and sulbactam sodium (Chen et al., 1992), reduced mortality rates

from a lethal Escherichia coli infection from 100% to 33.3% (Wang et al., 2006). Further investigations

into these antimicrobial effects found artesunate to be synergistic with β-lactam antibiotics against E.

coli by inhibiting a multidrug efflux pump system AcrAB-TolC (Li et al., 2011). In addition to these,

artemisinin has been proven to exert potent antiviral activity against a variety of different viruses,

inhibiting hepatitis B and C, bovine viral diarrhea virus, and Herpesviridae viruses including human

cytomegalovirus (Efferth et al., 2008). Recent findings indicate artesunate is 10-times as effective in

treating human cytomegalovirus compared to artemisinin (Chou et al., 2011). It is especially effective

in treating therapy-resistant mutants, and it displayed a synergistic effect with the current anti-viral

of choice, maribavir (Chou et al., 2011).

Clinical Trials

Many clinical trials have been done to examine the antimalarial properties of artemisinin such as one

including 2352 patients infected with Plasmodium falciparum or P. vivax which all recovered rapidly

after being administered artesunate, intramuscular artemether, dihydroartemisinin tablets or

artemisinin suppositories (Li et al., 2004). Early clinical trials date back to 1991 where artemisinin was

tested against multi-drug resistant Plasmodium strains in Thailand and proved to be 90-100%

effective (Bunnag et al., 1991). Erah et al. have recently reviewed all clinical trials for antimalarials

published between 2005 and 2009, a total of sixty-two, and have found that even with some

resistance to artemisinin arising in remote areas, it remains the best choice of treatment for

uncomplicated malaria (2010).

Different analogs of artemisinin have been used in some human clinical cases to treat for cancer,

such as artemether having successfully treated pituitary macroadenoma (Singh & Panwar, 2006).

Artesunate not only reduced a laryngeal squamous cell carcinoma by over 70% in two months (Singh

12
& Verma, 2002), but also stabilized a progressing stage IV uveal melanoma (Berger et al., 2005). A

large scale clinical trial involving 120 patients suffering from advanced non-small cell lung cancer

showed a 13% increase in 1-year survival rates in patients treated with chemotherapy of vinorelbine

and cisplatin in conjunction with artesunate compared to patients treated with only the

chemotherapy and a placebo(Zhang et al., 2008). The patients on artesunate also showed a

significant improvement in disease progression and control (Zhang et al., 2008). Two other notable

clinical trials assessing the anti-cancer properties of artemisinin derivatives include a UK trial which

was completed in 2011 about colorectal adenocarcinoma being treated with artesunate for which no

results were published (Crespo-Ortiz & Wei, 2012) and an ongoing German trial into the use of

artesunate to treat advanced breast cancer (Crespo-Ortiz & Wei, 2012).

A variety of small scale clinical trials have been performed to test the effect of artemisinin and its

analogs’ effects on Schistosoma infections, finding a 25% reduction of adult Schistosoma

haematobium helminthes following a treatment of artesunate and a 61% reduction with an ACT

treatment of artesunate-mefloquine which also reduced eggs by 96% in a study of 83 patients (Keiser

et al., 2010). Another small scale clinical trial found an astonishing 92.6% cure rate and 95%

reduction in excreted eggs in 27 children infected with S. haematobium who were treated with either

sulfadoxine/pyrimethamine and artesunate or with amodiaquine and artesunate (Boulanger et al.,

2007). Two large scale clinical trials involving 392 and 106 patients however found much lower cure

rates of 44% and 14% respectively (Utzinger et al., 2010)(Obonyo et al., 2010).

Toxicity

Tests of the toxicity of artemisinin in pregnant rats has been tested for at different doses for both

early pregnancies (7-13 days) and late pregnancies (14-20 days), results showing significant decreases

in maternal testosterone and progestagens which caused high percentages of post-implantation

losses (Boareto et al., 2008). Significant toxicity has been found in various animal trials including the

13
previously mentioned embryotoxicity, but also neuro-, geno-, hemato-, immuno-, cardio-, and

nephrotoxicity (Efferth & Kaina, 2010). Long-term low-concentration exposure to artemisinin due to

intra-muscular injections was significantly more toxic than short-term high-concentrations which had

no side-effects (Efferth & Kaina, 2010).

