THE FIRST MIRACLE DRUG 7

Before reading the book The Demon Under the Microscope by Thomas Hager it was my, and likely others as well, impression, erroneous as it turned out, that penicillin was the first ‘miracle’ anti-bacterial drug. It was not. The following is a brief recounting of what really was that drug.

In the summer of 1924 the teen age son of President Calvin Coolidge developed a blister on his big toe while playing tennis. The wound became infected with what looked like Streptococcus pyogenes and despite the best medical treatment available at the time he was dead within two weeks. In November 1936 Harvard senior, Franklin Delano Roosevelt Jr., was undergoing a round of cocktail and dinner parties and press conferences owing to his engagement to be married. Perhaps due to the stress and tiring activities of all this, young Roosevelt began feeling unwell with a sore throat and head which felt like it was full of concrete. Five days later he was admitted to Massachusetts General Hospital. Again despite the best medical treatment available at that time Roosevelt’s condition steadily deteriorated over the next three weeks as he was diagnosed with some strain of a streptococcus infection. In desperation he was given a new and still unproven drug. In two days there was a complete turnaround and Roosevelt soon left the hospital. The completely different outcome of these two cases was entirely due to this new drug.

Streptococcus infections, or strep for short, were estimated to kill 1.5 million victims per year in Europe and North America alone during the 1920’s. That same number adjusted for today’s population would total more than the current worldwide annual deaths from cholera, dysentery, typhoid, and AIDS combined. Such diseases as scarlet fever, rheumatic fever, and strep throat are caused by various species of streptococcus. With enough magnification all strains of strep look like twisted strings of beads (Latin streptococcus from Greek streptos twisted chain + kokkos berry or seed).

After the horrendous number of deaths of soldiers from infected wounds in WW1 the Germans, English, and French, and especially the Germans concentrated on finding medications which would cure these infections. A young German medic during WW1, Gerhard Domagk, experienced firsthand the futility of the medical treatment given to wounded soldiers in fighting infection. After the war he determined to combat this scourge of deadly infection by graduating from medical school in 1921 and devoting himself to finding cures. After first working at a medical school he went to work in the pharmaceutical department of Friedrich Bayer & Company.

German companies were the world leaders in the manufacturing of dyes for cloth and other materials. A Jewish German chemist, Paul Ehrlich, conceived the idea and developed a method of using dyes to stain bacteria so they could be studied under a microscope. He had received a Nobel Prize in medicine for his work on immunity and serum therapy in 1908. Domagk, and other German researchers started using dye molecules, especially what was called an azo dye in attempting to develop an anti-bacterial medication composed of the dye molecule coupled with other molecules. Domagk had six laboratory assistants - all of them women. How is that for diversity in the workplace for the 1920’s? After many trials and failures, Domagk tried combining the azo dye molecule with a molecule called sulfanilamide. This medication showed great promise treating some types of strep and after much further experimentation and refinement a drug called Prontosil was marketed by Bayer. Dr. Gerhard Domagk was named a Nobel Prize recipient by the Swedish committee in 1939. However Adolph Hitler himself prohibited Domagk from accepting the prize because a couple of years early a German opponent of the Nazi regime had been awarded the Nobel Peace Prize by the Norwegian Nobel committee. It made no difference to Hitler that the Swedish committee was different from the Norwegian committee – he wasn’t going to have anything to do with Nobel period. Domagk was invited to Stockholm to receive his Nobel Prize in 1947 when Hitler was history.

This new anti-bacterial drug, Prontosil, and further similar drugs developed by the Germans, French, and English worked almost miraculously in laboratory tests on mice and rabbits and then on human patients. There was no such thing as a clinical trial in the 1930’s so the patients became by default guinea pigs. Still the cure rates were as nothing seen in medicine before. The one puzzling aspect was that while the results in vivo in the laboratory and with human patients were spectacular, in vitro it was a dismal failure – the pathogens in test tubes were not affected by the drug.

The Germans and as a result the French and English as well were so hung up on using dye molecules that it was practically by accident that a group of test mice were treated with pure sulfanilamide in a French lab. When the sulfanilamide alone worked as effectively as the previous drugs linked to the azo dye there was shock and as expected, doubt in laboratories around Europe. After the results were confirmed by others the rush was on to turn out variations of sulfa based medications. One mystery was solved by the discovery of sulfa being the active anti-bacterial agent. Sulfa had to be released from the rest of the Prontosil molecule in order to become active. This could happen in the body of an animal, where enzymes in the body could split the Prontosil molecule into two pieces, releasing pure sulfa as the medicine, but not in a test tube which contained no enzymes.

