THE 400-YEAR-OLD SAGA OF THE ANTIMALARIALS AND THEIR USE FOR COVID-19

The antimalarial drug hydroxychloroquine received considerable attention as possible treatment and preventative against Covid-19 as early as February of 2020. Influential voices like that of Elon Musk and particularly that of President Donald J. Trump advocated the drug as a “game changer.” Doctors gave hospitalized patients the drug in the early days of the pandemic not because there was scientific evidence of its efficacy, but because they didn’t have much else to offer.

The antimalarial drugs: hydroxychloroquine and chloroquine are a synthetic form of

quinine, a compound originally found in the bark of the cinchona plant native to Peru and initially used centuries ago for the treatment of fevers and heart palpitations by the Incas. The flowering plant is a genus of the family Rubiaceae containing at least 23 species, native to the tropical Andean forests of western South America. Its bark known as quinquina is a transliteration of the Peruvian word for the tree, kinakina. Its introduction into western medicine to initially treat fevers is as fascinating as a fable. The first use of the drug by Europeans to cure “the fever” was seen as a miracle. Some believed that the use of the drug for COVID-19 would produce yet another miracle! use of the hat the first use of a quinine drug was seen as an and

Bark and flower of Kinakina (quinquina) plant

The Discovery of Quinine

As far as we know, the first use of the medicinal bark by a prominent European that resulted in its widespread use in Europe dates back to 1638. As the story goes, the beautiful Ana de Osorio, the spouse of Don Luis Jerónimo Fernández de Cabrera Bobadilla Cerda y Mendoza, the 4th Count of Chinchón, Spain, and Viceroy of Peru (the Peruvian Viceroyalty initially included all of South America under Spanish control), was stricken with high fever, evening sweats, weight loss and dizzy spells. As wife of the Viceroy of Peru, her life had been one long whirl of balls, banquets and fiestas.

After more than a week with no improvement, the alarmed Don Luis recalled his doctor, Juan de Vega, who arrived on horseback on the double.

“Do something doctor or my beloved wife — the Contessa of Chinchón is going to die,” he proclaimed in tears, stomping his feet and beating his breast. His devastation seemed total.

“I have purged her repeatedly Dom Luis, and let the leaches drain her impure, contaminated blood, and still the fever doesn’t break,” he said. “Forgive me Don Luis, may God help her.”
She lay in her royal canopied bed drenched in her own sweat; her eyes sunken, her cheeks hollowed, her complexión ashen from the excessive purging and blood gouging by the leeches.

It is said that Dr. Juan de Vega gathered all his courage and whispered in the Viceroy’s ear that it was time to ask the Archbishop of Lima, to administer the last sacraments of the Catholic Church. Hearing this, suddenly, and rather unexpectedly, the Viceroy became infuriated. A tussle broke out beween the doctor and the Viceroy who kicked him hard in the stomach and threw the doctor out of the royal chamber for giving up so easily on his beloved Contessa.

“She is only thirty-eight years old, the mother of my children and you want me to give up on her?” he said. “Get out of here. I don’t want to see you anymore!”
Dr. de Vega saw both his royal commission as the distinguished doctor to the Viceroy’s household, and his own life dangling on a hangman’s noose. Totally shaken, on his way out, he knelt in the courtyard of the palace and prayed to the patron saint of Lima: Santa Rosa da Lima for inspiration and salvation. He then wondered around the city aimlessly until nightfall. Tired and thirsty, he entered a tavern frequented by Spanish soldiers and there, he met an officer in His Majesty’s King Philip IV’s army. After listening to Dr. de Vega’s dilema, the officer told him that he had a powder made from a bark of a tree, given to him by a native Inca healer, a Curandeira, that can cure the fever. He swore that it had cured him of the fever he acquired during an expedition in the Andean rain forest.
Dr. de Vega had nothing to lose. If the powder worked, it could be his salvation; otherwise, he could be hanged if the Contessa died.

Next morning, Dr. de Vega begged an audience with the Viceroy who was in a ‘holy mood’ after attending High Mass for the Contessa and praying with the Archbishop who administered the last sacraments to his moribund wife.

Wasting no time, he hurriedly related to the Viceroy about the Inca bark that could cure the fever. With the seemingly dying Contessa in the royal chamber, the Viceroy reluctantly accepted, on the condition that the doctor himself take the mysterious powdered bark before the Contessa imbibed her hefty dose. Three days after drinking the bitter powder mixed with water and sugar twice a day, the fever broke, and the Contessa was cured of the malady. She was so grateful to have her health back that she obtained and distributed the powder to the fever sufferers in Lima, sometimes in person, and at other times through the Jesuits of St. Paul’s College. In deference to the Contessa and her generosity, the Kinakina plant was named la planta de Contessa de Chinchón. Dr. da Vega was ecstatic, an attributed his luck to the intercession of Santa Rosa da Lima.