Prospects

ACTs have already become the first line of defence for malaria in most parts of the world, but

research into artemisinin is ongoing and accelerating. Recently a new continuous-flow synthetic

procedure for artemisinin has been developed in Germany which will allow the synthesis of

artemisinin to be both cheaper and easier (Halford, 2012), being able to produce 2000 grams a day

with the reactor which may cost as little as $10000 (Kupferschmidt, 2012). The shortcomings of

artemisinin, high recrudescence and relapse rates due to not killing primary liver stages and

hypnozoites of Plasmodium, seem to be dealt with soon as a new combination-therapy including

curcumin has been found to protect from relapses and recrudescence by activating a TLR2-mediated

immune response resulting in anti-parasite antibodies being produced (Vathsala et al., 2012).

Artemisinin and its derivatives show a lot of promise as anti-cancer drugs, with artemether,

artesunate and dihydroartemisinin all being licensed for therapeutic use in cancer therapy (Crespo-

Ortiz & Wei, 2012).Due to their specific anti-cancer mechanisms and molecular targets not yet having

been fully elucidated, artemisinins hold much potential for discovery and improvement in their

already significant anti-cancer properties. Research is ongoing and the near future will hold much

advancement in this area.

The efficacy of artemisinin and its derivatives to treat schistosomiasis as combination therapies is low

compared to that of praziquantel (Utzinger et al., 2010), but it does seem promising for countries

which have both a high malaria and a high schistosomiasis burden, as its use may have a double

benefit in that scenario (Obonyo et al., 2010). The ambiguous clinical trial results are also open for

14
further investigations: the high cure rates of the small scale clinical trials are unlikely to be attributed

solely to chance. There is a need for further clinical trials testing a variety of other ACT combinations,

as the large scale trials were limited to sulfalene and pyrimethamine (Utzinger et al., 2010).

The potential uses of artemisinin in supporting treatments of sepsis are inspiring, however research

in this area is small and much is still to understand and elucidate. On the other hand, the possibility

of an ACT-style antibiotic of artesunate combined with β-lactam antibiotics may fuel research in this

area, especially due to the recent surges of drug-resistance in E. coli (Yu, 2011).

15
Artemisia herba-alba Asso.

General Facts and Traditional Uses

Artemisia herba-alba, commonly known as white wormwood or desert wormwood, is an artemisian

species found in the steppes of

the Middle East (Mohamed et al.,

2010), with a characteristically

whitish appearance, see Figure 8,

hence the common name. As is

common with artemisian species,

A. herba-alba has been used

extensively as a traditional

medicine to cure a variety of

Figure 8. Artemisia herba-alba, showing the whitish colour.
[ http://eol.org/pages/6180100/overview]
conditions, including toothache,

intestinal and respiratory diseases, enteritis, and diabetes mellitus (Wright, 2002). Other traditional

medicinal uses described include administration as an antibacterial, analgesic, and antispasmodic

herbal tea (Laid et al., 2008), to treat for arterial hypertension (Ziyyat et al., 1997) and to kill ascaris

worms (Mohamed et al., 2010).

Biological Activity

Research into A. herba-alba has elucidated and discovered a variety of statistically significant

medicinal benefits, such as moderate anti-oxidant levels which, in rats, prevented weight gain, and

resulted in an increase in iron status, conjugated dienes, plasma glucose and lipids, which suggests a

potential use of A. herba-alba in combating obesity, oxidative stress, and free-radical related

disorders (Abid et al., 2007).

16
The flavonoids extracted from A. herba-alba have also been shown to have immune-modulatory

activity, see Figure 9. They down-regulate a Th1 cytokine response and up-regulate a Th2 response,

Figure 9. Showing the effect of varying concentrations of flavonoids extracted from

Artemisia herba-alba on interleukin 12 (IL-12) expression in peripheral blood mononuclear
cells from patients with Adamantiades-Behcet’s disease. IL-12 plays an important role in
polarizing Th1 type cells (Messaoudene et al., 2011).
[journal-inflammation.com/content/8/1/35/figure/F3]

while protecting against nitric oxide induced damage by inhibiting NO production, suggesting

potential uses in treating inflammatory diseases such as Adamantiades-Behcet’s disease

(Messaoudene et al., 2011).

A. herba-alba is frequently used as an antidote in Jordan to treat for snake-bites and scorpion stings

(Wright, 2002), it was shown to inhibit 100% of the hemolytic effect of the venoms (Sallal & Alkofahi,

1996).

A. herba-alba also exhibits potent parasiticidal activity: the nematicidal activity of A. herba-alba was

tested against 19 other herbs to treat for two root-knot nematodes: A. herba-alba was the most

effective causing up to 54% mortality after three days of administration (Al-Banna et al., 2003).

