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Finding ways to reduce the risk of malaria, especially in developing countries is becoming of increasing importance. The Chinese medicinal plant Artemisinin annua L. is central in finding successful ways to control malaria. A. annua is a plant that produces low yields,
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There are four parasite species that cause malaria in humans. These are Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale. Plasmodium falciparum and Plasmodium vivax are the most common; however Plasmodium falciparum is seen as the most deadly (Dalrymple et al. 2012). The malaria parasite is transmitted to the female mosquito from an infected individual as a blood meal is taken. The first blood meal is a prelude to reproduction, as blood is necessary for reproduction to occur. After a blood meal, the parasite carried by the mosquito undergoes a life cycle change before it becomes infectious to other individuals through subsequent blood meals. As the temperature of the environment decreases, the period required for this life cycle change increases. Due to the short life-span of the mosquito, transmission of the parasite becomes less likely as the environmental temperature falls below 16°C. At very low temperatures, many species of mosquito suspend biting meaning the stability and transmission of malaria is greatly reduced in temperate regions (Sachs and Malaney 2002). A study of the mosquito species carried out by Panosian Dunavan (2005) states that sub-Saharan Africa is the largest sanctuary of Plasmodium falciparum, the most lethal of the protozoan parasite species causing malaria in humans. Sub-Saharan Africa is also the home of Anopheles gambiae, the most aggressive of the more than 60 species of mosquito currently transmitting malaria to humans (Dunavan et al. 2005). The high transmission rates in sub-Saharan Africa reflect the large capacity of Africa's main vector carrying mosquito A. gambiae complex of species, with their high tendency towards anthropophily (Sachs and Malaney 2002).
Location and Habitat
The burden of malaria is by no means evenly distributed. The disease is heavily centred in the tropics, increasing in prevalence in sub-tropical regions in five continents. In many temperate zones with strong seasonality and cold winters, attempts to eradicate malaria have been successful. In these zones, the base reproductive rate of malaria is much lower than that of the tropics, meaning moderate control efforts and disease management can eliminate the disease with little socio-economic costs. Rainfall and humidity can also affect transmission, although the predominant factor in explaining the geographical distribution of malaria is seasonal temperature with temperate regions having much lower seasonal temperatures and thus fewer cases of malaria. Cold winters are also successful in eliminating malaria from many temperate zones (Sachs and Malaney 2002).
The Economic and Social Burden of Malaria
Malaria is one of the top three killers amongst communicable diseases (Sachs and Malaney 2002). In 2010, malaria caused an estimated 665,000 deaths, mostly to children in sub-Saharan Africa (Dalrymple et al. 2012). Every year there are 500 million P. falciparum infections in Africa alone, accounting for 30-50% of inpatient admissions (Dunavan et al. 2005). There are 300-500 million clinical cases each year and every 40 seconds a child dies from malaria. This is a daily loss of 2,000 lives worldwide (Sachs and Malaney 2002). The World Health Organisation (WHO) estimates that in 2009, 225 million cases of malaria occurred with >780, 000 deaths (Elfawal et al. 2012). Malaria causes fever and chills, anaemia, seizures, heart and lung failure and often death (Dunavan et al. 2005). The increased prevalence of malaria in recent years could be due to population movements into malaria dense regions and changing agricultural processes, such as dam building, irrigation schemes and deforestation. In the long term, climate change and the El Niño southern oscillation could both be factors in increasing the malarial resistance to drugs and insecticides. Malaria has become so prevalent in some regions of sub-Saharan Africa that genetic polymorphisms such as sickle-cell trait are being selected for as protection against malaria. Sickle-cell trait provides protection from malaria when it is inherited from one parent however is fatal if inherited from both parents. The chance of death from malaria is so high in some regions of sub-Saharan Africa that it justifies welcoming a potentially fatal genetic mutation into the gene pool, due to the fact that it provides some protection to the increasingly prevalent malaria transmission. Malaria brings about economic costs for the countries that have the disease. These costs can be split into private medical costs and non-private medical costs. Private medical costs are items such as bed-nets, anti-malarial drugs, transportation, prevention, diagnosis and treatment. Non-private costs are public expenditures, prevention and treatment and from the government - vector control, health facilities and education and research (Sachs and Malaney 2002). Malaria is highly prevalent is less economically developed countries, those that do not have the finances available to pay for these costs and so subsequently, are unable to control the transmission of malaria.
