The Story of Quinine

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Malaria is one of the most distressing diseases known to humanity. Even today, it continues to kill at least two million people worldwide every year. Hippocrates was the first physician to report this disease in the fifth century BCE. The oldest information concerning the treatment of the disease is mentioned in the Book of Medicinal Plants of the Chinese Emperor Shen Nung (around 2700 BCE). This shows the disease has been a menace since time immemorial.

Malaria is an infectious disease caused by single-cell Plasmodia that are transmitted to humans and animals through the bite of the Anopheles mosquito, which acts as a host for the Plasmodia’s development. These parasites invade red blood cells (erythrocytes) and multiply every few days, finally bursting the erythrocytes and releasing new parasites, which then invade other erythrocytes and continue to multiply. The initial symptoms of the disease include mild headaches, backache, and fatigue followed by chills and shivers, and finally vomiting, convulsions, severe fever, and sweating. These feverish symptoms can repeat either everyday or every three or four days. The patient feels run down, and if not treated, the patient dies.

Humanity long searched for a cure for the disease, and bloodletting was the most frequent treatment because this was the recommended treatment for inflammatory diseases in Galenic medicine. Although it was suggested in the second century AD that minute creatures living in marshes caused the disease, this was not accepted by the Galenic physicians and was dismissed for centuries. However, marshes were drained as a precaution, because another theory suggested that marsh gas was the cause. The name “Mala aria,” which in Italian means “bad air,” was later accepted as the name of the disease in English. In 1880, a French surgeon, Dr. Alphonse Laveran, discovered  Plasmodium malariae in the blood of Algerian soldiers, and two years later, an American, Dr. Alfred Freeman, established that malaria was transmitted by mosquitoes.

The story of Cinchona bark—which is the source of quinine, the only treatment for malaria until recently—is as interesting as the story of the disease. No medicine has been as effective as quinine in discrediting Galenic medicine. The use of Cinchona bark in effective medicines for malaria marked the end of many useless treatments.

Father Calancha, a priest living in South America, wrote in his book of 1663, Chronicles of Moral Order of Saint Augustine in Peru, that a decoction of the bark of the “Fever Tree” (weighing the same as two small silver coins) from the Loja region of Ecuador would cure malaria when drunk. There are many stories about the source of this knowledge. One mentions how a stranger stricken with malaria drank extremely bitter water from a pool filled with fallen Cinchona trees following a storm and was healed. Another story tells how Jesuit priests discovered it while chewing the barks of trees for the purpose of botanical classification. According to another story, while boating through a forest, a surgeon observed lions nibbling the bark of Cinchona trees and thus discovered its virtues. The most famous story concerns the Countess of Chinchon, the wife of the viceroy of Peru. As the story goes, the countess fell ill with malaria in 1638, and all treatments failed to cure her. The Governor of Loja sent her a box of Cinchona bark, and the countess rapidly recovered. On her return to Spain, she distributed the bark to the needy, and the powder became known as “Contessa Powder.” However, none of this story is true.

However, this story was repeatedly cited in medical books until recently as fact. In 1941, Dr. Haggis, a historian of medicine, found that the first countess of Chinchon died in Spain three years before her husband was appointed as viceroy of Peru. The second Countess, according to her diary discovered in 1930, had a healthy life and died in Colombia without returning to Spain.

In 1742, the Botanist Carl Linnaeus, inspired by the story, named the tree Cinchona. The local name of the plant in the Andes was Quina quina, which in the Aztec language meant “Bark of barks.” In the local dialect, the repetition of a name implied a medicinal use. Another theory about the bark is that Aztecs concealed its medicinal properties from the Spaniards in the hope that malaria would eradicate them.

