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The story of sulfa drugs

The story of sulfa drugs(1)

Polish flag and war scenery

It all started on June 28, 1914, when a car on the streets of Sarajevo made a mistake in one corner. His 19-year-old Serbian student Gavrilo Princip, who was there, rushed to find out who the two were on the car by chance and quickly fired them one by one. The two, each shot through the neck and belly, die after tens of minutes.

The victims were Grand Duke Frandinant, the heir to the throne of the Austro-Hungarian Empire, and his wife Zoffy.

From here, things expand at an unpredictable rate. Austria, which lost its heir to the throne, declared war on Serbia in retaliation. When the Russian Empire, which was the backing of Serbia, promised support, Germany, France and Britain announced their participation in a billiard ceremony. After this, Japan and the United States also participated in the war, and the war expanded to a scale that covered the world. A little maze of cars in Sarajevo has brought humanity an unprecedented vortex.

In this war, that is, in World War I, the latest weapons such as chemical weapons and tanks were introduced, and the human damage was orders of magnitude greater than in previous wars. The total number of killed in action is estimated to be more than 10 million.

There are numbers that are often overlooked when it comes to the number of deaths in combat in World War I. That is, the number of people who died from infectious diseases from wounds was about the same as the number of soldiers who died directly from being injured by shells.

Infectious diseases are inherent on the battlefield, and it is strange that infectious diseases do not spread because soldiers who are weakened by fatigue and exposed to intense stress are densely placed in an unsanitary environment. ..

The oldest record of infectious diseases on the battlefield is the epidemic of "Athens' disease" in the Peloponnesian War, which began in 431 BC. An infectious disease struck the city of Athens, which had been fighting Sparta with siege tactics, causing damage to the loss of one-third of the population. Pericles, one of the leading politicians, also died of the disease, forcing Athens to surrender. The disease was once thought to be plague, but recent studies suggest that it is most likely smallpox or typhus.

The Roman Empire, which was in its heyday, was forced to withdraw during the Parthian War due to the outbreak of a disease that appeared to be smallpox, while keeping the capital of the enemy country falling. Emperor Napoleon I of France was also hit by the cold, hunger, and typhus in the Russian campaign, and more than 600,000 expeditionary forces were almost wiped out. In addition to this, there are many known examples in the history of the world where the outbreak of illness influenced the course of the war.

As the times change, the appearance of the battlefield changes, and the diseases that occur change accordingly. The weapons used in World War I have undergone major changes in quantity and quality compared to previous wars. Due to the extended range of guns and the large number of machine guns and cannons, it became difficult for both sides to approach the enemy. Naturally, the soldiers had no choice but to dig a trench and stand up. A long trench line from Switzerland to the Mediterranean was built, and the war, which was initially thought to end in about half a year, fell into a stalemate.

Humid and unsanitary pits were hotbeds for all pathogens. Dysentery. Typhus • Cholera, as well as lice-borne Q fever, were widespread among soldiers. When the battle begins, the soldiers are hurt by the rain and the flying shells, and they are covered with earth and sand.

This also caused a terrifying infection. There are bacteria in the soil called anaerobic bacteria that can only live in an airless environment, and they enter through the wound.

Tetanus is a well-known such infectious disease, but gas gangrene was the most problematic on the battlefield of World War I. This is caused by a bacterium called Clostridium Genus that enters through the wound and propagates. The gas released by gangrene accumulates under the skin and gives off a characteristic foul odor. Speaking of cure, there was no choice but to cut the area where the gangrene occurred. It goes without saying that the surgery itself performed at the field hospital was extremely painful and dangerous.

Furthermore, at the end of the Great War, the largest infectious disease in history, the Spanish flu, struck the world. This is known as the first and worst influenza pandemic on record. The disease broke out in the United States in the spring, and a wave of epidemics traveled around the world twice in a year and a half. It is estimated that 600 million people were infected and 50 million people were killed out of the world population of about 1.8 billion at that time (all figures are estimated, various theories).

