Quinine comes from the bark of a tree native to South America. According to legend it was first brought to Europe by a Countess who had been treated with it in Peru in the 1600s. The bark was named cinchona in 1742 by Linnaeus. In 1820, two French chemists isolated quinine from the cinchona bark and quinine became a treatment of reference for intermittent fever throughout the world. Quinine remains an important and effective treatment for malaria today, despite sporadic observations of quinine resistance.(1)
Research by German scientists to discover a substitute for quinine led to the synthesis in 1934 of Resochin (chloroquine) and Sontochin (3-methyl-chloroquine). These compounds belonged to a new class of antimalarials, the four-amino quinolines. The German research went no further and the formula for Resochin was passed to a US sister company. During World War II, French soldiers happened upon a stash of German-manufactured Sontochin in Tunis and handed it over to the Americans. American researchers made slight adjustments to the captured drug to enhance its efficacy. The new formulation was called chloroquine. Only after comparing chloroquine to the older and supposedly toxic Resochin, did they realize that the two chemical compounds were identical.1
Following the war, chloroquine and DDT emerged as the two principal weapons in WHO’s global eradication malaria campaign. Subsequently, chloroquine resistant P. falciparum probably arose in four separate locations starting with the Thai-Cambodian border around 1957; in Venezuela and parts of Colombia around 1960; in Papua New Guinea in the mid-1970s and in Africa starting in 1978 in Kenya and Tanzania and spreading by 1983 to Sudan, Uganda, Zambia and Malawi.(1)
A pyrimidine derivative, proguanil, also emerged from the antimalarial pipeline during World War II. Proguanil’s success in treating humans led to further study of its chemical class and to the development of pyrimethamine. Resistance to the two monotherapies appeared quickly (within one year in the case of proguanil). Sulfones and sulfonamides were then combined with proguanil or pyrimethamine in hopes of increasing efficacy and forestalling or preventing resistance. By 1953, P. falciparum resistance had already been noted in Tanzania. When Sulfadoxine/Pyrimethamine (SP) was introduced in Thailand in 1967, resistance appeared that same year and resistance spread quickly throughout South-East Asia. Resistance to SP in Africa remained low until the late 1990s but since then it has spread rapidly.1
The development of mefloquine was a collaborative achievement of the US Army Medical Research and Development Command, WHO/TDR and Hoffman-La Roche, Inc. Mefloquine’s efficacy in preventing falciparum malaria when taken regularly was shown in 1974 and its potential as a successful treatment agent was shown soon after. Resistance to mefloquine began to appear in Asia in 1985, around the time the drug became generally available.(1)
Artemisinin was isolated by Chinese scientists in 1972 from Artemisia annua (sweet wormwood), better known to Chinese herbalists for more than 2000 years as Qinghao. In the early 1970s, initial testing by Chinese scientists of Qinghao extracts in mice infected with malaria showed it to be as effective as chloroquine and quinine in clearing the parasite. Mao Tse Tung’s scientists then began testing in humans and in 1979 published their findings in the Chinese Medical Journal.1
Artemisinin and other artemether-group drugs have been the main line of defense against drug resistant malaria in many parts of South-East Asia. Artemisinin has been a very potent and effective antimalarial drug, especially when used in combination with other malaria medicines.2 Combining an artemisinin drug with a partner drug that has a longer half-life was found to improve the efficacy of the artemisinin. It also reduced treatment duration with the artemisinin and appeared to reduce the likelihood of development of resistance to the partner drug. In the early part of this century, Artemisinin-based combination therapy (ACT) had been shown to improve treatment efficacy and was thought to be a key to containing resistance in Southeast Asia.
The scale-up of ACTs represented a major breakthrough in the global fight against malaria at the start of the 21st century.
However, in 2009, evidence of resistance to artemisinin-based combination therapy (ACT) was reported. Initially in the Thai-Cambodia border region, and now increasingly in Southeast Asia, ACTs are taking longer and longer to clear the parasite from patients. MMV’s first step is to determine whether resistance is only to artemisinin, or whether all artemisinin-like molecules (i.e. endoperoxides) in our pipeline are compromised.
1. US Institute of Medicine (IOM) from the report, Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance, 2004, pp. 126-128.
2. CDC malaria history site, 2005