Twelve years after Father Calancha wrote his famous chronicle, another Jesuit priest, Father Bartolome Tafur, brought some Cinchona bark from his voyage from South America back to Rome, where he started curing his badly stricken community of malaria. After a while, the Jesuits in South America began exporting the bark to Rome regularly. To prevent its extinction from overharvesting, they instructed the locals to plant five Cinchona trees in the shape of a crucifix for every tree they felled. Pilgrims visiting Rome would leave with boxes of “Jesuit bark.” This way, the news of the virtues of the Jesuit powder spread fast through Spain, France, and Italy, but the scientists brushed it off and ignored its curative properties.

In 1649, Cardinal John de Lugo was so aghast at the thick-skinned attitude of the medical profession that he ordered Pope Innocent X’s physician to prepare a report on the bark. This report remarked that the bark was the most effective remedy found so far. The cardinal then ordered the powder to be packed into a prescription called “Schedula Romana.” Although the prescription was recommended to be used under medical supervision, because of the indifference of the medical profession, patients often had to administer it themselves. The success of the bark at treating malaria made it very popular. When the cardinal heard that the young Dauphin, who would later be Louis XIV, had caught malaria, he went to Paris to cure the prince.

When the Austrian Archduke Leopold fell ill in 1652, his physician cured him with the bark. However, when the disease came back after a month, his physician discontinued the treatment, thinking it useless, and the archduke died. In fact, the archduke was stricken with double quartan malaria, which his doctor was unaware of. The physician, Dr. Joan Jacob Chiflet, wrote a book about the perceived failure of the bark. Physicians, who were already unwilling to challenge Galenic medicine, were relieved by the publication of the book and abandoned treatment with the bark completely. A rumor then suddenly spread that the Jesuits were trying to kill the world’s Protestants with the bark, and religious revolts prevented the use of the bark in countries with a protestant majority.

Meanwhile, in 1655, no deaths from malaria were reported in the holy city for the first time in its history, while the disease took its toll in protestant countries. England also took its share from malaria outbreaks. When Oliver Cromwell, a devout protestant, fell ill with malaria, it was unthinkable for him to use Cardinal Powder. Eventually, Cromwell died of malaria in 1658.  

In 1670, a young medical student and apprentice pharmacist, Robert Talbor, declared himself to be a specialist in feverish diseases and started gaining fame. He wrote a book entitled Pyretology, or the causes of malaria and its treatment. This book  warned about the dangers of using the Jesuit powder and recommended his secret formula as a cure. As his fame rose, he increased his fees to an astronomical scale. His fame disturbed the Royal Medical Academy, who confronted him. After his success in treating the malaria of King Charles II, the king rewarded him with a knighthood and appointed him as his personal physician in 1678. Talbor then started treating the other nobles and went to France to cure Louis XIV’s only son of malaria. During the treatment, the court physicians tried to challenge his knowledge. They asked him what the fever was. Talbor replied, “I do not know, Sirs. You may know it, but I cure it. Do you?” After successful treatment, Louis XIV convinced Talbor to sell his secret formula for 3,000 gold coins, promising to keep it secret until Talbor’s death. Additionally, Talbor kept the right to make the medicine for ten years.

When Talbor died in 1681 at the age of 39, his secret formula was printed in newspapers: six drams of rose petals, two ounces of lemon juice, and a decoction of cinchona bark mixed in wine. Clever Talbor had changed the variety of wine from time to time to intrigue his patients. After his death, he was accused of being an ignorant crook, which he was, because without a proper medical education, he had declared himself a medical specialist. He had caused thousands of deaths by claiming the bark was ineffective.

However, he was not ignorant, and he was clever enough to realize that an apprentice pharmacist would not be credible enough to convince the British that the Jesuit bark was effective. In the view of medical historians, the widespread use of Cinchona bark would have taken centuries rather than years if it wasn’t for Talbor.

Finally, toward the end of the 17th century, cinchona bark took its place in the British Pharmacopoeia as “Peruvian Bark.” Its use also became popular in Germany. Excessive demand gave rise to dishonest traders. Crooked merchants started marketing the barks of other trees after making them bitter with the juice of aloes. This often caused debate about the efficacy of the bark. Between 1730 and 1800, botanical expeditions to South American countries enabled the classification of the Cinchona species, and the most effective varieties were determined.

