LOCAL ANAESTHETICS—THE ORIGINS OF LIGNOCAINE
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By the 1930s local
anaesthesia had become a much broader discipline. Many different nerve blocks
were being used including splanchnic and paravertebral blocks, caudal blocks
and even diagnostic and therapeutic sympathetic blocks. In a review of local
anesthesia in 1934, Matas wrote … the local anesthetist has outgrown his name
and primitive functions. He has now stepped into a new world of complex and
varied medical and surgical relations in which simple analgesia for the
prevention and suppression of surgical pain stands only as a symbol for the
primitive trunk of a tree which is now overshadowed by the foliage of its innumerable
ramifications. But the choice of drugs remained restricted. Procaine, being
relatively safe, was the most acceptable. Nupercaine and amethocaine had found
a place in spinal and topical anaesthesia but there was still no safe, long
acting drug with wide application. And there were no signs that anyone was
going to discover one. The next major development, the discovery of lignocaine,
happened completely by accident. In 1896, a 23-year-old German chemist, Hans
von Euler, moved to Stockholm to work with the famous Professor Svante
Arrhenius at Stockholm University. In 1929 he was awarded the Nobel Prize with
Sir Arthur Harden from London for their work on fermentation. His subsequent
research focused on genetics, trying to find chemical solutions to physiological
properties. His research focused on mutant barley strains that appeared to be
more resistant to insects. The result of this research was the isolation of a
compound named gramin which von Euler believed could have application as an
insecticide. He gave the task of synthesizing gramin to a young chemist, Holger
Erdtman. There were two isomers of gramin, and Erdtman, to his disappointment,
created the wrong one with his initial experiments. However he tested the new
compound, isogramin, for completeness. During the testing he tasted it and
discovered that his tongue went numb. While he quietly filed away this piece of
information the gramin project was unravelling. A German group published the
discovery before them and then others showed that gramin did not really confer
resistance to insects. Erdtman was now free to explore his new discovery.
Isogramin proved to be extremely poisonous but Erdtman felt that the local
anesthetic properties may also be found in the precursors used in its
manufacture. Further experiments concluded that an anilide produced as an
intermediate also produced anaesthesia of the tongue. In 1935, Nils Löfgren,
another young chemist, came to work with Erdtman. They produced sixteen
anilides with anaesthetic properties but none appeared to be superior to
procaine. They published their results in 1937 and Erdtman left the university
shortly after that. Löfgren continued his research, making compounds, numbering
them and testing them on his tongue. Compound LL30 probably went on the shelf
with all the others in about 1942. At this time an adventurous young chemistry
student, Bengt Lundqvist, joined Löfgren’s team. He realized that testing on
the tongue was not ideal and that the substances should be tested by injection.
Their laboratory did not contain experimental animals so he subjected himself
to all these experiments. He borrowed some articles on local anaesthesia from a
medical student friend, took some LL30 from the laboratory and performed a
series of digital and spinal blocks on himself in his home. He concluded that
compound LL30 was the best local anaesthetic substance that existed. Toxicology
tests were then carried out by Leonard Goldberg at the Karolinska Institute.
Fourteen days and hundreds of mice later, he had concluded that LL30 was far
superior to procaine. It was less toxic, more effective and seemed to have a
longer duration of action. Things moved fairly rapidly from there. Löfgren and
Lundquist applied for a patent on the July 15, 1943. In August they licensed
the product to Pharmacia for a two-week trial, but at the end of the two weeks,
no-one had contacted them. A great deal of indecision followed. The science
attaché to the US embassy offered them $15,000 for an immediate takeover, other
companies began to show an interest and reportedly ICI flew Löfgren in the tail
of a Mustang, a plane transporting ball bearings to England by night during the
war. Clearly Löfgren was acquiring his pupil’s sense of adventure. Eventually
they sold the patent to Astra on November 22, 1943. As part of the deal,
Löfgren and Lundquist retained a 4% royalty on all sales for seventeen years
and a payment of 15000 Swedish crowns. Astra was then faced with the problem of
mass production, which was difficult during wartime as there was a shortage of
raw materials. They chose the name Xylocain for the product and patented it in
27 countries. The initial testing was carried out by Torsten Gordh at the
Karolinska Hospital in Stockholm in 1945. At the conclusion of these tests,
Xylocain was registered on the November 21 1947 and released on to the market
in early 1948. Gordh summarized his findings in a Swedish medical journal: It
will fulfill the classic requirements of an ideal local anaesthetic, as it has
low toxicity, is nonirritant to tissues, is water soluble, can be sterilized
and permits storage with adrenaline. Lidocain has further, a fast and efficient
effect with sufficient duration and is, in my opinion, the most ideal of
hitherto-known local anaesthetics. It is further remarkably useful in all
areas, where any form of local anaesthesia can be performed. Unfortunately
neither of the designers of this drug really reaped its rewards. Löfgren became
wealthy but found himself excluded from many research grants as a result. He
suffered from many bouts of depression and eventually took his own life at the
age of 53. Lundqvist fractured his skull during a fall down some stairs at the
Institute. Later he bought a yacht with his royalties and, after a day of
diving under the boat to clean it, died of a cerebral haemorrhage at the age of
LOCAL ANAESTHETICS—THE ORIGINS OF LIGNOCAINE
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