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Malaria Overview
Current Situation
Malaria is a disease which causes approximately 1 million deaths per year. Most of the people that die are children living in resource-poor countries in Sub-Saharan Africa. The disease is caused by a small parasite, known as Plasmodium, entering the human body through the bite of a female mosquito. There is no vaccine and the only way to treat people that have been infected with the parasite is through the use of drugs. Currently we are faced with a crisis, as many of the drugs which have been used for years to treat malaria are failing to cure infections because of parasite resistance to the drugs. As a result deaths from malaria are globally on the increase. In fact more people die of malaria now than they did 20 years ago. One way to combat this problem is to develop new drugs with novel targets which the parasite cannot easily become resistant to.
Malaria: A Disease of Poverty and the Tropics
Over 75% of the estimated 1 million deaths each year occur in children living in Sub-Saharan Africa. This region is particularly affected by malaria due to a combination of economic and ecological factors unique to this continent. Figure 1 illustrates the extent of world poverty.
Fig. 1 World Poverty Map (2000). "Maps courtesy of www.theodora.com/maps used with permission
Figure 2 maps the global distribution of malaria transmission risk. This shows that countries with moderate poverty (more than 25% of population lives below $2/day) and extreme poverty (more than 25% of population lives below $1/day) are often the same countries with a high transmission risk of malaria.
Figure 2. Global distribution of malaria transmission risk, 2003. World Malaria Report 2005 (WHO).
Malaria and poverty are intrinsically linked, with each exacerbating the other. Studies have shown that taking into account initial poverty, economic policy, tropical location, and life expectancy among other factors, countries with intensive malaria grow 1.3% less per person per year. Strikingly, a 10% reduction in malaria is associated with 0.3% higher growth. Furthermore, epidemiological conditions exclusive to Sub-Saharan Africa result in very high transmission rates of malaria, making complete eradication of the disease (as has been possible in more temperate regions), most unlikely.
The introduction of chloroquine (CQ) in the 1940s had a huge impact on global health; however, today resistance to the drug has been observed in every region where Plasmodium falciparum occurs (Figure 3).
Figure 3. Drug resistance to P. falciparum from studies in sentinel sites (up to 2004). World Malaria Report 2005 (WHO).
Resistance developed from several independent foci, and over the next 20 years gradually spread throughout South America and Southeast Asia arriving in East Africa in the late 1970s. CQ resistance has since spread across all of Sub-Saharan Africa. As a result, many countries switched their first-line antimalarial drug to sulfadoxine-pyrimethamine (SP); however, resistance to SP grew and spread quickly, especially in Southeast Asia, South America and more recently in many areas of Africa. This loss of effectiveness of the newer antimalarial drugs has also occurred at an alarming rate. For example, resistance to mefloquine was reported as early as five years after its introduction as a prophylactic treatment in parts of Thailand, whereas resistance to atovaquone was even more rapid, emerging in the same year as its launch (Table 1).
Table 1. Reports of resistance to common antimalarial drugs (taken from Wongsrichanalai et al., Lancet Infect Dis. (2002) 2, 209-218.)
| Drug | Introduced | First Reported Resistance | Effectiveness (years) |
| Quinine | 1632 | 1910 | 278 |
| Chloroquine | 1945 | 1957 | 12 |
| Proguanil | 1948 | 1949 | 1 |
| Sulfadoxine-pyrimethamine | 1967 | 1967 | <1 |
| Mefloquine | 1977 | 1982 | 5 |
| Atovaquone | 1996 | 1996 | <1 |
Initiatives have been introduced to stem the number of drug-resistance mediated clinical failures, such as the introduction of artemisinin derivative based combination therapy (ACTs) and the deployment of new drugs (e.g. LapDap). However it is clear that a better understanding of resistance mechanisms to currently used drugs is required to support the development of such strategies and help prevent the development of resistance to new therapies.
Chemotherapy has been and will remain the central strategy for malaria treatment. As a result there is an urgent need for the development of new antimalarial drugs. The ultimate goal is to register drugs with a suitable product profile for uncomplicated malaria. This includes efficacy against drug-resistant strains, cure within three days (using single daily doses), low toxicity especially in children and in pregnant women, low risk of emergence of resistance, adeptness in formulation and packaging, good product stability and a low cost of goods. As a consequence of the need to adhere to these strict criteria, it is estimated that only 1–2% of projects will make it to the later stages of clinical development.
In an effort to improve the success rate of drug development, several approaches are being investigated. These include the re-design of existing drugs, the novel use of older drugs, the development of drugs from natural products and rational targeting of novel parasite-specific targets as identified by an improved understanding of parasite biology. All four strategies have the potential to produce therapeutically relevant drugs and it is hoped that in the near future a new arsenal of drugs will be available to stem the tide of antimalarial drug resistance.