In 1820, two famous French scientists, Pelletier and Caventou, successfully isolated the alkaloid quinine from Cinchona bark. As a show of great generosity, they declined to patent their discovery. After publication of this discovery, many companies started manufacturing quinine. The only financial reward these great scientists received was an award of 10,000 French Francs from the Paris Academy of Sciences.

Scientific studies conducted on Cinchona bark laid the foundations for modern production and synthesis techniques and chemotherapy. The isolation of quinine enabled physicians to adjust the dosage of the medicine. It was now possible to determine the quality of a bark by quinine assays. The best yielding species was found to be Cinchona calisaya. In the 1840s, the French botanist Dr. Weddell germinated seeds brought from Bolivia in the Paris Botanical Gardens and sent more to botanical gardens in England and the Netherlands. Meanwhile, some cultivation experiments were unsuccessfully tried in Algeria. The prospect of growing the tree outside South America encouraged Europeans attempting to break the monopoly of Bolivia, Peru, Colombia and Ecuador on the supply of the bark. These countries prohibited any part of the plant from being exported out of their countries. The French entrepreneur Mr. Delondre established a quinine factory near Curzo in the Peruvian mountains to avoid transportation costs. However, he realized too late that there was insufficient bark available in the vicinity, because the exclusive rights to collect Cinchona bark in the area belonged to an American company. The factory closed down without producing a single gram of quinine.

The Netherlands held a colony in Java, a climatically suitable location to cultivate Cinchona, but there were no seeds or seedlings to grow. When the director of the Java Botanical Garden—Mr. Justus Hasskarl, of German origin—was about to travel to South America on a secret mission to acquire seed material, a German journalist broke the news. Although the Government of the Netherlands denied it, Mr. Hasskarl’s mission ended before it started. In the following year, when this news was forgotten, Hasskarl went to South America under the name Müller as a tourist. He started collecting seeds in the Cinchona-growing regions as souvenirs.

When his entry to the growing regions for Cinchona calisaya was denied, he went to the regional governor with an attractive offer. After his refusal, he bribed an official to supply him one bag of seeds for a bag of gold. He was supplied 21 box loads of seeds and seedlings. On his return voyage to Java, he learned in one of the ports that his wife and four daughters had drowned when their ship sank during their voyage from Germany to Java. On his return to Java, he was rewarded with the two highest orders of the state and appointed to the task of establishing Cinchona plantations in Java. However, after a few years, when his seeds and seedlings proved to be useless, he was dismissed from his duties. He went back to Germany and lived as a very rich man until his death at the age of 83 in 1884. 

Two million healthy trees were grown with great difficulty during the next 20 years from 150 of Hasskarl’s surviving plants and seeds obtained from a secret source by the Consulate of the Netherlands in La Paz. However, a Dutch chemist found the quinine content in the leaves very low. It was also claimed the trees were not even C. calisaya.

The British, on the other hand, wanted to find a stable and cheap source of quinine because of the anxiety over the deaths of a million people in India every year. They appointed a young civil servant, Clements Markham, of the East India Company to solve the problem. Markham engaged the famous botanist Richard Spruce to collect Cinchona seeds. Despite his bad health, Spruce was able to collect over 100,000 seeds and seedlings of the red barked Cinchona succirubra. They were planted in 1860 in India and grew, but like in Java, the quinine content of the bark was very low.

