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Malaria: What is it?

Malaria is a debilitating disease. It triggers periodic flu-like attacks with headaches, chills and severe fevers that can last for 48 to 72 hours.

It is caused by Plasmodium parasites that are spread from human to human through bites from infected mosquitoes.

If not treated with anti-malarial drugs, the disease is often fatal. Today in Africa, malaria is responsible for one in every five childhood deaths.

Areas where malaria is endemic (there is some level of malarial infection maintained within the population) are coloured yellow. Diagram: CDC Division of Parasitic Diseases.

 

Plasmodium parasites use human red blood cells, which contain large quantities of haemoglobin, as food sources.

Haemoglobin is a protein used in the body for oxygen transport. If there is not enough haemoglobin (which contains iron), parts of the body will not receive adequate oxygen to keep the cells in the body producing energy.

This results in anaemia (low iron levels), causing fatigue and other symptoms.

Diagram: Based on work by National Human Genome Research Institute (US)

Interestingly, many people who live in areas where malaria is prevalent have developed resistance to the Plasmodium parasite. This appears to be linked to the genetically shaped-altered haemoglobin (sickle-like shapes, as opposed to the usual spheres).

 

How was malaria originally treated?

The first significant drug for malaria was quinine, a bitter-tasting white powder that comes from the bark of the cinchona tree. This tree is found in the Andes mountain ranges of Ecuador and Peru.

Quinine was introduced to Europe in the mid-seventeenth century and demand for quinine resulted in most cinchona trees being cut down.

A steady supply of quinine was re-established in the 20th century, when a chemical method of making quinine from coal tar was introduced.

For more information, refer to:

Centres for Disease Control and Prevention website: http://www.cdc.gov/malaria/about/history/

World Health Organisation website: http://www.who.int/features/factfiles/malaria/malaria_facts/en/index.html

Magdalen College School, Oxford website: http://www.chem.ox.ac.uk/mom/quinine/quinine.htm

Doctors Without Borders website: http://www.msf.org/msf/articles/2011/04/frontline-a-better-way-to-beat-malaria.cfm

 

The Global Malaria Eradication Program

Chloroquine is a chlorine and quinine-based drug that shows improved anti-malarial properties. Its development was a significant part of the Global Malaria Eradication Program.

A Mosquito biting a human. Picture: Centres for Disease Control and Prevention

This program began in the 1950’s, when the World Health Organisation attempted to eliminate malaria by spraying Chloroquine and DDT (potent anti-malarial drugs) over malaria-infected countries.

The idea was to kill off both the Plasmodium bacteria and the mosquitoes transmitting them.

There was some success seen from this program, with malaria being eradicated from 37 of the 143 countries where the disease had been a constant problem.

Over the duration of the program, a sharp drop in numbers of malaria cases from 110 million in 1955 to less than one million in 1968 was seen in India.

In Sri Lanka a decrease from 2.8 million cases of  malaria in 1946 to just 18 cases in 1966 was seen.

Once the program stopped, there was huge resurgence of malaria in these regions.

Fallout from the failed eradication program included the Plasmodium parasite developing resistance to both chloroquine and DDT insecticides.

This prompted a call for scientists to design other anti-malarial drugs, resulting in development of Ferroquine and the artemisinin family of drugs.

Ferroquine, an iron-quinine derivative, is one of the most recent quinine-based drugs with potential to wipe out Plasmodium parasites resistant to chloroquine.    

There is a very good journal article (Tropical Medicine and International Health (2009) 14 (7) : 1-7) that describes the 1950’s initiative and the current WHO perspective on malaria. Available at: https://docs.google.com/viewer?a=v&q=cache:jrCMllzfXAoJ:www.afro.who.int/index.php?option%3Dcom_docman%26task%3Ddoc_download%26gid%3D4133+malaria+eradication+WHO+1950&hl=en&gl=nz&pid=bl&srcid=ADGEESga30czeJunyLiQ9xD8ZSpKczIgwN_uNXhMhK5RWFz1sKS6oEDVvgUJNZCZFvGVvunCHLtCqS4kOs1Y3MOPU2gwzNj4ZY0EVXD7jQHt4TFkFC2tlwPEGvusWmme6ZN9S8vLI3Zx&sig=AHIEtbTJGjUuaMty5rwNHMV-MiXAglZ8fw

 

How Chloroquine and Ferroquine work

The Cl (Chlorine) and Fe (Iron) parts of chloroquine and ferroquine are thought to be used to get the active quinine part of the drug close enough to kill Plasmodium parasites; they are important for drug delivery.

Plasmodium parasites affect humans by destroying haemoglobin molecules in food vacuoles of red blood cells.

This destruction causes a build-up of free iron in the cell, which would normally poison the parasite.

Spontaneous oxidation-reduction reactions use free iron to generate dangerous hydroxyl radicals, which damage DNA, proteins and other important parts of the infected cell, killing the parasites.

Iron is oxidised by hydrogen peroxide, which is produced by the liver in small quantities.

However, Plasmodium has a system to deal with the free iron by chemically binding it into ‘dimers’ (double iron molecules Fe2) to prevent it being poisonous.

There are two ways these drugs are thought to hinder Plasmodium:

Once the drugs are delivered into the food vacuoles of red blood cells they increase the pH (make the food vacuole more basic). This helps to prevent the parasites from reproducing.

The second way is by ‘capping’ the free iron in the vacuole to prevent the parasites from making the harmless Fe2 molecule. This causes a build-up of free iron in the cell that poisons the parasite.  

Refer to these online journal articles for more information:

J. Antimicrob. Chemother.(2001) 48 (2): 179-184. Available at http://jac.oxfordjournals.org/content/48/2/179.full#ref-19

 Journal of Cell Biology (1985) 101 (6): 2302-2309. Available at http://jcb.rupress.org/content/101/6/2302.abstract?ijkey=2108a9235d03fda791e32a1d31ff8a4b8384b4c7&keytype2=tf_ipsecsha

 

Current Anti-Malarial Drugs: Artemisinins

The World Health Organisation guidelines now call for artesunate, an artemisinin drug, as the treatment of choice for children with severe malaria.

Quinine and quinine-based drugs are now being phased out as they are considered to have more side effects and be less effective than the artemisinin drugs.

Artemisia Annua. Photo: Kristian Peters

Artemisinin drugs have been developed from the Chinese herb qinghao, also known as Artemisia annua that has been used in China for over 1000 years to treat malaria.

They are believed to work by using lots of different free radicals to intensifying the attack on Plasmodium parasites. As of 2010, the exact way they work has not been discovered.

For more information, see the journal article: Jerapan Krungkrai et al. /Asian Pacific Journal of Tropical Medicine (2010)748-753.

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