A great Fiesta was subsequently held in the palace courtyard attended by the local Indians honoring the ageless curandeira Zuma Ka-Ata-Killa Ynca who came all the way from the highlands of Cuzco, near Machu Pichu in a horse buggy and by foot over mountain ranges and valleys. The day after, a ball and banquet were also held with much pomp in the Palace Grand Hall in honor of the Contessa and Dr. Juan de Vega. It was attended by the Spanish gentry and foreign dignitaries in Peru.

After the Viceroy’s commission was over, the Count and Contessa of Chinchón accompanied by Dr. de Vega returned to Spain in 1640 to their castle and their vast lands. The Contessa carried with her loads of the miracle bark and dispensed it generously at no cost to the “fever ridden” peasants in the Count’s vast domain. She is remembered even today for her great generosity. Dr. de Vega, also took with him a large quantity of the bark which he sold in Seville for 100 reals per pound and became rich.

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Quinquina gained wide popularity after the Jesuits introduced it to Europe, and its miraculous benefits became known to Pope Innocent X who ordered his counselor Fr. Juan de Lugo, to request his doctor, Dr. Fonsega to investigate the bark of the mysterious tree from Peru. In 1649, after a visit to Peru, Dr. Fonsega reported that the bark was effectively used in the treatment of fevers and heart palpitations by the Incas for centuries. Subsequently, in Europe, quinquina was named the “Powder of Jesuits.” In 1666, the famous English physician Thomas Sydenham in his book “Methods for Curing the Fevers,” mentioned the “Powder of Jesuits.” In the late 17th Century it apparently successfully treated King Louis XIV of France and his son of the fever acquired in the backwaters of Versailles, and was referred to as “the Cardinal Powder.” It was also reputed to have cured King Charles of England, where it was called “the English Remedy.”

The alkaloid of quinquina was first isolated and called cinchonine in 1816 by a Portuguese doctor, Bernardino Antonio Gomes. The second alkaloid, quinine, was isolated by two French pharmacists, Pierre-Joseph Pelletier and Joseph Bienaime Caventou.

In 1853, Louis Pasteur named the compound that he thought was an impure quinine, “quinidine.” Although quinine was used to treat the fevers, malaria was not yet described as the cause of the relentless, debilitating fever that in its severe form could result in death. Only in 1880 in the military hospital in Algeria, Alphonse Laveran, a military doctor in France’s Service de Santé des Armées, discovered the malaria parasite. Finally, it was the English physician Sir Ronald Ross, who on his return to British India in 1895, set forth to prove that mosquitoes were connected with the propagation of malaria. His research earned him the Nobel Prize in 1902

It is of considerable interest that the British colonists in India used to drink quinine in water to prevent malaria. However, the bitter taste was highly unpleasant, so the British officers in the early 19th century took to adding a mixture of water, sugar, lime and gin to the quinine in order to make the drink more palatable and the much sought after summer cocktail, gin and tonic was born.

World War II rendered the supply of quinquina extremely difficult to obtain and prompted the synthesis of hydroquinidine. The work of Woodard and Doering, both chemists at Harvard University, introduced hydroquinidine as an agent in 1945 to treat heart rhythm disorders. Heart rhythm experts used Quinidine until recently to treat a variety of heart rhythm maladies. The use of the drug was discontinued because of the risk of developing a lethal rhythm know as Torsade des Pointes.

Hydroxychloroquine sulfate was first synthesized in 1950 by introducing a hydroxyl group to chloroquine. It was demonstrated to be much less toxic than chloroquine in animals and was subsequently used worldwide for the treatment of malaria, lupus, and rheumatoid arthritis, and most recently for COVID-19.

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ANTIMALARIALS FOR COVID-19: FACT OR FANTASY?

The President’s enthusiasm for the malarial drugs hydroxychloroquine and chloroquine was based on anecdotal reports from China and the small Marseille study done by Dr. Didier Raoult and tweeted by Elon Musk and reported by Fox News. Although the study presumably showed that the drug decreased the virus in the nose, no information was provided on mortality, respiratory failure, and time to improvement or discharge from the hospital. As far as we know, this was a poorly done non-randomized study that did not prove the efficacy of the drug for COVID-19.

On March 19, the President mentioned the malarial drugs during a daily briefing on the pandemic. “Nothing will stand in our way as we pursue any avenue to find what best works against this horrible virus,” he said. “Now, a drug called chloroquine — and some people would add to it ‘hydroxy-.’ Hydroxychloroquine. So chloroquine or hydroxychloroquine. … It is known as a malaria drug, and it’s been around for a long time and it’s very powerful. But the nice part is, it’s been around for a long time, so we know that if it — if things don’t go as planned, it’s not going to kill anybody.” A few hours later, he promoted the drugs to the nation’s governors on a conference call. He tweeted that the drugs would become “one of the biggest game changers in the history of medicine.” On the other hand Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases and a member of the Task Force contradicted the President saying that there was no evidence that the drug is effective in the treatment of COVID-19.

