- Purpose
- Typical Antibacterial
Prontosil
In its Dec. 28, 1936, issue, Time magazine reported that Eleanor Roosevelt, wife of the president, had missed the family Thanksgiving dinner. Instead of the dinner, she went to Boston, where son, Franklin Jr., was suffering from sinus trouble.
Not only did the 22-year-old Roosevelt have sinus trouble, he also had septic sore throat, and there was a possibility of Streptococcus haemolyticus, the magazine reported, which once in the bloodstream might destroy his red cells.
When Roosevelt's throat swelled and became raw and he developed a high fever, George Loring Tobey Jr., a Boston ear, nose, and throat specialist, according to the magazine, gave him hypodermic injections of what was then a little-known drug called Prontosil and oral doses of a modification called Protolyn. The story has, of course, a happy ending with Roosevelt rallying quickly.
This episode and the resultant publicity in Time and many other magazines and newspapers went far in making the "notable new drug"--Prontosil--and, subsequently, other sulfonamides, leading antibacterials.
Prontosil was developed by Gerhard Domagk, working in the Bayer sector of I. G. Farbenindustrie. In 1927, Domagk was appointed director of Bayer's Institute of Pathology & Bacteriology, where he began to test the effect of each newly synthesized dye on streptococci in vitro. If the dye seemed to attack the bacteria, Domagk would test the effect on mice.
In 1932, colleagues brought Domagk a new dye, sulfamidochrysoidine, called Prontosil Rubrum, for its red color. It seemed to have no effect on the bacteria in vitro, but he went ahead and tested it on 26 mice injected with streptococci. Fourteen were kept as controls, and 12 were treated after the injection with a large dose of the dye, administered by stomach tube. All of the controls died within a few days, while all of the treated mice survived.
Nobody knows why Domagk did not publish the results of his work until 1935, but speculation is that it may have been because Bayer wanted to keep the results secret until the drug was ready for patenting. This, ironically, was not to be.
News of the new antibacterial leaked out. Researchers at Pasteur Institute in Paris, after a request to Bayer for samples of the new drug was refused, were able to synthesize Prontosil or a reasonable facsimile. They found that the molecule was made up of two parts--triaminobenzene, which produced the red color, and p-aminobenzene sulfonamide, later known as sulfanilamide, which was the active part.
COURTESY OF BAYER |
IN THE LAB This portrait of Domagk was painted by Otto Dix. |
The patent problem arose because sulfanilamide had been synthesized by Austrian chemist Paul Gelmo and reported in his doctoral dissertation in 1908. It was used as a dye intermediate, and the patent on it had expired years before Domagk's discovery. Thus, any number of pharmaceutical companies rushed to produce and improve sulfa drugs. It is estimated that more than 5,000 compounds were prepared in the late 1930s and early 1940s, but only about 20 were shown to have any medical value.
Among these were sulfapyradine, used to treat pneumonia; sulfathiozole, used against both pneumonia and staphylococcal infections; sulfadiazine, used to treat pneumonococcal, streptococcal, and staphylococcal infections; and sulfaguanadine for dysentery.
Ironically, the drug's popularity brought tragedy as well as benefit. In 1937, S. E. Massengill Co., a small drug formulator in Bristol, Tenn., decided people might prefer a liquid form of the drug and mixed up a potion it called "Elixer of Sulfanilamide." Unfortunately, Massengill used diethylene glycol, a highly toxic chemical, as the solvent. Without making any tests, the "Elixer" was released, resulting in the deaths of 108 people, mostly children, largely from kidney and liver failure.
Massengill got off easy. Under U.S. regulatory laws in place at the time, the government was only able to seize the product because it was misbranded. To be called an elixir, ethanol had to be used. Massengill paid a $16,000 fine.
The tragedy did not stop sulfa drugs; the recognized benefits brought huge growth. In 1937, U.S. output was about 350,000 lb, doubling by 1940. By 1942, more than an estimated 10 million lb was produced in the U.S.
A significant reason for the growth between 1940 and 1942 was the use of sulfa drugs in the war effort. American soldiers were taught to sprinkle sulfa powder immediately on any open wound to prevent infection. To that end, every soldier was issued a first aid pack designed to be attached to his belt. In that pouch were a package of sulfa powder and a bandage to dress the wound. In addition, sulfa powder and sulfa tablets were main components of the combat medic's kit.
The story of sulfa drugs does not end with World War II, but it certainly slows down. They continued to be used for many bacterial infections well into the 1950s, although by then they were getting competition from newer antibacterials, beginning with the enormous popularity of penicillin in the 1950s.
Today their use is limited. The main use for sulfa drugs is as a treatment for urinary tract infections.