The event that ended the Bolivian trade in Cinchona bark took place in the midst of the 19th century. In 1860, the English bark trader Charles Ledger asked his devout servant—Manual Mamani, who had worked for him for 18 years—to obtain the seeds of a cinchona species whose whereabouts were kept top secret. Mamani initially refused this request and left the position. After four years of absence, he suddenly returned and handed over some seeds that were carefully hidden in his long hair before disappearing again for good. Some years later, Ledger learned Mamani had been tortured to death at a Bolivian prison. Ledger sent the seeds to his brother in London, who did his best to persuade the British authorities to become interested in the seeds. However, it was the Dutch who eventually purchased some of the seeds for a modest $20, making it one of the most profitable deals in history. This modest deal enabled the Netherlands to create an international monopoly, and 90 percent of the quinine production was Dutch controlled, because while other species contained only 3–5% quinine, this new species, named C. ledgeriana, contained 13%. Dutch agronomists created a hardy variety by grafting this species on the rootstock of C. succirubra and destroyed all the other Cinchona species to avoid cross-fertilization.

Throughout history, malaria has been a disease affecting humanity. It killed great leaders such as Alexander the Great and inflicted more damage to armies than their enemies did. During World War II, over half a million American soldiers in Africa and the South Pacific were exposed to this plague. Up until the middle of the war, Cinchona products (bark, totaquina, and quinine) became crucial materials. In the 1920s, the Americans had planned to establish their own plantations. A forester named Arthur Fischer had established a plantation in the Philippines with seeds smuggled from the Dutch plantations in Java. Nine years later, a small factory in Manila started producing totaquina.

In 1942, the Japanese captured the factory with all its stock. It also destroyed all of the 38,000 hectares of Cinchona plantations in Java after invading the island. This was the allies’ last source of quinine, because the Germans had captured most of the European reserves of quinine after invading Amsterdam. This deprived the allies of 90 percent of the world’s quinine stocks. This development forced research into synthesizing antimalarials, and medicines such as atabrine, chloroquine, and pimacrine were thus developed.

In 1942, when 80,000 American soldiers, stranded in the Bataan peninsula of the Philippines, were stricken with malaria, a Colonel Fischer on duty there asked for barks to be stripped from the trees planted in Bukidnon in the southern Philippines three years earlier and sent immediately. Stricken with malaria, he went to the southern Philippines to supervise the stripping of the bark. Unfortunately, the plane carrying the bark was shot down before it reached Bataan. Meanwhile, a priest knowledgeable in chemistry was trying to produce quinine in an old bathtub when the news of the fall of Bataan came. Colonel Fischer was among the last personnel to leave the Philippines on a plane sent by General Mc Arthur. He took with him the seeds of C. ledgeriana that he had collected. These were germinated in the USA and four million seedlings were sent to Costa Rica for cultivation. The war ended before the bark was harvested, but the dream of Colonel Fischer had enabled developing countries to have their own sources of quinine. After the war, Colonel Fischer was decorated with the two highest honors of the state.

Although synthetic antimalarials have reduced the demand for quinine, its contribution to medical history and its positive role in the development of modern medicine will always be remembered with respect.

Cinchona bark and quinine have contributed immensely to the history of the world. Without it, the Panama Canal would never have been opened; tea plantations in Assam, India would not have been established; oilrigs in Venezuela and Borneo would never have been constructed; and railways would not have been built in the Amazon.

Today, Indonesia and India are the main Cinchona producers. The Cinchona with the highest yield of quinine are grown in Tanzania, Kenya, Guatemala, and Bolivia. The Netherlands is the biggest producer of quinine, using barks harvested in Indonesia.

Quinine is used today against falciparum malaria, which is resistant to chloroquine. It is also used in cold medicines and an ingredient of bitter tonics.

Another alkaloid also obtained from cinchona bark, quinidine, is used as an anti-arrhythmic to regulate heart rhythm.

References
1. B. Griggs, Green Pharmacy, Robert Hale, London (1981).
2. L. Aikman, Nature’s Healing Arts: From Folk Medicine to Modern Drugs, National Geograp­hic Society, Washington (1977).
3. M.B. Kreig, Green Medicine, Rand Me Nally, New York (1964)
4. Dünyamızın Nimetleri, Ansiklopedik bir Ekonomi Coğrafyası, Türkiye Yayınevi, İstanbul (1947).



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