On 9 April, the US president tweeted thanking India and her people on the decision to send HCQ to the US. Extraordinary times call for extraordinary measures. In times of crisis, friendships are either strengthened or irreparable damage is done to it. The current situation revolving the drug also highlights the increasing role of science and commerce in foreign affairs.
Teemed the miracle drug for the fight against Covid-19 by the US President, the erstwhile low profile, generic Hydroxychloroquine (HCQ) is making headlines lately. With the export of the drug banned from its largest manufacturing base in India, the United States has finally secured an order of over 25 million units displaying the growing camaraderie between the two nations. The domestic debate has been focused on the potential prophylactic effects and the potential side effects of what seems to be the most widely accepted method of treatment for the Cytokine Storm that leads to Multi Organ failure and ultimately death due to Covid-19.
Chloroquine and its less toxic derivative- Hydroxychloroquine have an intriguing and versatile history, intertwined with European Colonialism in areas where Malaria was endemic. Malaria and similar febrile illnesses were first described by Hippocrates as periodic fevers associated with swamps. Loosely translated from Italian “mal’aria” that means “bad airs”, Malaria was one of the greatest early threats to European Colonialism. It was as early as 1638 that the first documented use of the Cinchona tree (bark) for Malaria treatment (and other ailments in the Andes) was found. The tree in abundance in nature began to be used as a traditional medicinal agent.
The Wife of the then Viceroy of Peru opted this method of treatment over the known therapies at the time. According to local legend, a native with high fever discovered the effectiveness of the bark when he drank water (which tasted bitter) from a pool in the jungle. Thinking he was poisoned, the native lay there for a few hours and observed that the pool was surrounded by the quina-quina tree which had probably contaminated the pool.
Soon, his fever miraculously abated. The tree was subsequently named after the Countess of Chinchon by the botanist Carl Linnaeus to honour her, for carrying the miracle powder back to Europe. As Malaria spread through the 17th Century, more and more of the miraculous and bitter tasting bark of the Cinchona was sent back to Europe. Not surprisingly religion and politics soon got involved. The supply was controlled by the Church and known widely as “Sacred Powder”. It was providing significant remedy and relief to various fevers that plagued the swampish regions of Europe.
The ability of Colonial Powers to invade Malaria ridden parts of the new world were directly proportional to their ability to acquire enough of the miracle powder to protect their troops from this devastating fever. This eventually led to an arms race of smuggling of seeds and plants for cultivation in colonies. Closer to home, the British East Indian Company focussed its efforts on trying to cultivate – the difficult to grow Cinchona Tree in the plantations on the Nigiri Hills, a move that was an economic failure but still crucial to British Colonial domination in this Malaria endemic region.
The extraction of Quinine as a pharmaceutical agent from this miraculous powder was first done by French researchers Pierre Joseph Pelletier and Joseph Benaime Caventou in 1820. No longer would powdered tree bark mixed with wine to mask its bitter taste be the therapeutic agent of choice. It was replaced with purified quinine as a new standard of care for Malaria.
In fact, one of the first clinical trials from 1866 to 1868 yielded a cure rate of >98% in the 3,600 patients treated for Malaria and other fevers. Subsequent research led to its widespread use for Malaria prophylaxis by the mid 1800’s. In fact, by 1825, soldiers of the East India Company were mixing their daily dose of Quinine with sugar, water and gin to create the Gin and Tonic drink which is widely popular to date.
For almost a century, Quinine remained the main treatment for Malaria till the development of more effective and better tolerated synthetics. The Dutch colony of Java Indonesia had the most widespread cultivation of the Cinchona Trees, accounting for 90% of the Worlds Quinine Supply. The capture of Indonesia by the Japanese during World War 2 in 1941 led to the race for the development of synthetic quinine replacements – a move that finally led to the discovery of Chloroquine and all other known anti-Malarials.
Interestingly, Chloroquine was first synthesised by the scientist Hands Andersag at the Elberfeld Laboratories of Bayer, in 1938 under the name “Resochin” but was discarded as it was considered too toxic for Human use.
Another Bayer scientist continued experiments on “Resochin” and another derivative called “Sontonchin”, testing over 1000 patients including a series of experiments at a Mental Hospital in Dresden in 1939. In 1939, the Winthorp Chemical Company through a series of complex arrangements with Bayer got manufacturing rights for the drug and subsequently filed patents in 1941, although the Germans had in fact filed prior patents. The first Chloroquine trials in the US began in 1944 continuing for two years and testing over 5,000 patients for every possible side effect.
In April 1945, towards the collapse of Germany, a task force from the British Military Division called the Supreme Headquarters Allied Expeditionary Forces (SHAEF) visited the Elderfeild Laboratories for a detailed discussion with them. While Hydroxychloroquine was granted FDA approvals in 1945, Hydroxychloroquine Sulphate, first synthesised in 1946, demonstrated 40% lower toxicity than even Chloroquine. Its Immunomodulatory effects have caused increased use for treatment of autoimmune diseases like lupus, rheumatoid arthritis and post Lyme Arthritis. From 1955 to 2013, it was sold by Sanofi Aventis under the brand name “Planquenil”, till the expiry of the patent and conversion to a generic drug.
Scientists studying plasma of critically ill Covid Patients found high concentrations of Cytokines, leading to the hypothesis that in the severe manifestations of SARS-CoC2, cytokine storms could potentially be a cause of rapid degradation.
In vitro studies of HQC as a known, safe and tolerated anti-inflammatory drug with antiviral activity showed positive results. However, clinical studies to test its efficacy in Covid-19 patients are still on going. Limited evidence and lack of consensus amongst the medical community have led to global hoarding, export bans and a series of other policies that are creating shortages for patients with other life threatening and dilapidating illnesses such as Lupus. These other patients are unable to get prescription refills due to diversion of supplies to fight the Covid Epidemic.
The coming weeks are crucial for the fight against Coronavirus. We also hope to gain adequate answers to the efficacy of this class of drugs with over 15 trial results expected shortly. If HCQ emerges victorious in this fight, the pressure will be on India to ramp up manufacturing. India currently produced over 70% of the global output of HCQ, with a manufacturing capacity of over 40 tonnes or 200 million tablets of 200mg each month.
Hydroxychloroquine has had an interesting journey — starting with 16th Century European Colonialism in South America to modern day generic drug manufacturing. To think it all started with bitter tasting pools of water in the jungles of South-America. Its destiny has finally come to rest on India’s shores. India will have to balance the need of its national stockpile along with the expectations of the larger global community. If it is able to juggle both needs it will perhaps be its single biggest contribution to humanity and towards its soft power ambitions. The world is watching with bated breath.
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Vinayak Dalmia is an entrepreneur and political thinker. He has worked with the Indian Prime Minister's Office and McKinsey &: Co. Vinayak regularly writes and ...
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