By 1937 sulfa drugs were being widely used in the United States and therein lay a cautionary tale. In Tulsa, Oklahoma Dr. James Stephenson observed that many sick patients including a majority of children began showing up in Tulsa hospitals and later in hospitals in other cities around the country. A number of them began dying with renal failure. Sulfa pills, capsules, injectable solutions, and powders had recently hit the market from a variety of pharmaceutical manufacturers. Every drug store in Tulsa was selling sulfa to anyone who asked for it. Dr. Stephenson traced the problem to a proprietary drug called Elixir Sulfanilamide produced by the Massengill Company. Sulfa is difficult to dissolve, alcohol does not work well nor does many of the common medicinal solvents. The head chemist for Massengill, Harold Watkins, found that diethylene glycol, an industrial solvent, worked very well to dissolve the sulfa. As it turned out, the problem was it also worked very well in bring on renal failure and death which reached 67 confirmed. As difficult as it is to believe today, the Massengill Company ran no tests on laboratory animals nor did they do any clinical tests with their medicine. The FDA had been established in 1906, but was of minimal effect in regulating the medical field. Like other issues perhaps the pendulum has swung too much the other way today. Although Watkins was slow in admitting blame for the sickness and death of the people who took his medicine he clearly realized his culpability – he committed suicide eight months later by putting a loaded hand gun to his head and squeezing the trigger.

Sulfa drugs generally had no serious side effects (except when mixed with poison, e.g. diethylene glycol). I can attest there were some relatively minor ones however. When I was a teenager I was given a sulfa drug for a forgotten illness and when I got up from bed to go to the bathroom I felt so dizzy that I almost, but not quite, fell to the floor. The medication was discontinued and I believe logic would dictate that I recovered anyway.

In 1939 a drug called sulfapyridine was developed in the United States as a cure for pneumonia. Within a few years this drug was saving the lives (why not say postponing the deaths? Isn’t that more accurate?) of 33 thousand pneumonia patients each year in the United States alone. By 1942 at least 3600 sulfa derivatives had been synthesized and studied and more than 30 of them had been sold in the United States. Sulfapyridine was, gram for gram, 18 times more powerful than Prontosil; sulfathiazole was 54 times more effective; sulfadiazine was 100 times more effective. The number of diseases that could be treated with the new sulfa drugs was also growing. Sulfathiazole worked as well as the other drugs against strep and also was effective against staphylococcal infections.

There seemed to be an ever increasing spectrum of diseases which could be treated successfully with sulfa drugs. The one thing unexplained was how the medicine worked, but that was discovered eight years after Prontosil was formulated. Sulfa was less of a magic bullet than a clever imposter. It was observed that sulfa never worked as well when there was dead tissue around or a lot of pus as in uncleaned wounds. There was a yeast extract called para-aminobenzoic acid (PABA) a chemical involved in bacterial metabolism which had astonishing anti-sulfa abilities. Some bacteria can make their own PABA; others can not and have to find it in their own environment. For these bacteria PABA is an essential metabolite. If they can not find it they starve. The sulfa and PABA molecules are so similar that an enzyme critical in keeping the bacteria healthy mistakes one for the other, binding sulfa instead of PABA, but since sulfa could not be metabolized, the enzyme, with sulfa stuck to it, becomes useless. The bacteria, denied a nutrient they need, eventually starve to death.

Sulfa drugs of course had not yet been discovered by WW1 so that acute respiratory diseases, including influenza, pneumonia, bronchitis, and other diseases killed circa 50,000 U.S. soldiers. In WW11, with twice as many men and women in uniform, only 1265 died from these diseases. The main difference was the widespread use of sulfa drugs in WW11. The wartime sulfa production was more than 4500 tons in 1943 alone, enough to treat more than 100 million patients. In December 1943 British Prime Minister Winston Churchill undertook a long and exhausting, for a 69 year old heavy smoker and legendary drinker, trip to Cairo, then to Teheran to meet with wartime allies Roosevelt and Stalin, back Cairo to meet again with Roosevelt, and finally on to Tunis for a couple of days rest at Eisenhower’s villa. When he arrived he had a sore throat and a fever of 101ºF. X-rays revealed that he had contacted pneumonia. He was given sulfa drugs, but suffered two bouts of atrial fibrillation and an episode of cardiac failure. Finally the medication kicked in and Churchill’s temperature returned to normal. Two weeks after he became sick he flew to Marrakech, Morocco and then home. For a while it was touch and go for one of the two leaders of the free world with sulfa drugs being the determinant.

I would be remiss if I did not mention what everyone reading this must be thinking about now. How about the problem of drug resistance with sulfa? The answer is what you might expect. With the massive overuse of sulfa drugs, as there was and is with penicillin and other modern antibiotics, resistance to the drugs became an increasing problem in lowering their effectiveness. Killing off non-resistant bacteria and thereby leaving a few resistant strains is a still an unsolved problem for these disease fighting medications.

Incidentally in 1928 British medical researcher Alexander Fleming notice that one of his bacteria plates which had been contaminated with a mold had the odd effect of clearing a zone around itself in which the bacteria did not grow. Fleming logically thought that the mold was releasing some sort of substance that hindered the growth of the bacteria. Purifying an amount of the mold sufficient to conduct in vivo tests proved so difficult that he largely dropped the research and turned to – sulfa. He returned to penicillin years later and along with two other British medical researchers received a Nobel Prize for medicine in 1945.