The History of Malaria Treatment
From Legends to Modern Treatments
Malaria is older than humankind. This parasitic disease, which has killed millions of people, is believed to have affected hosts as far back as the dinosaurs. This special monograph on the history of malaria treatment features photographs from the personal collection of Quique Bassat, head of the Malaria Programme at ISGlobal.
QUIQUE BASSAT – PAU RUBIO
Advertising brochure for Grove’s Bromo quinine, explaining the Peruvian legend.
THE PERUVIAN LEGEND
Legend has it that the first malaria treatment was discovered by an indigenous Peruvian named Pedro Leiva. One day, while running a high fever, he ventured deep into the Andean rain forest. He stopped to drink from a pond and noted that the water had a bitter taste. Looking up, he saw that the trunk of a cinchona tree had fallen into the pond. Not long after, his fever subsided.
source: WWW.NCBI.NLM.NIH.GOV
ARTEMISIA ANNUA: AN
ANCIENT REMEDY
Whether or not there is any truth to the Peruvian legend, we do know of a malaria remedy that has been used in traditional Chinese medicine for over 1,000 years: the leaves of Artemisia annua, known as sweet wormwood, which are used to make an antimalarial herbal tea still in use today.
PHOTO: ARTEMISIA ANNUA / WIKIMEDIA COMMONS.
CINCHONA POWDER
Quinine has been used to treat malaria for more than 400 years. In the 17th century, it was common for missionaries in South America to treat the disease using the bark of the cinchona (quina-quina) tree ground to a fine powder.
source: WWW.NCBI.NLM.NIH.GOV
Ceramic recipient used to store cinchona powder. Photo: Quique Bassat.
Illustration in Ricardo Palma’s book showing the legend of the Countess and her powders.
THE SPANISH LEGEND
According to another legend, quinine was introduced to Europe in 1638 by Francisca Enríquez de Rivera, Countess of Chinchón and wife of the viceroy of Peru. The countess came down with a severe fever. After the usual treatment —bleeding— proved ineffective, the countess was finally cured by cinchona powder from Loxa (currently Loja, Ecuador).
source: RICARDO PALMA, Los polvos de la condesa.
Cinchona
The story of the Countess of Chinchón may just be a legend. Nevertheless, in 1742 the Swedish botanist Carl Linnaeus assigned the name Cinchona in her honour to the genus that includes the quina-quina tree.
Recipient to store cinchona. Photo: Quique Bassat.
19th Century
The 19th century was a turning point in the history of malaria treatment. The pharmacists Pelletier and Caventou managed to isolate quinine. Declining to seek a patent, they gave away their discovery as a gift to humanity and opened the door to much larger-scale production of the drug.
Recipient for storing quinine hydrochloride made by Pelletier, Delondre and Levaillant. Photo: Quique Bassat.
FROM “CINCHONA POWDER”
TO QUININE
The active ingredient was first isolated and extracted from cinchona bark in 1820 by the French pharmacists Pierre Pelletier and Joseph Caventou. Pelletier and Caventou called this substance “quinine” and made no attempt to patent their discovery, essentially giving it away as a gift to humanity.
source: irwin w. Sherman. Drugs That Changed the World: How Therapeutic Agents Shaped Our Lives. CRC PRESS.
EXTEMPORANEOUS FORMULATIONS
The second half of the 19th century saw the proliferation of extemporaneous formulations—that is, made-to-order preparations containing quinine or quinine derivatives.
19th century quinine preparation. Photo: Quique Bassat.
TONIC WATER
The most common way of taking cinchona powder was by dissolving it in water or wine. The powder had such a bitter taste that people took to mixing it with sugar and other ingredients, leading to the invention of tonic water. This beverage was typically made at home until 1858, when an Englishman named Erasmus Bond introduced the first commercial tonic water.
source:WWW.SLATE.COM
Bottle with tonic by Swamp Chill and Fever. Photo: Quique Bassat.
GIN AND TONIC:
A WEAPON AGAINST MALARIA
The gin and tonic was originally developed as a way to take quinine. Treating and, above all, preventing malaria was essential to the health of the British Empire in India and other tropical regions. British officials, obliged to take their daily dose of quinine, took to mixing the bitter powder with sugar and soda water—and the addition of a splash of gin made the drink all the more appetising.
sources:WWW.SLATE.COM | WWW.JOTDOWN.ES
Photo by pholies on Pixabay.
