Paracetamol History and Development

Widely employed as a medicinal remedy, paracetamol functions both as a pain reliever and fever reducer, celebrated for its analgesic and antipyretic properties. Its inception can be traced back to 1893 at the University of Strasbourg, where Professor Adolf Kussmaul tasked assistants Arnold Cahn and Paul Hepp with administering naphthalene treatment to patients. Despite the intended antiseptic effect being limited, the identification of paracetamol in the urine of patients who had ingested phenacetin resulted in a significant reduction in fever.

In 1887, Bayer introduced phenacetin as a less harmful alternative to acetanilide, solidifying the company's standing as a pharmaceutical leader. Despite its initial success, concerns regarding carcinogenicity and kidney damage led to a decline in phenacetin usage after approximately 90 years.

Recognized as a urinary metabolite of acetanilide in 1889, paracetamol did not garner much attention at the time. It wasn't until 1948-1949, when Brodie and Axelrod unveiled paracetamol as the primary metabolite of both acetanilide and phenacetin, that interest in paracetamol experienced a resurgence. Their research revealed that both acetanilide and phenacetin underwent metabolism into paracetamol, endowing them with their antipyretic and analgesic properties.

In 1950, the initial paracetamol product, Triagesic, containing paracetamol, aspirin, and caffeine, entered the U.S. market but was promptly withdrawn due to reported cases of blood diseases. Subsequent confirmation that paracetamol was not linked to blood damage paved the way for its reintroduction to the American market by 1955.

The year 1956 marked the introduction of 500 mg paracetamol tablets in the UK, swiftly gaining popularity as an over-the-counter analgesic. Its appeal was partly attributed to its gentler impact on the stomach compared to certain other pain relievers.
Paracetamol History and Development

History of phenacetin

Phenacetin (or acetophenetidin) is used as an analgesic and antipyretic drug for human and animals.  It was widely used between its introduction in 1887 and the 1983 ban imposed by the FDA on its use in the United States.

Phenacetin was marketed in 1888 and it could be stated that the development of phenacetin should be regarded as the beginning of the pharmaceutical industry in its modern form. It was introduced by the Bayer Company.

Phenacetin was first prepared by C. Hinsberg in 1887 who was seeking a use for a quantity of p-nitrophenol that he had a accumulated as a byproduct of dye works. Bayer’s chemists synthesized some derivatives of which the 4-epoxy acetanilide was less toxic, and was marketed as an analgesic and antipyretic under the name of phenacetin.

Phenacetin was a highly successful product and established the Bayer Company as a leading pharmaceutical manufacturer.

Phenacetin was first produced in the United States in the 1920s. Total annual sales of phenacetin for medical use were estimated to be less than 640,000 kg by the late 1970s.

Phenacetin was widely used for about 90 years until mounting concerns over carcinogenicity and kidney-damaging properties in chronic treatment.
History of phenacetin

Dr. von Mering (28 February 1849, in Cologne – 5 January 1908)

Joseph Freiha von Mering was born in Halle an der Saale, Germany. He was well versed in pharmacology, laryngology and internal medicine and learned biochemistry from Hoppe-Seyler.

He studied in Bonn and in Greifswald, a small Prussian university town which had earlier joined the Hanseatic League. He graduated from the University of Strasbourg in 1873.
In 1877, Harmon Northrop Morse synthesized paracetamol at Johns Hopkins University by way of p-nitrophenol with tin in arctic acetic acid.

But it was not until 1887 that clinical pharmacologist Joseph von Mering attempted paracetamol on patients.

In 1893, von Mering issued a document informing on the clinical results of paracetamol with phenacetin, another aniline differential. Von Mering asserted that, unlike phenacetin, paracetamol had a small propensity to produce methemoglobinemia.

Paracetamol was then rejected in favor of phenacetin. It was not until the 1940s that paracetamol was reinvestigated after it was found present in proteins closed with phenacetin.

In 1889 together with Oskar Minkowski, von Mering discovered the direct connection between the pancreas and diabetes which led to the discovery of insulin. They found that the pancreas supplies a hormone essential to glucose metabolism. He reported in 1890 that the surgical removal of the pancreas from a healthy animal would cause diabetes.

Mering joined Naunyn’s Strasbourg Clinic of Internal Medicine, and in 1890 was appointed Associate Professor of Medicine at the outpatient department of Halle, Germany, and in 1900 as full professor of Internal Medicine in Medical Policlinic of Halle.

In 1903, Mering developed the chemicals structure of a drug that might produce sleep. Unable to synthesize the compound himself, he asked the great Emil Fisher at the University of Berlin for help and it was Fisher’s group that created the first of the barbiturates.
Dr. von Mering (28 February 1849, in Cologne – 5 January 1908)

History of Paracetamol

Paracetamol is a very widely used as medicine. It is painkiller and reduces the temperature of patients with fever.

These actions are known respectively as analgesic and antipyretic.

In 1893, the white, odorless crystalline compound with a bitter taste that became known as paracetamol was discovered.

This happened at University of Strasburg when Professor Adolf Kussmaul, Department of Internal Medicine , asked two young assistants, Arnold Cahn and Paul Hepp, to treat patients with naphthalene as it had been used elsewhere as an internal antiseptic.

The medicine had little effect on worms, but, paracetamol was found in the urine of patients who had taken phenacetin, who had a great reduction in fever temperature.

In 1887, the Bayer company introduced the 4-ethoxy derivative, phenacetin, as a less toxic analogue of acetanilide.

It was highly successful product and established the Bayer Company as a leading pharmaceutical manufacturer.

Phenacetin was widely used for about 90 years until mounting concerns over carcinogecity and kidney damaging properties.

In 1889 it was demonstrated that paracetamol was a urinary metabolite of acetanilide. These discoveries, however, failed to attract much attention and were largely ignored at the time.

The use of paracetamol was first reported in 1893 by von Mehring who concluded that because of its hematological side effects of methaemoglobinaemia, it could not be recommended despite prompt antipyretic and analgesic actions.

It 1948-1949, Brodie and Axelrod discovered that paracetamol was the main metabolite of both acetanilide and phenacetin, that paracetamol experienced a resurgence of interest. As a derivative of p-aminophenol, paracetamol corresponds to the active principal metabolite phenacetin.

Their investigations showed that both acetanilide and phenacetin were metabolized into paracetamol and to which they owed their antipyretic and analgesic properties.

It was eventually ascertained that phenacetin had its own pharmacological action and was not dependent on paracetamol for its effects.

Because a high proportion of phenacetin is converted into paracetamol in the liver, however, phenacetin required a large dosage to achieve any direct analgesic effect.

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

Due to the report that Triagesic had been stricken with blood diseases, agranulocytoses, a sudden severe drop of white blood cell, it was immediately removed form the market.

Within a few years when became apparent that paracetamol had not connection with blood damage, by 1955 paracetamol was back in the American market.

In 1956, 500 mg tablets of paracetamol went on sale in the United Kingdom and its popularity as an over-the-counter analgesic rapidly increased.

This popularity was partly explained by the fact that paracetamol was proven to be easier on the stomach than some other analgesics.
History of Paracetamol