History a cure or a treatment to prevent the

History
and Discovery of Artemesinin

Malaria is one of the worlds deadliest diseases
accounting for a total of 438,000 deaths in 2015 alone. (“Number of malaria
deaths”, 2018) Being a disease that has such a high number of mortalities
attracts many scientists and research groups to attempt to find a cure or a
treatment to prevent the disease killing so many people. Furthermore, during
the Vietnam–US War in the 1960s, many Vietnamese soldiers suffered from serious
malaria due to a mutated form of Plasmodium falciparum. Under the
request of the North Vietnamese government to provide effective drugs against
multidrug-resistant malaria, China started, on May 23, 1967, a project to search
for new antimalaria drugs. The project was named “Project 523” and involved
sixty research organizations and more than 500 scientists. All activities of
the project were branded under the group name of “Project 523”. (Guo, 2018)

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In
1969 Youyou Tu lead a group from the Institute of Chinese Materia Medica (ICMM)
along with a group of scientists from the China Academy of Traditional Chinese
Medicine. The group of scientists collected over one hundred samples of
traditional Chinese folk medicines and tested there efficacy against malaria. After
many tests and screenings, it was found that an alcoholic extract of Artemisia
exhibited an inhibitory response to Plasmodium falciparum (The bacteria causing Malaria) by up to 80%.
This finding enabled the team to carry out more extensive research on the
efficacy of Artemisia and its antimalarial properties. The team made a
breakthrough when they decided to use ether as the extraction method instead of
ethanol; by doing this the O-O single bond in the compound remained which was
later discovered to be the mode of actoon of the drug. This isolated white
solids which displayed 100% inhibition against Plasmodium falciparum. The
white solids were found to be Artemisinin. (Guo, 2018)

 

The first clinical trials of artemisinin were
conducted between August and October in 1972 in the Hainan and in Beijing also
(30 cases in total).  In the trial
carried out in the Hainan province, a total of 21 malaria patients (9 infected
by Plasmodium falciparum and 11 infected by Plasmodium
vivax) were treated in three dose groups and all of them recovered from the
fevers with full clearance of the malaria parasites. The 9 patients treated in
the Beijing 302 Hospital were also successfully treated, proving the efficacy
of the drug and steering the antimalarial research towards artemisinin. (Tu,
2016)

 

Chemistry and How it Works

The chemical structure of artemisinin was
discovered in December 1972 by analysing the white substance using spectrophotometry,
mass spectrometry, polarimetric analysis and more techniques. This deduced that
the white substance, artemisinin, had the chemical formula of C15H22O5
and had a molecular weight of 282. (Onlinelibrary.wiley.com.lcproxy.shu.ac.uk,
2018)

Figure 1. Chemical structure of Artemisinin (Pubchem.ncbi.nlm.nih.gov,
2018)

 

 

 

 

 

 

 

 

 

There is still considerable debate amongst the
science community as to how artemisinin works against P. falciparum malaria
and its mode of action. One of the leading theories as of now is the production
of carbon-centered
free radicals or reactive oxygen species (ROS). 
The endoperoxide bridge of artemisinin is imperative for their
anti-malarial activity, as replacement of one peroxidic oxygen with a carbon
(e.g., 1-carba-10-deoxyartemisinin) results in a compound with no antimalarial
efficacy. Once formed, these free radicals cause damage to cellular targets in
the area by alkylation. A combination of hemin and high concentrations of artemisinin
readily oxidizes erythrocyte membrane thiols in vitro,
demonstrating the reactivity of artemisinin-derived radicals with biomolecules;
however, the extremely low toxicity of artemisinin at therapeutic doses and the
likelihood of these radicals for intramolecular reactions strongly suggest that
artemisinin-derived radicals, unlike typical alkyl agents, selectively damage
cellular targets. (Cui, 2018)

 

 

How it is Used

Artemisinin is used as a part of a combination
treatment to treat malaria, this is known as Artemisinin Combination Therapy
(ACT). This uses two different drugs with two different modes of action which
provides an adequate cure rate and delays the process of drug resistance. Companion drugs include
lumefantrine, mefloquine, amodiaquine, sulfadoxine/pyrimethamine, piperaquine
and chlorproguanil/dapsone. Artemisinin derivatives include dihydroartemisinin,
artesunate and artemether. A co-formulated drug is one in which two different
drugs are combined in one tablet, this is vital in ensuring both drugs are used.
ACTs are the mainstay of recommended treatment for P. falciparum malaria
and, as no alternative to artemisinin derivatives is expected to enter the
market for several years, their efficacy must be preserved. (World Health
Organization, 2018) Artemisinin based monotherapies are not recommended for the
treatment of P. falciparum as
this actively promotes resistance to the drug reducing the efficacy of the drug
for future uses. In cases of extremely severe malaria then the treatment route
should begin with injectable artesunate for 24 hours followed up by a 3-day
course of Artemisinin combination therapy. It is vital that these treatments
should not be given as monotherapies as not to promote artemisinin resistance. (World
Health Organization, 2018)

 

Artemisinin
Resistance

Artemisinin
resistance has been declared in five different countries (as of December 2017);
these countries make up the Greater Mekong Subregion: Myanmar, Thailand, Cambodia,
the Lao People’s Democratic Republic and Viet Nam. People treated for the
disease in most sites still make a full recovery, however, along the Thailand –
Cambodia border P. falciparum has developed a resistance to virtually all antimalarial drugs. P. falciparum
has developed a resistance to artemisinin due to several factors: poor
treatment practices, patients not adhering to the full course of prescribed
drugs, and the widespread availability of artemisinin-based monotherapies and forms
of the drug. (World Health Organization, 2018)

 

The
resistance is not currently a worldwide threat however if it emerges elsewhere in
the world independently then the problem could easily widen quickly as
currently there are no other antimalarial drugs or treatment courses with the
same efficacy as artemisinin combination therapy. Therefore, tackling this
problem has become a goal for the World Health Organisation who have set a
target of complete eradication of all species of human malaria by the year 2030
in the Greater Mekong Subregion. The WHO African region is another region where
artemisinin resistance has got to be tackled, with malaria accountable for
407,000 deaths in 2016. This can be done by improving the regulation of the
pharmaceutical markets and completely removing all oral based artemisinin
monotherapies around the world.  (World Health Organization, 2018)