Neostigmine and Pyridostigmine
Thomas Willis (1621–1675), Mary Walker (1888–1974)
FROM MYASTHENIA GRAVIS TO GULF WAR SYNDROME. The earliest report of myasthenia gravis (MG) appeared in 1672, when Thomas Willis, famed English anatomist and physician, wrote of a woman “who temporarily lost her power of speech and became ‘mute as a fish.’” More common symptoms of this nerve-muscle disorder include drooping eyelids and weakness of the arms and legs, particularly after exercise.
In 1934, physostigmine was used as an antidote for curare poisoning. Scottish physician Mary Walker thought that because MG symptoms resembled the muscle weakness caused by curare poisoning, a curare-like substance circulating in the blood might cause the disorder. She administered physostigmine to several of her patients. “Then . . . like Lazarus rising from the grave, they rose and walked across the room” (Jane Ellsworth, 1952).
Physostigmine acts by prolonging the effects of acetylcholine (ACh). After being released from nerve endings, the neurotransmitter chemical ACh crosses a synapse or gap and activates receptors on muscles, causing them to contract. Physostigmine is an anticholinesterase agent that acts by blocking the enzyme cholinesterase (responsible for the inactivation of ACh), thereby increasing ACh’s ability to cause muscle contractions.
In 1935, Walker tested neostigmine, a physostigmine-like drug first synthesized in 1931, and found it far superior. When injected, neostigmine caused more forceful muscle contractions that persisted far longer, with fewer side effects. The next significant advance for treating MG was pyridostigmine (Mestinon), which appeared in 1959. It is taken by mouth, has fewer side effects, and acts for an even longer period—particularly, overnight.
During the Persian Gulf War of 1990–1991, U.S. troops were given pyridostigmine to prevent the toxic effects and mortality associated with exposure to the nerve gas soman. While the conclusions are highly controversial, it has been argued that pyridostigmine, when taken with insect repellents, may have contributed to the Gulf War Syndrome, whose very diverse symptoms include memory problems, fatigue, joint pain, dizziness, and skin and immune system conditions.
SEE ALSO Curare (1850), Physostigmine (1875), Drug Receptors (1905), Neurotransmitters (1920), Tabun and Sarin (1936).
Patients with advanced cases of myasthenia gravis experience profound weakness of the extremities. Mary Walker’s first public demonstration that neostigmine could temporarily reverse these symptoms was likened to Lazarus rising from the grave.