Helminths were also found to be treatable with A. herba-alba, with Enterobius vermiculus infections

17
being 100% curable with three days of ingesting an aqueous A. herba-alba solution (Al-Waili, 1988).

French researchers have also tested the potential anti-leishmanial activity of A. herba-alba in vitro,

finding strong activity from essential oils at concentrations as low as 2μg/ml, with aqueous extracts

showing similar effectiveness at twice the concentration, 4μg/ml (Hatimi et al., 2001). Aqueous

extracts also showed similar parasiticidal activity as albendazole in treating ascaridosis in Heterakis

gallinarum infected turkey poults (Seddiek et al., 2011).

Anti-fungal activity has also been recorded for some essential oils in A. herba-alba, Carvone and

Piperitone, though the effect is very weak. Amphotericin B, for example, has a 5617-fold higher

efficacy against Candida albicans than A. herba-alba (Roger et al., 2008). On the other hand, in-vitro

trials of the oils showed very strong efficacy against Candida and Microsporum (Charchari et al.,

1996), suggesting that further research in this area is needed.

One traditional use of A. herba-alba that has been researched comparatively well is that of its use to

treat for diabetes mellitus and hypertension, as it is used in Iraq to treat for diabetes (Al-Shamaony

et al., 1994). A. herba-alba was given as an aqueous solution, as is prescribed in the traditional folk

medicine, to diabetic mice, which consequently showed a 22% reduction of plasma glucose after six

hours, and were protected from weight loss compared to untreated mice (Al-Shamaony et al., 1994).

The solution also caused a decrease in serum lipids which can cause coronary heart diseases at high

levels (Davidson, 1981), and are a consequence of diabetes, thus further supporting its use as a

potential treatment for diabetes mellitus (Wright, 2002).

The traditional uses of the herb as an antibacterial have also been tested, and have been found to be

present in the form of essential oils (Yashphe et al., 2006). The efficacy of A. herba-alba against

different bacteria was tested and has been found to vary depending on the population tested

(Mohamed et al., 2010). Anti-bacterial action was found against both gram-positive and gram-

negative bacteria but was usually low, with the strongest activity overall being against Streptococcus,

Pseudomonas and Serratia, with Escherichia coli being least affected (Mohamed et al., 2010). In

18
addition to these anti-bacterial effects, anti-spasmodic activity was also investigated and found to be

100-1000 times higher than the anti-bacterial activity (Yashphe et al., 1987), which is thought to be

the reason for A. herba-alba’s traditional use against intestinal disturbances. This variation in

population efficacy opens up the possibility of culturing A. herba-alba to increase overall

concentrations of the essential oils responsible for the anti-bacterial and anti-spasmodic activity.

A. herba-alba also shows promising use as an anti-depressant, by having high affinity to the GABAA-

benzodiazepine receptor site (Stafford et al., 2005).

Lastly, A. herba-alba also acts in inhibiting anti-biotic resistance from developing in certain bacteria,

if it is given in conjunction with an antibiotic (Aburjai et al., 2001) and it can also act as a protective

agent against ethanol induced damage to the stomach, suggesting that it can strengthen the gastric

mucosal barrier (Gharzouli et al., 1999).

Clinical Trials

There is currently some interest in researching the positive effects of A. herba-alba extracts on

diabetes. Small scale preliminary trials have been conducted to confirm the blood-sugar-lowering

effects of the extract, in addition to stating that no side-effects were observed and that the patients

had good remission from the diabetic symptoms (Al-Waili, 2007).

Toxicity

No toxicity tests have been done on A. herba-alba, but it can be supposed through the wide use as a

traditional medicine, that no significant toxicity is present, however further research into this area is

necessary.

19
Prospects

No clinical trials are currently being performed on A. herba-alba, and there seems to be little interest

in it compared to some other species in the genus such as A. annua. It does hold a lot of potential

though, especially in its use as an anti-diabetic drug. It is possible that with major discoveries in

related species, A. herba-alba may receive more attention and get its own time to shine.