On March 23, the President during the daily coronavirus briefing, said: “At my direction, the federal government is working to help obtain large quantities of the drug. And you can look from any standpoint tomorrow, in New York — we think tomorrow pretty early — the hydroxychloroquine and the Z-Pak, I think as a combination, probably, is looking very, very good.” And he told an anecdotal story of success: “You probably saw a couple of articles today came out where a gentleman — they thought he was not going to make it. He said goodbye to his family,” the President said. “They had given him the drug just a little while before, but he thought it was over. His family thought he was going to die. And a number of hours later, he woke up, felt good. Then he woke up again, and he felt really good. And he’s in good shape.”

The President’s advocacy of the drug led to a substantial shortage among patients who rely on it to treat other illnesses.

On May 18, the President announced that he had been taking hydroxychloroquine, as a preventive measure and continued to test negative for the coronavirus. “All I can tell you is so far I seem to be OK,” he said, adding that he had been taking the drug for about a week and a half, with the approval of the White House physician. “I get a lot of tremendously positive news on the hydroxy,” he continued, explaining that his decision to try the drug was based on one of his favorite refrains: “What do you have to lose?” His announcement came as a surprise to many of his aides and drew criticism from a range of medical experts. Dr. Steven E. Nissen, the chief academic officer of the Miller Family Heart, Vascular & Thoracic Institute stated: “My concern would be that the public not hear comments about the use of hydroxychloroquine and believe that taking this drug to prevent Covid-19 infection is without hazards. In fact, there are serious hazards.”

Both drugs, hydroxychloroquine and chloroquine have the potential of causing a dangerous rhythm known as Torsade des Pointes, which can result in a black out spell or cardiac arrest and instant death in susceptible individuals. At the Mount Sinai Medical Center in New York, we established a protocol recommending ECG’s before starting the drug and during follow-up. The risk of a cardiac arrhythmia is greater when combined with the antibiotic Azithromycin (Z-Pak). We stopped using the drug for COVID-18 by mid-April, when it was clear that the drug was ineffective.

For some time it remained unclear whether the antimalarial drugs with or without azithromycin was beneficial for COVID-19. The efficacy touted by some doctors was at best anecdotal. The consensus among most doctors, namely academicians and clinician-scientists was that there was no proof that the drug works and can be harmful to some patients. It had been tried in the prevention of influenza and failed; it had no effect in HIV and Hepatitis C infection nor was it effective in Dengue fever and Ebola. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19, reported no benefit. However, a non-randomized observational study showed that treatment with hydroxychloroquine alone and in combination with azithromycin was associated with reduction in COVID-19 associated mortality. Nonetheless, the authors called for prospective trials to examine this impact of the antimalarial drugs on COVID-19. Soon thereafter, a clinical trial of hydroxychloroquine for the treatment of hospitalized adults with COVID-19 was halted after the drug was found to be ineffective, the National Institutes of Health (NIH) announced on June 19, 2020. Another set of studies, both Randomizes Control Trials: 1) Part of a massive trial in the UK called Randomized Evaluation of Covid-19 Therapy, or “RECOVERY.” And 2) A study from the University of Minnesota. These two trials showed that Hydroxychloroquine does not appear to keep people from getting the disease after they’ve been exposed to someone who has it, nor does it positively affect mortality nor reduce symptoms for non-hospitalized patients. A more recent multicenter, randomized, open-label, three-group, controlled trial involving hospitalized patients with suspected or confirmed Covid-19 who were receiving either no supplemental oxygen or a maximum of 4 liters per minute was reported in The New England Journal of Medicine. A total of 667 patients underwent randomization of which 504 patients had confirmed Covid-19. Hydroxychloroquine alone or hydroxychloroquine plus azithromycin showed no benefit as compared to standard care. On the other hand, ECG abnormalities and elevation of liver-enzyme levels were more frequent in patients receiving hydroxychloroquine, alone or with azithromycin, than in those who were not receiving either agent. Subsequent multiple scientific studies showed the inefficacy of the drug for COVID-19.

Not surprisingly then, the FDA revoked emergency authorization for hydroxychloroquine and chloroquine to treat COVID-19, saying the evidence shows the recommended dose is unlikely to be effective against the virus. This is despite the federal stockpile of 66 million doses of hydroxychloroquine and chloroquine.

It seems an utter waste of stockpiling a drug in such a large quantity based on anecdotal evidence.

The nearly 400-year-old fable of the Count and Contessa of Chinchón makes one wonder what doctors and scientists of the future might find as fantasy from our current moment in history. Perhaps they would find a tale far less imaginable and far more terrifying in its outcome.

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About the Author:

J. Anthony Gomes is a Professor of Medicine at The Mount Sinai Medical Center, NYC. He has published more than 150 articles in Cardiovascular Medicine and two textbooks of Cardiology, Signal Averaged Electrocar­diography: Basic Concepts Methods and Application (Kluwer Aca­demic Press, London/Amsterdam, 1993) and Heart Rhythm Disorders(Springer-Nature, 2020). He has also published articles in the humanities in anthologies, books, newspapers, and magazines; two books of poetry entitled Visions from Grymes Hill (Turn of River Press, Stanford, Connecticut, USA, 1994) and Mirrored Reflections (GOA 1556 and Fundacão Oriente, 2013); and three novels, The Sting of Peppercorns,Nas Garras Do Destino, and Have A Heart .