QUININE WINE
Wine drinkers developed similar methods for taking quinine. The custom of dissolving the bitter powder in wine led to the commercial production of quinine wine, a beverage that reached the height of its popularity in the late 19th century, when it was marketed as a restorative tonic for the whole family.
Another popular concoction was Grove’s Chill Tonic, which the British Army used to prevent malaria in the tropics. It was also a big hit among consumers back in Britain, where advertisements touted the syrup’s ability to make “children and adults as fat as pigs”.
DUTCH QUININE. THE NEW MONOPOLY:
CHARLES LEDGER
By the 19th century, at the height of the colonial era, quinine had become a highly sought-after product. The major European powers had tried unsuccessfully to control the production of the raw material used in the manufacture of antimalarial drugs.
Knowing this, the bankrupt adventurer Charles Ledger saw quinine as a potential business opportunity. He had spent several years travelling around South America on an audacious mission: buying alpacas with a view to introducing them into Australia. He later remembered a magnificent cinchona forest he had seen in Bolivia.
He sent his assistant, Manuel Incra Mamani, back to Bolivia in search of the memorable place. After five years, Mamani finally returned with the seeds of this extraordinary species. Ledger first tried to interest the British government in his discovery. When this was unsuccessful, he finally managed to offload the seeds by selling them to a Dutch official for a song.
The Dutch began planting the seeds in Indonesia. Their plantation soon became highly productive, yielding the highest-quality product available anywhere and enabling the Dutch to corner the quinine market.
source: Irwin W. Sherman. Drugs That Changed the World: How Therapeutic Agents Shaped Our Lives. CRC PRESS.
Malaria and War
Like a powerful but invisible army, malaria-causing Plasmodium parasites have played a fundamental role in military history, decimating armies and often causing more casualties than enemy forces. Hence the strategic importance of malaria treatment in times of war.
Recipient used during the American Civil War for storing quinine. Photo: Quique Bassat.
AMERICAN CIVIL WAR
Union troops approaching the Chickahominy River from the north were suddenly attacked by an unexpected enemy, a disease that came to be known as Chickahominy fever. As Colonel Wesley Brainerd wrote, “There seemed to be no antidote but quinine in immense quantities. The Army lost far more men by this disease than by the bullets of the enemy.[1].
ltogether, one million cases of malaria were recorded during the American Civil War.[2]. More than 22% of the Union soldiers who required medical treatment were diagnosed with malaria[3].
This photo shows a quinine canteen used by a Confederate soldier.
sources: [1] Smithsonian Civil War: Inside the National Collection. Smithsonian Institution, 29 oct. 2013. [2] BOLLET AJ. AN ANALYSIS OF THE MEDICAL PROBLEMS OF THE CIVIL WAR. TRANS AM CLIN CLIMATOL ASSOC. 1992;103:128-41. [3] Reilly RF. Medical and surgical care during the American Civil War, 1861–1865. Proceedings (Baylor University Medical Center). 2016;29(2):138-142.
FIRST WORLD WAR
Quinine also played a crucial role in the First World War, during which malaria took a heavy toll. More than 1.5 million soldiers were affected by the disease.[4]
A number of malaria outbreaks took place over the course of the war. One epidemic immobilized the forces on the Macedonian Front for three years. Eighty percent of the French troops in the area were hospitalised with the disease. The British Army, with an average force of about 124,000 troops in the area, saw a total of 162,512 hospitalisations for malaria, compared with a total of 23,762 soldiers killed, wounded, missing in action or captured by the enemy.[5]
sources: [4] Brabin, BJ. Malaria’s contribution to World War One – the unexpected adversary. Malaria Journal201413:497 | https://malariajournal.biomedcentral.com [5] Russell, Paul P., West Luther S., and Manwell, Reginald U.: Practical Malariology .Philadelphia: W. B. Saunders Co., 1946. (2) MacDonald, A. G.: Prevention of Malaria. In History of the Great War Based on Official Documents. Medical Services, Hygiene of the War, edited by W. G. Macpherson, W. H, Horrocks, and W. W. 0. Beveridge. London: His Majesty’s Stationery Office,: 1928, vol. II, pp. 189-238.