20
Artemisia afra Jacq.

General Facts and Traditional Uses

Artemisia afra, another important artemisian

species with medicinal properties, is the only

indigenous species from the Artemisia genus in the

African continent, being prevalent from South

Africa up to Ethiopia (van der Walt, 2004), see

Figure 10. Due to its status as a medicinal herb in

Africa, being used by many native groups, and due

Figure 10. Artemisia afra. Notice the typical
to the discovery of the medicinal benefits of A. artemisian leaves. [www.plantzafrica.com]

annua, interest and research into this promising herb has increased significantly since 2001 (Liu et al.,

2008), see Figure 11. The traditional African medicinal uses of A. afra include the treatment of colds,

coughs, influenza, sore throat,

asthma, pneumonia, blocked nose,

stomach ailments, headache,

earache, poor appetite, heartburn,

parasites, measles, gout, diabetes,

colic, flatulence, constipation,

malaria, and wounds (Van Wyk,

2008), showing the vast range of

diseases and conditions it is Figure 11. Showing the increase in number of results on Scirus,
a search engine for scientific articles, for Artemisia afra.
applied for and thus its large [omicsonline.org/2153-0645/2153-0645-2-105.php]

medicinal potential.

21
Biological Activity

A variety of these traditional uses have been tested for statistically significant benefits resulting from

the use of A. afra, such as for the stomach ailments for which ethanolic extracts of A. afra leaves

resulted in reductions in spontaneous rhythmic and agonist-induced contractions of isolated mouse

duodenum and guinea pig ileum (Mulatu & Mekonnen, 2007), thus confirming traditional practices.

Strong anti-oxidant activity has also been found in A. afra (Graven et al., 1992), resulting in efficient

anticoccidial action in poultry (Naidoo et al., 2008) and use in treating fever, rheumatism, and

diabetes (Halliwell & Gutteridge, 1989). The anti-oxidant activity is thought to be due to it acting as a

non-specific donor for hydrogen atoms (Liu et al., 2008) and by being an effective hydroxyl radical

scavenging agent (Burits et al., 2001).

Neurological effects have been found for aqueous A. afra extracts, notably a dose-dependent

sedative effect on the CNS through binding to the GABAA-benzodiazepine receptor site (Stafford et al.,

2005), and ethanol extracts of A. afra show low affinity to serotonin transmitter proteins, indicating

potential uses as an anti-depressant for A. afra (Nielsen et al., 2004).

Cardiovascular activity has been evident in A. afra as well, having a concentration-dependent

hypotensive and biphasic effect on the heart (Liu et al., 2008). An extracted compound from A. afra

named scopoletin also caused decreases in inotropic activity and heart rate (Guantai & Addae-

Mensah, 1999), suggesting uses for A. afra in managing hypertensive conditions (Patil et al., 2011). A.

afra displayed cardioprotective effects in a study where isoproterenol-induced myocardial injury in

rats were treated for with aqueous extracts of A. afra, improving the lipid imbalance caused by ISO

and the atherogenic index (Sunmonu & Afolayan, 2010).

Antibacterial and antifungal activity has also been tested for in A. afra, showing high degrees of

growth inhibition of 15 species of bacteria and one species of fungi (Graven et al., 1992). In another

22
study, researchers found potent in vitro anti-mycobacterial activity and pulmonary inflammation

modulation in Mycobacterium tuberculosis-infected mice (Ntutela et al., 2009).

While screening 7500 different plant extracts for anti-cancer properties, A. afra was one of 32 plant

extracts to have showed significant anti-cancer activity, specifically against melanoma, renal, and

breast cancer (Fouche et al., 2008). Following from this, its anti-cancer properties have also been

labeled as ‘moderate’ when it was tested against 60 cancer cell lines, with its most significant activity

being logged for colon, melanoma, and non-small cell lung cancer (Patil et al., 2011). Flavonoids

found in A. afra have exhibited anti-carcinogenic, anti-mutagenic, and anti-tumorigenic properties

(Patil et al., 2011)

Lastly, A. afra has also been screened for anti-malarial properties, which showed promising in-vitro

anti-plasmodial activity when seven flavonoids and sesquiterpene lactones were extracted through

guided bio-essay fractionation and tested (Kraft et al., 2003). Highly potent anti-plasmodial activity of

A. afra has also been found by a different research team, showing the highest activity is achieved

when the extract is extracted in dichloromethane (Clarkson et al., 2004). The anti-plasmodial activity

is only present in apolar solutions, resulting in the traditional herbal teas not having any antimalarial

uses (Liu et al., 2010).

Clinical Trials

Up until now there have been no clinical trials performed on A. afra, however there has been a

request to perform a clinical trial on the use of A. afra in treating mild and moderate asthmatic

subjects, however the permission was not granted due to a lack of safety data (Patil et al., 2011). Also,

The International Center for Indigenous Phytotherapy Studies is a new research effort based in South

Africa which with a fund of $4.4million will perform clinical trials on the most frequently used plants

in traditional medicine in Africa (Basi, 2007).

