Malaria - Agues and Strains Professor Sir Nick White Professor of Tropical Medicine, Mahidol and Oxford Universities We think of malaria today as a tropical disease but, until the early twentieth century, the infection ranged as far north as the Arctic Circle and was prevalent throughout Europe and the Eastern half of North America. The British defeat at the decisive battle of Yorktown in the American War of Independence has been blamed (by some!) on the debilitating effects of malaria on the British and German troops. Oxford has a long history of research on malaria and its treatment. Over 350 years ago, Thomas Sydenham (a former Fellow of All Souls) and Thomas Willis (Christchurch and founding member of the Royal Society, Sedleian Professor of Natural Philosophy at Oxford, and bitter rival of Sydenham), both wrote extensively about fevers, and their experience of treatment of agues with the newly introduced Jesuit’s bark. The bark of the Cinchona tree contains the antimalarial alkaloids quinine, quinidine (the diastereomer of quinine), cinchonine and cinchonidine. Before he took up the Regius Professorship in Oxford, William Osler was very familiar with malaria in Baltimore (where he may have been the first to institute a routine blood test-the malaria blood smear-in all febrile patients). In 1902, the second Nobel Prize in Physiology or Medicine was awarded to Ronald Ross for his discovery that “dapple winged” (anopheline) mosquitoes transmitted malaria. Nearly two decades later, in Oxford, London, Epsom and Aldershot, Ross led large studies of antimalarial treatment in soldiers returning from the First World War. In 1924, the first synthetic antimalarial (plasmoquine) was discovered by scientists working for Bayer in Germany. Then followed mepacrine (1932) and chloroquine (1934), but most of the world still relied on quinine -and by then 90 per cent of the world’s quinine supply came from the island of Java (where the Dutch had planted the high yielding Cinchona ledgeriana). During the Second World War, military authorities, knowing that malaria often killed more soldiers than bullets during wartime, and that a Japanese expansion in the Pacific would endanger the quinine supply, instituted a desperate search for synthetic alternatives. In the United States, chloroquine was rediscovered and, in the UK, a new type of antimalarial (proguanil; Paludrine®) was discovered by chemists at ICI. Proguanil was evaluated initially in Liverpool and in Oxford. After the War, following the success in eliminating malaria from Europe and North America, the newly formed World Health Organisation (WHO) embarked on an ambitious attempt to eradicate all malaria from the world. It is often said that this was successful in eliminating malariologists but failed to eliminate malaria. In the aftermath of this failure, malaria went off the agenda and by the 1970s, was returning with a vengeance across the tropical world. In 1979, supported by David Weatherall from the Nuffield Department of Medicine and the Wellcome Trust, David and Mary Warrell left Oxford for Thailand to set up a small research collaboration in the Faculty of Tropical Medicine of
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Although Sydenham and Willis may have differed, all the physicians were united in their disdain (? jealousy) of (Sir) Richard Talbor, an apothecary, who won fame and fortune, and the recognition of both Charles II and Louis XV. Using the “English remedy”, his own special concoction of the Cinchona bark, Talbor cured the tertian fevers of both Charles II and the dauphin, the last living son of Louis XIV.
Mahidol University in Bangkok. I joined a year later having had some training in the MRC Department of Clinical Pharmacology under David Grahame-Smith. Initially we studied snake bite, rabies and, in Eastern Thailand - severe malaria. For reasons which still remain a mystery, antimalarial drug resistance usually starts first somewhere near the Thailand-Cambodia border. By the 1980s, strains of Plasmodium falciparum (the main cause of malaria deaths) resistant to chloroquine and several other antimalarials were widespread in Southeast Asia and we had been forced to return to quinine for the treatment of falciparum malaria. But there was confusion about the dose. The Cinchona dose regimens had not changed much since those recommended by the Jesuits in the “Schedula Romana” 350 years previously, but they had been challenged by recent research in the Vietnam War. It was now recommended
