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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
2
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
3
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
4
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.
5
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
morphological characteristics of the genus: “Leaves
that are alternate, and much divided pinnately into
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
Figure 2. Morphology of Artemisia vulgaris, showing the alternate leaves, tiny flower heads and other common characteristics. [www.plant-pictures.de]
6
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.
7
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
(TCM), the conditions that it supposedly
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
Figure 3. Artemisia annua being grown in a Chinese garden specifically for its medicinal properties. [permaculturetokyo.blogspot.com]
8
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
(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
peroxide bridge which generates carbon-centered
free radicals or reactive oxygen species (ROS)
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]
Figure 5. Showing the structure of artemisinin and some derivatives. Notice the peroxide bridge present in all of them. [www.scielo.br]
9
(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.
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
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]
10
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
11
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
12
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
13
& 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
14
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
15
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).
16
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
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).
Figure 8. Artemisia herba-alba, showing the whitish colour. [ http://eol.org/pages/6180100/overview]
17
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,
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
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]
18
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
19
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.
20
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.
21
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
to the discovery of the medicinal benefits of A.
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
applied for and thus its large
medicinal potential.
Figure 10. Artemisia afra. Notice the typical artemisian leaves. [www.plantzafrica.com]
Figure 11. Showing the increase in number of results on Scirus, a search engine for scientific articles, for Artemisia afra. [omicsonline.org/2153-0645/2153-0645-2-105.php]
22
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
23
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).
24
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.
25
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.
26
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.
27
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.
28
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