Artemisinin-based combination therapies (ACTs) are a possible malarial treatment (Mutabingwa 2005). The main issue with the use of Artemisinin is producing enough to meet the world demand (Milhous and Weina 2010). Artemisinin is a sesquiterpenoid synthesized in the glandular trichomes of the Chinese medicinal plant Artemisinin annua L. (Graham et al. 2010). ACTs are current WHO recommended first line drugs for the treatment of uncomplicated malaria caused by Plasmodium falciparum. Artemisinin and its metabolite dihydroartemisinin are highly active against malaria parasites, but have a very short half life. This makes them somewhat unsuitable for malaria prevention (Ogwang et al. 2012). A study of this therapy (Mutabingwa, 2005) explores this option. In 2005, ACTs were the best anti-malarial drugs available. They have been shown to successfully reduce the overall malarial transmission, but only at low intensities. Limiting factors are high costs, no public awareness, limited knowledge on the safety of ACTs during pregnancy, slow deployment and inappropriate drug use. In 2005, alternative ways for increased production of ACTs were desperately needed, but had not yet been discovered. ACTs have been known to reduce overall malarial transmission through action of viability of gametocytes, leading to reduced infectivity of mosquitoes. Early treatment is needed as ACTs have a gametocidal effect on stages one to three, but not on stage four. Conclusions were made that more effective controls were Insecticides and Insect Treated Nets (ITNs), and that these should be accessed by many, due to sustainable funding which became available from the Global Fund (Mutabingwa 2005).
A study of the genetic map of Artemisia annua L. (Graham et al. 2010) confirmed that parasite resistance to A. annua has been found in western Cambodia. This increasing problem of artemisinin resistance was best addressed by increasing the availability of ACTs and discouraging the use of artemisinin monotherapies. Funding for ACTs increased and yet the supply chain was unable to produce high quality artemisinin in the quantities that were required, meaning the supply of ACTs was left reliant on the agricultural production of artemisinin. Plant based production was challenging, as at the time, A. annua was undeveloped as a crop. An alternative method of production was hypothesised, that of a microbial-based system that was able to synthesise an artemisinin precursor for chemical conversion. This was in development as a supplement to agricultural production, as agricultural production needed to continue, being that it was an essential source of supply. Producing improved varieties of A. annua for developing nations brought immediate benefit to the existing supply chain by reducing production costs, stabilising supplies and improving grower confidence in the crop (Graham et al. 2010). ANY MORE EFFICIENT METHODS?
Comparison of the in-vitro anti-malaria activity of A. annua herbal tea and artemisinin was carried out (De Donno et al. 2012) A. annua tea was previously proven to be an effective treatment for malaria. The effects of A. annua tea were tested on Plasmodium falciparum cultures in-vitro. The effects were tested against chloroquinine (CQ)-sensitive D10 and CQ-resistant W2 strains of P. falciparum using the parasite lactate dehydrogenase assay. Results of the tests carried out were consistent with the clinical efficacy of A. annua tea [50% inhibitory concentration for strain D10= 1.11 0.21 µg/ml; IC50 for strain W2 = 0.88 0.35 µg/ml]. The concentration of artemisinin in A. annua tea (0.18 0.02% of dry weight) was shown to be far too low to be responsible for any anti-malarial activity. It was therefore thought to be likely that the artemisinin in the tea co-solubilised with other ingredients (some of which may provide protection from malaria) which acted synergistically with it. Further research in this area would be needed to determine whether the presence of anti-malarial compounds in A. annua tea hinders the development of parasite resistance compared with pure artemisinin (De Donno et al. 2012). This study was only carried out on Plasmodium falciparum. For more reliable results, the same test would need to be carried out on more species. The efficacy of the tea has also not been investigated in vitro; this would need to be carried out to obtain better results.