23
Toxicity

Toxicity tests done on A. afra extracts in rodents have found them to be non-toxic with high LD50S of

2.45 and 8.96 g/kg for intraperitoneal and oral doses, and even demonstrated to be

hepatoprotective at high doses (Mukinda & Syce, 2007). Also, no significant changes in morphology,

physiology and behavior were observed after three months of administration (Mukinda & Syce,

2007).

Prospects

Due to the recent findings on A. afra’s biological activities, research into the biological effects of A.

afra is speeding up, with over half of all publications on A. afra, 27 out of 42, having been published

between 2001 and 2008 (Van Wyk, 2008). A comprehensive review (Patil et al., 2011) has been

published in November 2011 on A. afra, compiling all known scientific data on the species and will

most probably act as a primer for many new research endeavors into exploring this plant which may

hold as much or more medicinal importance than A. annua.

24
Conclusion

This report set out to provide a comprehensive outline of the medically most important Artemisia

species and to extrapolate that medical knowledge to the genus as a whole. Artemisia annua is the

plant which has brought plant-based medication back into the spotlight. Its biological activities are

well-researched and broad, and this set it out as being an ideal species to introduce the genus.

Artemisia herba-alba followed, being a species which is widely known as a medicinal plant with a

wide range of in vitro and animal-based experiments having been performed to outline its biological

activities, but it lacks clinical trials, a situation many medicinal plants find themselves in. The last

species, Artemisia afra, is a species which is currently receiving much attention and is likely to have

extensive research performed on it in the near future; however it currently has fewer proven

medicinal benefits than the others. These three different situations complement each other to

provide a general view of the genus itself.

At this point it is possible to extrapolate from these findings to detail similarities among these three

species and to suggest new routes to take in researching this genus in the future. All three species

have exhibited some degree of parasiticidal activity, and it is certain that this activity was only

discovered in A. herba-alba and A. afra due to the potent anti-malarial activity of A. annua.

Nonetheless, parasiticidal activity seems common in the Artemisia genus, and further research into

this area to discover more members with potent anti-parasite activity is recommended. A. annua

and A. afra have both exhibited anti-cancer activity, and it might be an idea to screen other members

of the genus for these effects, including A. herba-alba. Artemisia ssp. seem to have anti-oxidant, anti-

fungal, anti-bacterial, and immuno-modulatory activities which are all potential areas for future

research. Overall, the majority of traditional uses for the different herbs have been proven to have a

scientific foundation. This opens up the possibility for increased testing of traditional uses of other

herbal medicine, such as the new research effort based in South Africa. The future of plant-based

medication is bright.

25
Due to this report handling traditional medicine of indigenous people, a lot of information is

unavailable. Artemisinin had been used for extended periods of time in China before the first reports

were translated into English. The length of this report also limited the amount of information that

was able to be put forth: there are a variety of other species of interest in the Artemisia genus which

were not able to be described here, such as Artemisia absinthium, A. vulgaris, and A. montana. A.

absinthium has for example strong potential as medication for Crohn’s disease (Omer et al., 2007), as

well as antibacterial, antifungal (Juteau et al., 2003), anthelmintic (Tariq et al., 2009) and a variety of

other biological activities. A. vulgaris on the other hand showed potency in treating trichinellosis

(Caner et al., 2008) whereas research in A. montana has resulted in the extraction of three aldose

reductase inhibitors: important potential candidates to treat or prevent diabetic conditions (Jung et

al., 2011). In the end, this report is in no way exhaustive: research on plant-based medicine is rapid,

with over half-a-dozen of the journals referenced to in this report having been published within a

month of writing it.

On the other hand, this report succeeds in what it set out to achieve: to give an overview of the

Artemisia genus in general, while focusing on the medicinal benefits. These are now clearly outlined

for three species and the medicinal benefits have been extrapolated to the entire genus. The report

has demonstrated the importance of this genus and the untapped potential it still holds. Research is

ongoing, and hopefully in the future A. annua will not be the main focus of a report on this genus,

but rather be accompanied on equal footing with other species which have helped mankind as much

as it did.

26
Acknowledgements

I would like to thank my dissertation supervisor, Dr. Tony Polwart, for helping me throughout the
writing of this report.

I also want to thank Keele University for providing me with library books and the online journals I
would not have had access to without them.

Finally, I want to say thank you to my parents for financially enabling me to be at University and
writing this report.

27
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