The death toll from the Spanish flu far exceeded that of World War I, and is said to have been a factor in accelerating the end of the war.

The story of sulfa drugs(2)

Injecting from a dropper into a test tube in virus research

During and after World War I, the need for infectious disease control was higher than ever. Disinfectants that appeared in the 19th century had improved considerably, but were powerless against bacteria that had already grown in the body.

In the early 20th century, salvarsan, which is effective against the pathogen of syphilis, was developed by Ehrlich and Hata and others, paving the way for chemotherapy for infectious diseases. Inspired by this, many researchers have begun to search for compounds that are effective against various bacteria. But those attempts had little fruit in him. Some were effective in vitro but not in vivo. Some killed pathogens efficiently, but also had a strong negative effect on laboratory animals.

Ehrlich himself worked energetically to create a drug that would follow salvarsan. But all the compounds he tested by the time he died at the age of 61 had failed. The only successful example, salvarsan, was also severely criticized for its strong side effects. The stress he received here may have shortened his life.

In the mid-1920s, pessimism was widespread in how chemicals were used to treat infectious diseases. Some remedies have emerged, but none have been adequately effective against tropical protozoan infections. Chemotherapy remains powerless against the bacterial infections that have plagued humanity, such as cholera, plague, and dysentery. Many people withdrew from research because they gave up on the fact that bacteria could not be defeated with the weapon of chemical substances.

There were those who dared to challenge this seemingly hopeless territory and invest huge amounts of money and personnel. It was Hörlein, head of the pharmaceutical research division at I.G. Falben, a giant chemical contour in Germany.

Hörlein needed a good pathologist to create a truly effective drug. It was young researcher Gerhard Domagk who read the treatises in the relevant fields and made a white arrow. At a local university, suffering from a lack of research funding, he jumps at Hörlein's invitation. Thus, in 1927, Gerhard Domagk's talent was combined with the world's best research environment.

Gerhard Domagk was a medic in the Ukrainian battlefield when he was young and witnessed the dire situation of gas gangrene. He was determined to fight this bacterial infection, which claimed the lives and limbs of many of his companions, for a lifetime.

Gerhard Domagk set up his research system in a building built for him. Should be tested

A team for synthesizing compounds, a team for investigating the effects on various pathogens, a team for investigating what kind of reaction occurred in the body of laboratory animals, etc. were formed, and a system that works in an orderly manner was constructed. If Ehrlich and Qin created the prototype for drug discovery, then Gerhard Domagk was the first to put in place a modern drug discovery system.

They were very German and worked hard. Gerhard Domagk himself conducted the experiment on "histopathological examination", in which the organs of experimental animals were sliced ​​thinly and stained to confirm the site of infection, without leaving it to others. However, even four years after the start of the project, no light was visible.

The veins were finally found in the summer of 1931. Dye compounds that have supported the prosperity of the German chemical industry include a group of compounds called azo compounds. These were compounds in which two nitrogen atoms were bonded so that two benzene rings were sandwiched between them. While trying various parts bonded to this benzene ring, I found one that was more effective than ever. Some of them not only extended the lives of infected laboratory animals, but even completely restored them.

But the joy of the team didn't last long. The test results are not stable. Even a slight change in the fabrication would change the effect completely, and even if the same product was made and retested, the original results were often not reproduced. We have already tested about 3000 compounds, and even if we try to synthesize a new compound that breaks through the situation, new ideas are already exhausted.

When you run out of ideas, bringing in ideas from other disciplines often leads to good results. At this time, the new proposal was made by Hörlein himself, the head of the pharmaceutical research division. When he searched for a dye to dye wool, he experienced that when he attached an atomic group containing a sulfur atom called a namide group to the benzene ring, it became a dye that was hard to remove. His idea was that a compound that easily binds to wool might also easily bind to bacteria.

In the fall of 1932, a sulfonamide group was attached to an azo compound and his compound was synthesized. The results of administering the synthesized wine red compound to animals were truly amazing. When the compound was given orally or by injection to a streptococcal-infected mouse, almost everything was completely recovered.

