Malaria is an infectious disease spread by mosquitoes. More than 1 million people a year die of it. Many agents have been developed to fight malaria. But, since parasites develop resistance to available medicines, new research is needed. Pharmaceutical industry has engaged in many research programmes to address this challenge.
Malaria is a parasitic infectious disease. It is transmitted through the bite of bloodsucking anopheles mosquitoes, which infects the victim with one of the four plasmodium species that cause the disease, of which plasmodium falciparum is the most lethal. The name of the disease stems from the Italian words “mala” and “aria” which together mean “bad air”.
Malaria has been known for thousands of years. Analysis of archaeological remains in a cemetery in southern Italy, using the latest DNA techniques, has established the existence in about 450 AD of a particularly virulent form of malaria, lending weight to the hypothesis that a widespread outbreak of the disease contributed to the fall of the Roman Empire. The first effective quinine-based treatment for malaria was given to Europeans as early as the beginning of the 17th century.
During the first half of the 20th century, malaria was a serious health problem in all regions of the world, including a good part of Europe and North America. In the late 1950s belief spread that malaria might one day be completely eradicated. Through a combination of social and economic developments, prompt and effective treatment, and additional mosquito control, mainly the spraying of the inside of houses with DDT, it was eliminated from Europe, North America, Australia and much of the Middle East by 1970.
A decline in funding, insect resistance to insecticides and growing environmental concerns related to DDT, led to the malaria eradication campaign being abandoned in 1972. The disease has been rebounding ever since. It is now reappearing in some countries that had previously eliminated it.
Between 300 and 500 million new cases occur each year and more than one million people – mainly children under five living in sub-Saharan Africa – die from it. Malaria is prevalent in the least developed countries, but more than 10,000 cases are reported annually among European travellers. Climate changes could increase its reach.
Molecular derivatives of quinine, such as chloroquine, primaquine, mefloquine or amodiaquine, and other antiprotozoal medicines have been used for decades in the prevention and treatment of malaria, but many countries are experiencing high levels of resistance to these classes of compounds.
As a result, health authorities now recommend the combination of sulphadoxinepyrimethamine (which consists of a sulphonamide and a blocker of the parasite’s enzyme dihydrofolic acid reductase) as first-line treatment, but resistance to this is also spreading. Amodiaquine alone or in combination with sulphadoxine-pyrimeth amine, although associated with minor side-effects, is effective when used to treat malaria in pregnancy.
The World Health Organisation (WHO) has been urging developing countries to tackle rising resistance to antimalarial medicines, particularly with the use of artemisininbased combination therapies. The principal structure of artemisinin has been found in the Chinese mugwort (artemisia annua). For centuries, extracts from this plant have been used in Chinese medicine to lower fever.
Artemisinin-based Combination Therapies (ACT) are currently the WHO suggested first-line treatments for uncomplicated plasmodium falciparum malaria and consist of two different antimalarial medicines combined in the same tablet, e.g. artesunate plus mefloquine or dihydroartemisinin plus piperaquine, or artemeter plus lumefantrin. The two antimalarials work in different ways, so it seems unlikely that the malaria parasite evolves resistance to these combinations.
In addition, while the artemisin derivative remains in the body just for few hours, the second compound persists much longer allowing a protection towards new infections. For the treatment of children, two preparations of an ACT are available which dissolve in water. Until recently, carers were forced to crush the bitter-tasting anti-malarial pill and mix it with sugar in order to trick children into swallowing it.
The main interventions to reduce the burden of malaria in Africa, where 90 per cent of morbidity and mortality are concentrated, are:
i.) preventing parasite-carrying anopheles mosquitoes from infecting humans either by spraying insecticides or by using insecticide-treated bed nets. This is complemented by indoor residual spraying, killing the larvae, and environmental management;
ii.) provision of prompt treatment in or near the home;
iii.) providing intermittent preventive therapy, i.e. anti-malarial medications to symptom-free pregnant women in high-transmission areas to protect both expectant mother and newborn;
iv.) supporting and improving forecasting, mapping areas at risk and providing technical help for the prevention of and response to malaria outbreaks.
Researchers affiliated with the WHO Global Malaria Programme (WHO/GMP) have reported that if patients with severe malaria cannot be treated orally and access to injections will take several hours, a single artesunate suppository at the time of referral substantially reduces the risk of death or permanent disability. In a large clinical trial in patients with severe malaria (SEAQUAMAT) the use of iv artesunate showed an absolute reduction of mortality of 35 per cent when compared with intravenous injection of quinine.
New combination treatments of antibiotics and chloroquine are being tested in large clinical trials. Encouraging early data have shown that the combination with a macrolide compound is three times as effective as chloroquine alone.
For children aged one to four years, a malaria vaccine is being developed. The vaccine is directed at the pre-erythrocyte stage, being specifically designed to prevent liver cells from being invaded by sporozoïtes and to destroy any hepatocytes that are already infected. Clinical results from large field trials in several African countries look very encouraging with a protection rate of roughly 60 per cent.
Attempts to develop a malaria vaccine are complicated by the fact that the pathogen is a complex multi-cellular parasite, with various life stages that occur in both its human and mosquito hosts. Researchers have targeted three stages: the pre-erythrocyte stage to block infection; the blood stage (merozoïte) to reduce the severity of the disease; and the sexual stage (transmission-blocking vaccine) to break the cycle of infection and limit the spreading of the disease.
New findings that the artemisinine compounds work by blocking the enzyme ATP6 of the parasite have opened another avenue to look for further key molecules which may interfere with the enzyme system of the plasmodium species.
New prevention strategies may also be needed. In the Sahel and sub-Saharan regions of Africa, malaria transmission is highly seasonal. During a short period of high malaria transmission, mortality and morbidity are high in children under age of five years. In such a setting, seasonal intermittent preventive treatment - a full dose of antimalarial treatment given at defined times without previous testing for malaria infection – has proven to be highly effective and efficient.
Recent research has shown that infection of liver cells is the first step for plasmodium in establishing a malarial infection. The parasite, in its sporozoïte phase, moves through the organ, damaging liver cells, which in turn produce hepatocyte growth factor (HGF). This makes other cells in the liver susceptible to plasmodium infection. The research finding may also explain why malaria can be more severe in patients with hepatitis B, who produce more HGF than normal. HGF and its receptor may be two new potential targets for innovative treatment strategies.
Plasmodium falciparum can switch the host receptors used for invasion of human red blood cells. This property has been known for more than ten years, but the underlying mechanism has been unclear. Meanwhile, research has identified the PfRh4 gene as responsible for switching. This mechanism has important implications for future vaccine design.
According to the latest reports, when the parasite enters red blood cells in its merozoïte form, it uses so-called Gs receptors. These belong to the group of beta-adrenergic receptors, which can be inactivated by beta-blockers. If the use of these compounds were feasible, it would overcome the problem of resistance as it would interfere with a structural element of the human body and not of the parasite.