at the Ross Institute of the London School of Hygiene and Tropical Medicine detected malaria parasites in the livers of rhesus monkeys infected with a primate malaria species. They subsequently found similar stages in liver biopsy specimens from human volunteers experimentally infected with P. vivax, and confirmed the same early sanctuary for P. falciparum (Garnham, 1966).

MILESTONES IN ANTIMALARIAL DRUG DISCOVERY AND DRUG RESISTANCE

Quinine

“The Peruvian bark of which the Jesuites powder is made, is an excellent thing against all sorts of Agues,”

–William Slamon, Synopsis medicinae (1671)

The pharmaceutical compound known as quinine comes from the bitter bark of a high altitude tree native to South America. As legend has it, the Spanish Countess of Chinchon was treated with the tree’s bark in Peru in the 1600s. For many years, she was credited with bringing the bark—variously known as “Jesuit’s powder,” “Cardinal’s powder,” or “Peruvian bark”—back to Spain. However, since she later died in Peru, it is far more likely that Cardinal Juan de Lugo or another Jesuit priest introduced the remedy to Europe. In 1742, Linnaeus named the tree cinchona after the Countess, accidentally omitting the first “h” in her name (Meshnick, 1998).

In 1820, the French chemists Joseph Pelletier and Jean Biename Caventou isolated quinine from cinchona bark. Quinine quickly became a favored therapy for intermittent fever throughout the world. In the mid-19th century, British and Dutch botanical explorers combed the Andean cloud forest for cinchona in order to establish plantations in India, Ceylon, and the Dutch East Indies. However, many transplants produced only low-yield quinine crops. Eventually, for a few guilders, the Dutch government purchased 14 pounds of cinchona seed collected by Charles Ledger, an Englishman living in Peru. By grafting what was eventually named C. ledgeriana onto the hardier C. succirubra (McHale, 1986), the Dutch soon dominated cinchona cultivation, eventually producing 80 percent of the world’s quinine on the Indonesian island of Java before it was invaded during World War II.

Quinine remains an important and effective malaria treatment nearly worldwide to the present day, despite sporadic observations of quinine resistance. The earliest anecdotal reports of resistance date to 1844 and 1910 (Talisuna et al., 2004). Quinine resistance in P. falciparum was first documented in human volunteers in Brazil and in Southeast Asia in the



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