The malaria medicine chest, part 1 1/10/02. By Nick White With the rise of resistance in the malaria parasite, many antimalarial drugs are becoming useless. Nick White examines the current, perilous situation.

Malaria, the most important parasitic disease of humans, is increasing in the tropical world. This is attributed directly to worsening antimalarial drug resistance.

Since the 1950s we have relied largely on chloroquine, a safe, inexpensive, widely available and once highly effective treatment. Unfortunately resistance to chloroquine now occurs throughout the tropical world, and resistance to its successor sulphadoxine–pyrimethamine (SP) has followed rapidly.

The rise of resistance

Whenever microorganisms are placed under intense selective pressure, such as that provided by widespread use of an anti-infective drug, resistance emerges. The selective pressure applied to malaria parasites has been enormous. Chloroquine was once the most widely used drug in the world, and it persists in the body for months. In many tropical areas, the majority of the population had chloroquine in their blood.

In addition there were misguided attempts to suppress malaria by the addition of antimalarial drugs to table salt. Again, everyone in the area had chloroquine or pyrimethamine in their blood all the time.

Eventually, spontaneously occurring but extremely rare mutant parasites emerged with reduced susceptibility to these antimalarial agents. The survival advantage of these resistant mutants, and their consequent preferential transmission, resulted in worsening antimalarial drug resistance and treatment failures. Because of the exponential nature of the process there is often a long lag period during which there appears to be little or no resistance. This is followed by an alarming rise. Sadly today chloroquine and SP are no longer effective in much of the tropical world.

The therapeutic armoury

With the end of the colonial era, and also fewer military incentives to develop antimalarial drugs, the therapeutic armoury has dwindled in the face of drug resistance. Many of the alternatives to chloroquine and SP that have been developed have problems.

Amodiaquine, a cousin of chloroquine, is more effective in treating malaria in areas of low-level resistance but is not effective against the multidrug-resistant Plasmodium falciparum infections prevalent in South America and South-east Asia.

Fortunately mefloquine, a product of US Army research stimulated by the Vietnam war, is effective against multidrug-resistant falciparum malaria. In Thailand, which has the dubious distinction of having the world's most drug-resistant parasites, mefloquine was introduced throughout the country in 1984. At first, antimalarial treatment with mefloquine proved highly effective but it too fell to resistance, and, by the mid-1990s, failure rates had reached 50 per cent.

Halofantrine, which like mefloquine was produced as a direct result of the Vietnam conflict, is highly effective against multidrug-resistant falciparum malaria. Unfortunately during clinical evaluation in Thailand – after it had been registered in several countries – halofantrine was found to predispose to potentially lethal cardiac arrhythmias. Its use is now restricted.

Atovaquone is a hydroxynaphthaquinone, the end product of a line of research which began just after the Second World War. Combined with proguanil, it is a highly effective antimalarial drug and it is structurally unrelated to existing compounds. The manufacture of atovaquone is prohibitively expensive, however, and this has limited its use largely to the treatment of affluent tourists.

Table 1
The medicine chest

Drug	Origins	Problems
Quinine	Derived from the bark of the cinchona tree. Isolated in Paris in 1820. Only effective treatment for malaria until 1930s	Unpleasant side effects
Atebrin (mepacrine)	Developed in the early 1930s, and used in World War II	Unpleasant side effects. No longer used
Chloroquine	Synthesised in Germany in the 1930, and developed after World War II	Largely ineffective for falciparum malaria because of resistance, but still used widely in Africa
Amodiaquine	Cousin of chloroquine. Developed in the early 1950s	No longer useful in South America and SE Asia
Proguanil	Developed in England in 1945. Forerunner of pyrimethamine	Resistance
Sulphadoxine-pyrimethamine (SP; Fansidar)	First used in SE Asia in the 1960s	Used in parts of Africa, but growing resistance everywhere it is used extensively
Artemisinin derivatives	Introduced in early 1970s in China	Widely used in SE Asia and being tested in Africa
Mefloquine (Lariam)	First used in 1971 by the US army in Vietnam	Growing resistance where it has been used alone
Halofantrin	Introduced in the 1980s	Possible dangerous cardiac side effects: use is now restricted.
Atovaquone	Became available in 1992 in combination with proguanil. Highly effective	Manufacture of atovaquone is prohibitively expensive

In part 2 of the malaria medicine chest Nick White examines the possibilities offered by artemisinin and combination therapy.

Professor Nick White is Director of the Wellcome Trust's South-east Asia Overseas Unit.