SECOND WORLD WAR
“It’s going to be a very long war if for every division I have facing the enemy, I have one sick in hospital and another recovering from this dreadful disease!” (General Douglas MacArthur, 1943)
Indonesia, home to 90% of the world’s quinine production, was invaded by Japan during the Second World War.
Meanwhile, the Plasmodium parasites and Anopheles mosquitos —nicknamed “Ann” by American troops— formed a third faction wholly apart from the interests of the Allies and the Axis powers.
In the United States Army alone, 695,000 soldiers were infected with malaria during the war.[6]. The development of pharmaceutical alternatives to quinine thus became a military objective of strategic importance, prompting the United States to launch an unprecedented campaign in search of new antimalarial drugs.
Source:
[6]Ognibene AJ, Barrett, O. Malaria: Introduction and Background. In: Internal Medicine in Vietnam (Vol II): General Medicine and Infectious Diseases. Ognibene AJ, Barrett O (eds.). Office of the Surgeon General, Center of Military History, U.S. Army; Washington, DC, 1982:271–278.
SECOND WORLD WAR:
ATEBRINE
Around the same time, the Allies decided to increase quinine production in Latin America and introduce mepacrine for the treatment of malaria.
Known by the trade name Atabrine, mepacrine is a synthetic medication that was approved in the 1930s.
Because of the unpleasant taste and side effects of Atabrine, many soldiers were reluctant to take it. Information campaigns were launched to encourage soldiers to take the required doses.
THE FIRST SYNTHETIC QUININE
In 1944, William Doering and Robert Woodward reported a long-awaited scientific breakthrough: the chemical synthesis of quinine.
Despite the enthusiastic response to this development, Doering and Woodward’s synthesis process was too complex to be useful for the commercial production of synthetic quinine. Better medicines would soon join Atabrine as commercially available alternatives.
source: Irwin W. Sherman. Drugs That Changed the World: How Therapeutic Agents Shaped Our Lives. CRC PRESS.
Photo: William Doering and Robert Woodward.
Box with chloroquine sulphate. Photo: Quique Bassat.
CHLOROQUINE
In 1946, after four years of intense research that involved the analysis of more than 14,000 compounds, the United States introduced a new synthetic antimalarial drug: chloroquine.
Chloroquine was more effective than Atabrine, had fewer side effects, and could be produced commercially. But in fact, it wasn’t entirely new: the compound that forms the basis of chloroquine—which would soon become the first-line treatment for malaria—had first been isolated by German chemists in the 1930s. With the advent of chloroquine, the World Health Organisation was able to launch a global malaria eradication programme in 1955. Thanks to the new drug and the insecticide DDT, malaria was eliminated in Australia, the United States, most of Europe and several other developed countries.[7]
source: [7] Sherman, Irwin W. Drugs That Changed the World: How Therapeutic Agents Shaped Our Lives. CRC PRESS, 2016
Vietnamese citizens taking their antimalarial treatment.
VIETNAM WAR
During the Vietnam War, malaria once again became a huge problem for both sides involved in the conflict.
The treatments available at the time proved ineffective against the proliferation of resistant parasites.
VIETNAM WAR: MEFLOQUINE
Through the Walter Reed Army Institute of Research, the United States launched an intensive programme to find an alternative drug.
The result was the development of mefloquine, which proved effective against chloroquine-resistant parasites and was soon adopted throughout the world despite its neurological side effects.
source: Irwin W. Sherman. Drugs That Changed the World: How Therapeutic Agents Shaped Our Lives. CRC PRESS.
Mefloquine made by Lariam. Photo: David Davies
VIETNAM WAR: ARTEMISININ
At the same time, China launched Project 523, a secret military programme tasked with finding a new antimalaria drug to help their Vietnamese allies.
Project 523 recruited five hundred scientists, who analysed over 2,000 plant extracts.
The result of this painstaking labour was the development of artemisinin, an extract of the plant Artemisia annua.