In a different experiment (Elfawal et al. 2012) it was suggested that dried whole plant A. annua could be used as an anti-malarial therapy. Artemisinin as ACTs are currently thought to be the best treatment option against malaria parasites that have evolved resistance to chloroquinine. Artemisinin has been shown to be effective against human cancer cell lines and some livestock diseases. Production of artemisinin required extraction from the cultivated herb A. annua, which is a generally regarded as safe (GRAS) herb suitable for human consumption. Large production costs and inadequate availability of artemisinin meant the effectiveness against malaria was limited. The drug was extracted from plant material, crystallised and used for the semi-synthesis of artemisinin derivates. This experiment omitted the extraction step, saving time and money, by using A. annua directly as a source of artemisinin. It was shown that mice which were fed dried WP material had up to 40x more artemisinin in their bloodstream than mice which were fed corresponding amounts of the pure drug. Active ingredients were delivered faster and in greater quantities from WP treatments than from the pure drug. The experiment was carried out to determine whether WP A. annua was able to kill malaria parasites in a rodent model. Plasmodium chabaudi was used in this experiment as a model organism. It was concluded that orally digested powdered dried leaves of WP A. annua were able to kill malaria parasites more effectively than the pure drug. Dried A. annua leaves which contained 14.8mg artemisinin per gram of dried leaves were used, and parasitemia was compared over time in mice treated with low-dose WP A. annua, low-dose pure artemisinin or placebo. After 24 hours, dead parasites were seen in mice treated with low-dose WP A. annua. Mice treated with low-dose WP A. annua showed significantly lower parasitemia than those treated with low-dose pure artemisinin and those treated with low-dose pure artemisinin did not show a significant difference in parasitemia from those treated with the placebo (Elfawal et al. 2012).
Population suppression strategies and the genetic control of mosquitoes (Wilke and Marrelli 2012) concentrated on the Sterile Insect Technique (SIT) as a method of malaria control. It is a species specific and environmentally benign method for insect population control. An experiment was carried out that involved mass rearing, radiation mediated sterilization and release of male insects into a target area. Successful mating with a sterile insect meant no offspring were produced and the population declined. This reduced the transmission of vector borne diseases. There are advantages to using this method. Males are good at seeking out females of the same species and as the population declines, the technique becomes more effective. It is also the most non-disruptive pest control method. It is species specific and does not release exotic agents into new environments. There are also disadvantages to this method. The released sterile insects have to compete for females and the opportunity to mate with wild males already in the environment. The production process of sterile insects decreases the competitive capacity of the insect to mate when compared with wild insects and finally, the success of this method also relies on the release of a large number of insects, which can be costly. (WILKE) There have been some successful SIT programs that eliminated and suppressed pests, but not specifically mosquitoes. In the case of mosquitoes, in the 1970's and 1980's 20 field trials were carried out that demonstrated the capacity of the Sterile Insect Technique in controlling the numbers of malaria carrying mosquitoes. Anopheles albimanus was successfully controlled in a field trial using chemo-sterilized mosquitoes. The use of SIT against malaria carrying mosquitoes is problematic, mainly due to the operational difficulty involved with exposing the mosquitoes to radiation and the density dependent nature of the target populations. Despite this, there is still much interest in using SIT as a method of mosquito control, leading to a resurgence of interest in recent years, with many research groups trying to overcome the difficulties associated with SIT which stopped it from becoming a widely used approach following early trials (Wilke and Marrelli 2012).
The release of Insects Carrying a Dominant Lethal Gene, or RIDL (Wilke and Marrelli 2012) was thought to be an improvement on the Sterile Insect Technique. The system involved introducing a lethal dominant gene that was controlled by a female-specific promoter. Expression of the lethal gene was inactivated by treatment with tetracycline, which allowed the colony to be maintained. When males and females were separated the tetracycline was removed which caused the death of female mosquitoes. The RIDL system is centred on the expression of tTa, a fusion protein that combines sequence- specific tetracycline-repressible binding of tRe to a eukaryotic transcriptional activator. In the absence of tetracycline, the protein binds to the tRe sequence, activating transcription from a nearby minimal promoter, as shown in figure 1 (Wilke and Marrelli 2012).
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Figure 1 shows tTa and the tetracycline-repressible expansion system.
When the mosquitoes were prepared for release, the repressor was inactivated and the lethal gene was expressed, which caused the death of all females. RIDL offers a solution to many of the drawbacks of the traditional system of SIT (Wilke and Marrelli 2012).
It was concluded that orally delivered WP A. annua is effective in killing malaria parasites in a mouse model. As the genetic makeup of mice is similar to that of humans, this is a positive start. To produce more conclusive results however, orally delivered WP A. annua needs to be tested on humans with malaria to see if the results produced are conclusive. An edible WP A. annua treatment approach could significantly increase the number of patients able to be treated and reduce costs of treatment. WP treatment is a more efficient delivery mechanism than purified A. annua, which is costly and inefficient. Using a high dosage treatment provides potential resistance against many infectious agents, meaning the approach outlined in this review would dramatically reduce costs of healthcare across many nations. A. annua production could also be implemented globally, focusing on plant cultivation and processing, providing socioeconomic stimulus for the countries growing the crop.