The search for chloroquine helped bring about the modern pharmaceutical industry

 

Trump has encouraged people to try an unproven medication — just as the U.S. did with its predecessor drug.

President Trump speaks with reporters April 22. He has frequently touted hydroxychloroquine as a possible treatment for covid-19. (Jabin Botsford/The Washington Post)
April 23, 2020 at 9:00 p.m. GMT+1

When President Trump turned himself into a drug salesman for chloroquine makers, telling people, no need to wait for the studies, just take the drug — “what do you have to lose?” — he disregarded decades of progress on pharmaceutical testing.

He asked willing Americans to become guinea pigs, to use a malaria drug and determine for themselves whether it works against covid-19, the disease caused by the novel coronavirus. But now studies are returning results showing that death rates are higher in covid-19 patients who were treated with hydroxychloroquine, the drug Trump touted.

Ironically, chloroquine — from which hydroxychloroquine is derived — is the very drug that catapulted American pharmaceutical companies and drug testing out of the medical Dark Ages and into the industry we now know.

This happened during World War II, when a half-million U.S. troops were stricken with malaria, some fatally. Most survivors were crippled by relapsing fever — and unable to fight. U.S. commanders were desperate to find a drug that could keep their troops on their feet.

 

In early battles in the Pacific theater, more men were lost to malaria than to enemy fire, sometimes at a ratio of 10 to 1. Many thousands of U.S. troops holding back the Japanese in horrid conditions contracted a type of malaria that relapsed almost monthly. Military leaders had no idea what to do with so many useless men and feared that they would lose the war.

U.S. scientists were asked to create the largest drug development program ever tried — nicknamed the Malaria Project, run by the same office that ran the Manhattan Project. This No. 1 medical priority of the war was conducted in secret, and its success was expected to be a true game changer.

But back then, U.S. drug companies were tiny compared with today’s giants. Some made no more than quack cures and remedies. The skills of U.S. chemists were limited by lack of experience. And most malaria experts knew little about drug development; they studied the mosquitoes that carry malaria.

 

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The Germans were by far the best at drug making. Bayer Co. — with blockbusters such as aspirin and heroin — set out to make a malaria drug after the disease crippled troops in World War I. Ninety percent of the world’s only treatment at the time, quinine (made from tree bark), was controlled by a Dutch cartel. Bayer wanted to steal that market with a “synthetic” version of it made in the company’s labs on the Rhine.

Bayer’s scientists started with fabric dyes, because certain colors attached to malarial parasites and killed them. The compounds were first tested on canaries with bird malaria. If the birds lived, the compounds were next used on late-stage syphilis patients undergoing “malaria therapy” at a Düsseldorf asylum. (High fevers caused by malaria could kill syphilis spirochetes in the brain.) And if the chemicals lowered those fevers, they were tried in troops.

 

By the 1930s, Bayer landed on a promising concoction made from a yellow dye, anchored by a chlorine side chain. This new drug — just one snip of a molecule away from becoming chloroquine — was atabrine. American troops took it during the war because the Japanese had blockaded the Dutch quinine supply. But the dosing was far too high and caused headaches, confusion, nausea, itchy hives, uncontrolled diarrhea, cramping, skin lesions, awful nightmares, paranoia and depression. Most troops spit out the bitter pills, turning the grounds around mess tents yellow.

Almost no one knew that shortly before Germany invaded Poland, Bayer had created something better: In a bold move that seems obvious only after the fact, they snipped off atabrine’s yellow dye to create a colorless, much-better-tolerated drug.

That was the future chloroquine — atabrine with its chlorine anchor, but no yellow dye. It became an American drug when U.S. forces captured it some five years later in the battle for Tunisia.

 

Archived records show that Germans in occupied Paris conspired to have a local drug company, Specia, make Bayer’s new compound for a large clinical trial run by French researcher Jean Schneider. He took 50,000 pills and seven boxes of liquid vials for tests on the residents of seven whitewashed adobe villages in Tunisia at the height of malaria season. Residents of two villages were given nothing, as controls; one village’s residents received atabrine for a comparison; and residents of four received a daily dose of the new drug. Twenty-two hundred men, women and children were used as test subjects.

When Allied forces rumbled in from Algeria, Schneider packed up three months of “remarkable” data that showed that this new drug cured and prevented malaria. He fled to the coastal city of Tunis, still under Nazi control, to wait out the battles, ready to give his work to whichever side won.

The Americans finally arrived in May 1943. Schneider cornered a U.S. foot soldier with instructions to take his reports, drug samples and a personal letter to the U.S. theater surgeon. The letter proposed a partnership with the Americans in which France would share in the success of this new drug once the war was over.

