Paracetamol: From Discovery to Widespread Use

The development of paracetamol began with the discovery of the fever-lowering effect of acetanilide, a finding that eventually led to the development of phenacetin by Bayer. Paracetamol, also known as N-acetyl-p-aminophenol, was synthesized by Bayer’s chemists in 1888. Despite its synthesis, it was not initially tested for its medicinal properties.

In 1893, paracetamol was clinically evaluated by Dr. Josef von Mering, a student of Oswald Schmiedeberg. Dr. von Mering discovered that the drug produced methemoglobinemia, a condition where hemoglobin is converted to methemoglobin, which cannot carry oxygen effectively. However, he mistakenly attributed this adverse effect directly to paracetamol, leading to the compound being ignored for its potential medicinal benefits.

Nearly a century later, paracetamol was reinvestigated in the United States at Yale University by David Lester and C. A. Greenberg. Their research demonstrated that paracetamol was the major metabolite of acetanilide and phenacetin and was relatively safe as an analgesic and antipyretic. This reinvestigation sparked renewed interest in the compound's potential.

Simultaneously, researchers Flinn and Brodie found that even at high oral doses, paracetamol did not result in the formation of methemoglobin. This finding further supported the safety profile of paracetamol, paving the way for its acceptance as a therapeutic agent.

In 1950, the first paracetamol product, a combination of paracetamol, aspirin, and caffeine, was introduced to the United States market under the name Triagesic. This combination product marked the beginning of paracetamol's widespread use as a pain reliever and fever reducer.

Today, paracetamol is one of the most commonly used over-the-counter medications for pain relief and fever reduction, recognized for its efficacy and safety when used as directed. Its journey from an overlooked compound to a household staple highlights the importance of revisiting and reevaluating scientific findings with fresh perspectives and advanced research methods.
Paracetamol: From Discovery to Widespread Use

David Lester (1916-1990) of Rutgers University

David Lester was an American biochemist. He was born on January 22 in 1916.

In 1893, paracetamol was discovered for the first time in human urine from a man who had been treated with phenacetain. It was only after the Second World War that David Lester and Leon Greenberg came across this discovery for a second time.

David Lester and C. A Greenberg demonstrated that paracetamol was the major metabolite of acetanilide and phenacetin, and was relatively safe as an analgesic and antipyretic.
David Lester of Rutgers University

Dr. von Mering and paracetamol

Paracetamol had been synthesized in 1877 at Johns Hopkins University in Baltimore. It had no evidence medical value and thereafter had simply sat on a shelf for sixteen years.

In 1893, P-hydroxy-acetanilide was evaluated clinically by Dr. von Mering (1849-1908), who found that the drug produced methemoglobinemia.

Von Mering collaborated with the Bayer Company in a clinical trial of P-hydroxy-acetanilide, which it was postulated to be a metabolite of phenacetin by Trefuel and Hinsberg in1894.

He published a paper reporting on the clinical results of paracetamol with phenacetin, another aniline derivative. Von Mering claimed that, P-hydroxy-acetanilide to be effective antipyretic and analgesic, but believed it also had a tendency to produce methemoglobinemia.

Paracetamol was then quickly discarded in favor of phenacetin. It would remain, unused and apparently useless, for nearly half a century until it was rescued.

Von Mering's claims remained essentially unchallenged for half a century, until two teams of researchers from the United States analyzed the metabolism of acetanilide and paracetamol.

Paracetamol was reinvestigated half a century later by David Lester and Leon Greenberg from Yale University, who showed that it was indeed a metabolite of phenacetin in humans. In 1947 they found strong evidence that paracetamol was a major metabolite of acetanilide in human blood.

Lester and Greenberg demonstrated that paracetamol was the major metabolite so acetanilide and phenacetin and was relatively safe as an analgesic and antipyretic. In a subsequent study they reported that large doses of paracetamol given to albino rats did not cause methemoglobinemia.
Dr. von Mering and paracetamol

Discovery of Paracetamol

The development of paracetamol began with the discovery of the fever lowering effect of acetanilide, a founding that resulted in the development of phenacitin by Bayer.

Paracetamol, N-acetyl-p-aminophenol, was a derivative synthesized by Bayer’s chemists in 1888 by Bayer but never tested for medicinal properties.

In 1893, it was evaluated clinically by Dr. von Mering, Schmiedeberg’s former student, who found that the drug produced methemoglobinemia.

However he believed mistakenly that it produced methemoglobinemia as an adverse effect and the compound was ignored.

A century later, paracetamol was reinvestigated in the United States, at the University of Yale by David Lester and C. A Greenberg, who demonstrated that paracetamol was the major metabolite of acetanilide and phenacetin, and was relatively safe as an analgesic and antipyretic.

At the same time, Flinn and Brodie found that even at high oral doses, paracetamol is not attended by the formation of methemoglobin.

In 1950 the first paracetamol product – a combination of paracetamol, aspirin and caffeine was in the United States market under the name Triagesic.
Discovery of Paracetamol