Unbelievable, the result was too good, and the team retested many times, but Maus was still sick. The only side effect was that the skin became reddish for a while after administration. It was the moment when humans first acquired an effective weapon against bacterial infections that had been plagued for a long time. Since this compound contains sulfur, it will be called a sulfa agent.

As it turned out later, the azo group, which was initially thought to be the main body of the action of sulfa drugs, was not directly related to the action of killing bacteria. The sulfonamide group, which was introduced to facilitate binding to bacteria, was the key to its antibacterial activity. It was found that even a simple compound (pure sulfa) that does not have an azo group and has only a sulfonamide moiety has a high antibacterial effect, and currently only this compound is used.

The story of sulfa drugs(3)

suck up the drug with a syringe

No matter how great a mouse works, there is no guarantee that it will work the same in humans. The opportunity to test the effects of sulfa drugs on the human body came in an unexpected way. In December 1935, Gerhard Domagk's daughter Hildegard had a needle stuck in her hand and broke in her. The needle was surgically removed, but her wound became purulent and worsened. Domagk decided, as the fever caused him to lose consciousness and even consider amputating his arm. He took out the sulfa drug that was in the laboratory and administered it to his daughter. After several days of medication, Hildegard's fever had diminished and had fully recovered by Christmas. The one that does not act on the human body and works only on bacteria was born here.

A year later, "Red Miracle Powder" will make its name known to the world. Sulfonamide rescued the son of Franklin Roosevelt, who was now the incumbent President of America, from the brink of death. When this was reported, global demand for sulfa drugs exploded. Pharmaceutical companies around the world have begun to make and sell sulfa drugs with similar structures.

Applicable diseases have spread to pneumonia, puerperal fever, meningitis, etc., as well as streptococcal infections. In 1941, the United States alone produced millions of sulfa drugs annually, and it is estimated that perhaps 500,000 lives were saved. Sulfa drugs have revolutionized medicine.

In 1939, Gerhard Domagk, the creator of this miracle drug, was awarded the Nobel Prize in Physiology or Medicine. It was an award befitting that achievement.

However, at that time, the situation in the world had already entered a dark era. Germany's invasion of Poland. The Nazi administration, which had invaded Poland and started World War II, had ordered the Germans to be banned from receiving the Nobel Prize. Domagk had to decline with tears, the highest honor for scientists. It was in 1947, after the end of the war, that Domagk was fine and accepted.

Unfortunately, the field of activity of sulfa drugs became the battlefield of World War II. In the German army, powdered sulfa drugs were sprinkled on soldiers when they were injured, dramatically reducing the gas gangrene that prevailed in World War I. Domagk's wish to eradicate gas gangrene with his own hands was fulfilled.

On New Guinea Island, which was a fierce battlefield of the Pacific War, the Japanese army has killed a total of 100,000 people, but the death toll from dysentery and malaria accounted for a large proportion. On the other hand, the Allied Forces, which carried large amounts of sulfa drugs, suffered from dysentery in 10,000 people, but only two died. For this reason, Japanese guards are said to have used that technique in an attempt to obtain sulfa drugs from US POWs.

In World War I, respiratory illnesses such as pneumonia caused as many as 50,000 casualties in the United States. However, in World War II, despite doubling the number of soldiers in the sortie, only 1,265 people died of respiratory illness. Official records from the US military indicate that the spread of sulfa drugs was a major factor.

Soldiers are not the only ones saved by sulfa drugs. In December 1943, Churchill, the Prime Minister of England, who was flying around in the cold wind to meet with world leaders, fell into pneumonia in Tunisia. As a result of the administration of sulfa drugs by a group of doctors from all over the world, Churchill's physical condition recovered and he was able to return home two weeks later. If this was the effect of sulfa drugs, then this alone deserves the name of "history-changing drug". Looking at this, it seems that the "miracle medicine" born under the Nazi administration, ironically, contributed more to the Allied side and helped the victory.

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