 

The new compound arrived in the United States and was immediately plugged into the Malaria Project, which by then had more than 50 universities and commercial labs and hundreds of chemists, clinical doctors, lab technicians, blood experts, malariologists, entomologists and parasitologists — many with big personalities and even bigger egos, pitching in to make a synthetic quinine.

For three years, these scientists unsuccessfully ran tests on compounds that killed thousands upon thousands of chicks and ducklings with bird malaria, hundreds of dogs in toxicity tests and many, many human subjects.

Just as Bayer had done in Germany in the 1920s and 1930s, U.S. researchers experimented on syphilitics undergoing malaria therapy at state hospitals in Massachusetts, Georgia, South Carolina, Illinois, New York and Washington, D.C. But they also used schizophrenics and others, even though evidence showed that these patients derived no benefit from malaria-induced fevers. The U.S. scientists performed a range of experiments on these mentally debilitated patients, which investigators called “clinical material.” Conservative estimates suggest that 10 to 20 percent of their “material” died of the malaria or the drugs, or both.

 

The biggest tests involved chloroquine, with multiphase clinical trials using convicted murderers and rapists at Stateville prison near Chicago; U.S. Marines with relapsing malaria at a camp in Klamath Falls, Ore.; 44 volunteer students at the U.S. Navy Hospital in Bethesda, Md.; and more than 1,000 sugar plantation workers in Peru. All studies added to Schneider’s results, indicating that this line of drugs worked.

But they also revealed startling problems. Chloroquine, especially, showed unpredictable side effects. Itchy hives. Vomiting. Severe diarrhea. Headaches. Bleached hair. Depression. Blurred vision. Suicidal thoughts. Nightmares. Trouble sleeping. Psychoses.

All told, Americans ran malaria-related clinical trials on more than 10,000 captive people and on U.S. military personnel and student volunteers. Germans ran their own malaria trials on troops and in concentration camps, including Dachau, where malaria expert Claus Schilling was hanged at the close of the war for his work. The U.S. military lawyers and judges running the war crimes trials there were unaware that the Malaria Project’s leading researchers had learned their techniques from Schilling.

 

The Malaria Project made more than 14,000 compounds. And through all the failures, the researchers became experts. Germany’s elite know-how — so exquisitely ahead of the world on drug development — died with Hitler.

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Chloroquine was advertised as a miracle cure after the war. Public health experts disagreed. They warned politicians of the drug’s shortcomings. But they were inconvenient to a larger Cold War plan that deployed it like aspirin in the tropics to try to eradicate malaria from the planet. As the experts predicted, many people had bad side effects and refused to take the medicine. Malarial parasites developed resistance, and chloroquine stopped working.

One positive outcome of the wartime medical work is that it helped form the foundation of what we know today about medical research, and blazed the path for better handling of “clinical material” in drug trials.

 

Despite chloroquine’s shortcomings, it has remained in use, including for people with lupus and rheumatoid arthritis. It also is still used to treat malaria in regions without drug resistance. And many people can tolerate it as a malaria prophylactic — but many cannot.

We know this drug is particularly dangerous in people with heart, eye, liver and kidney problems, which are found so commonly in the elderly. So those who tend to become the sickest with covid-19 are the very people most susceptible to the dangers of chloroquine.

The studies coming in this week suggesting that the drug might do more harm than good are upsetting. Even worse, the warning may get lost in all the political noise around this drug. I fear that for every patient who thinks the drug helped relieve symptoms, there is another who has been hurt by it.

My own sister, a high school clinician in Massachusetts, texted me last week, very upset: A former student of hers, now 23, had turned suicidal after taking hydroxychloroquine to try to prevent covid-19. She asked about the side effects, so I told her about the minor and the severe ones. And I warned her that evidence dating back to World War II suggests that it can cause psychosis in some people. This I saw firsthand in more than 500 boxes of archived materials I used to write a book called “The Malaria Project.”

The former student has since stopped taking hydroxychloroquine. But a distinct problem with this particular chloroquine derivative is that it stays in the body for up to six months, so those thoughts of suicide may stay with him through the summer. Physician researcher Remington Nevin thinks that in some people, all of these quinine replacement drugs function as a neurotoxin, with side effects that can last years.

Trump’s salesmanship of chloroquine has dragged regular people into the medical sciences with too little experience to understand the consequences. As with the wartime pressure that turned people into “clinical material” for the desperate and disorganized drug trials that led to chloroquine, pressure to find a cure for covid-19 is pressing the drug back into experimental service. This time, it’s putting a lot more people at risk.

Source: The Washington post 

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