The scientist who led the team that gave the world the most effective antimalarial drug discovered to date was a woman: the Chinese researcher Tu Youyou. In 2015, she received the Nobel Prize in Medicine for her valuable contribution.[8].
source: [8] HTTPS://WWW.NCBI.NLM.NIH.GOV/PMC/ARTICLES/PMC4702971/
Scientist Tu Youyou, in the 50s. Photo: Wikimedia Commons.
Modern Treatments
The 20th century, marked by wars in which malaria played a significant role, also saw the elimination of the disease throughout Western Europe.
Container and tube with Plasmochin simplex. Photo: Quique Bassat.
THE TREATMENT OF RECURRENT MALARIA:
FROM TOXIC REMEDIES TO PRIMAQUINE
Pamaquine, the first drug developed to prevent the recurrent episodes of malarial fever that affect patients infected by Plasmodium vivax or Plasmodium ovale, was synthesized in 1924. Its use was, however, associated with serious adverse effects.
It was replaced by primaquine, an antimalarial with a slightly lower grade of toxicity created in 1946. Common side effects include vomiting, diarrhoea and stomach cramps. In 2018, decades of research and development finally resulted in a new addition to this family of drugs: tafenoquine.
THE END OF MALARIA
IN SPAIN
Malaria had always been endemic in Spain throughout history. At the beginning of the 20th century, 4,000 people died every year in Spain as a result of this parasitic disease. With the advent of quinine and improved sanitary conditions, the number of cases started to fall significantly.
However, with an upturn in the number of cases in Spain after the Civil War, malaria once again became a public health problem, and in 1941 it was still the eleventh leading cause of death in the country.
Finally, the use of new antimalarial agents, the introduction of DDT and improved sanitary conditions brought an end to the transmission of the disease. The last death attributed to autochthonous malaria in Spain occurred in 1959, during General Franco’s dictatorship, and the last cases of the disease were recorded in 1961. In 1964, Spain became one of the last countries in Western Europe to be declared malaria-free by the World Health Organisation. It was followed by Italy in 1970, and Portugal and Greece in 1973.
source:WWW.NCBI.NLM.NIH.GOV
MALARIA: A MATTER OF STATE
In Italy, the elimination of malaria was, in large part, made possible by quinine. Over the course of several turbulent decades, the country went from being a monarchy to a fascist dictatorship and finally a republic. The one thing these successive governments had in common was that they all regulated the production of quinine through a state monopoly as a way to control the price of the drug. Other measures undertaken included the drainage of swampy areas, the distribution of quinine in state-run tobacco shops, and even the production of chocolate bars containing quinine!
MALARIA AND SYPHILIS
MALARIA AND SYPHILIS
Before the advent of antibiotics, malariotherapy (deliberately induced malaria) was used as a treatment in a number of very serious diseases, including late-stage syphilis. Intravenous inoculation with blood infected with malaria parasites had a foreseeable pyretic effect, increasing body temperature. This induced fever was believed to have beneficial effects on neurosyphilis. The discovery earned the Austrian psychiatrist Julius Wagner-Jauregg the Nobel Prize for Medicine in 1927, although the actual curative effect of malaria therapy is difficult to assess.
source: Irwin W. Sherman. Drugs That Changed the World: How Therapeutic Agents Shaped Our Lives. CRC PRESS.
Cover of the booklet entitled Our Clinical Experience with Malariotherapy for Progressive General Paralysis.
Photo of current malaria treatments, taken in the Awash health center. Photo: Quique Bassat.
MODERN TREATMENTS
Since 2012, the first-line treatment for severe malaria worldwide has been intravenous artesunate. The World Health Organisation’s decision to indicate artesunate as the first-line treatment rather than quinine was the first major change in the treatment paradigm for severe malaria in hundreds of years.
Artemisinin-based combination therapies are the first-line treatment for uncomplicated malaria and have played a key role in the reduction of malaria cases worldwide in recent decades. The bad news is that, as occurred previously with chloroquine, resistance to artemisinin has started to emerge in southeast Asia and these resistant strains of the parasite could spread to the rest of the world.
The increase in resistance to different antimalarial agents has made the development of new drugs to combat this disease an urgent priority.
LEARN MORE
The History of Malaria Treatment is a site by the Barcelona Institute for Global Health (ISGlobal).
You will find more information on malaria on the following links:
19th century quinine preparation. Photo: Quique Bassat.
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