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【答案】应助回帖
感谢参与，应助指数 +1
One hundred years ago, the first reports of Paul Ehrlich's “magic bullet,” Salvarsan 606, a novel approach to the treatment of infectious diseases, appeared in the U.S. medical literature. The initial article in the Journal was published on March 9, 1911, and described the use of Salvarsan in a single case of “chronic pemphigus” affecting a farmer from Linn County, Kansas. A week later, Captain Harold Jones reported on 20 soldiers with syphilis — whose names were given — treated with Salvarsan at Walter Reed General Hospital.[ 1]
In the ensuing months and years, the medical literature was awash with articles, letters, and book reviews on the magic bullet. Results of its use in thousands of patients were provided; battle lines were drawn between the old guard who stood by the time-tested mercurials and the young bucks who insisted that newer was better.[ 2] When the dust finally settled, Salvarsan stood as the undisputed champion, and the way in which therapies were developed and distributed had undergone a profound change. The era of what Ehrlich had dubbed “chemotherapy” — medical therapy with chemicals — had begun.
Ehrlich's work came at a heady moment in science. Louis Pasteur and Robert Koch had made their seminal observations about microbial pathogenesis; ether had become widely available, revolutionizing surgery; and the discoveries of Marie Curie and Wilhelm Roentgen had introduced the radiograph, radically altering the way the body was perceived. Medical science was the world's new darling — able, it seemed, to fix just about any problem. Modernity, with all its shiny-package appeal (and obligate nostalgia), had arrived.
Ehrlich's imagination and wide interests were of a piece with the audacity of the moment.[ 3] Fascinated by many phenomena, he was particularly intrigued by the discriminatory behavior of dyes in human tissue. He reasoned that since dyes were taken up preferentially by certain cells and cell structures and not by others, a “magic bullet” could be created that similarly struck only the intended target, leaving the surrounding cells untouched.
Arsenic-based compounds had long been known to have activity against an array of medical conditions. Hippocrates had written of the benefit of a naturally occurring form, orpiment, and the element appeared in various concoctions over the ensuing centuries. Arsenic was the key component in Fowler's solution, which was formulated more than 200 years ago and was used to treat leukemia and other ailments well into the 20th century. Indeed, arsenic-based therapies endure even today: arsenic trioxide was approved by the Food and Drug Administration in 2000 for the treatment of acute promyelocytic leukemia.
A chemical conjunction of arsenic and a dye had been formulated in 1869 by the French scientist Antoine Béchamp, whose main interest was the silkworm. He recognized the promise of arsenicals and sought to attenuate their toxicity by adding the dye aniline. His work was mostly ignored for 40 years, until Walter Schild, a German physician, used the compound (now called Atoxyl to suggest reduced toxicity) to treat skin conditions.[ 4] Then in 1905, Harold Wolferstan Thomas of the Liverpool School of Tropical Medicine studied the drug for the treatment of sleeping sickness, a lethal form of trypanosomiasis.
Thomas was aware of veterinary literature demonstrating the efficacy (but also the toxicity) of arsenic compounds given for equine and bovine trypanosomiasis. He reasoned that a less toxic drug such as Atoxyl might allow repeated and prolonged administration, so he studied its effects in experimentally infected monkeys, rabbits, and various rodents.
Ehrlich recognized the importance of Thomas's work and assembled a team that included Sahachiro Hata and the organic chemist Alfred Bertheim. Once they had clarified the structure of Atoxyl, they set out to “adjust” it chemically to increase its potency and reduce its toxicity. They approached the task with the thoughtful, methodical precision that characterized all Ehrlich's work: Bertheim synthesized more than 900 compounds, most derived from Atoxyl, while Hata studied candidate drugs in rabbits.[ 4]
The team inched forward, compound by compound, until they hit upon the right balance of activity and safety. Arsphenamine was the 606th compound tested and soon became known under the proprietary name Salvarsan 606. Because of solubility problems, Ehrlich et al. soon formulated neoarsphenamine (Neosalvarsan, compound no. 914). In the 1930s, the drug was further refined into Mapharsen, the active moiety of the original compound. This was the drug of choice for syphilis until the introduction of penicillin a decade later.
The speed with which Ehrlich's big idea was transformed into a drug in hand for daily clinical use is staggering, making it an early poster child for translational medicine. Within a year after the first clinical reports came out, it had been given to thousands of people.[ 3] Establishment of appropriate dosing and route of administration proved to be a substantial hurdle. There was also the matter of the brand name to be considered: as early as 1911, the number 606 had become so strongly associated with syphilis that it was reportedly “dropped as a telephone number in several exchanges.”[ 5]
Almost as swiftly as the drug was distributed, however, its limitations became evident. It was ineffective for late complications of syphilis, especially neurosyphilis. Relapses requiring retreatment were common. Furthermore, the list of toxic effects mounted as more doses were delivered: renal failure, optic neuritis, seizures, fever, rash — medical journals were chock-full of the latest.
Whatever Salvarsan's shortcomings, however, Ehrlich's pursuit of a cure for syphilis established the standard model for investigation of new compounds, an approach that's still in use. Furthermore, the ups and downs of Salvarsan's fate are familiar to anyone who has performed clinical trials of a novel agent. After a long, hard slog, a new drug for a pressing disease is identified; hope abounds. Early success is reported — perhaps this is the big one; hope abounds. The first reports of therapeutic failure arrive; hope falters. Reports mount of toxic effects, some of them severe; hope sinks and skids toward despair. Then, over time, more experience allows the new drug to find its rightful place, to settle into the wide middle ground between salvation and catastrophe.
But more than providing lessons for today's scientists regarding “best practices” for drug investigation and development, the Salvarsan story illuminates the one essential attribute that separated Ehrlich from the other brilliant scientists of a century ago: Ehrlich showed that one must dream big in order to move science forward. Though modest in demeanor, he acted boldly, daring to formulate a cure to the most common devastating infection of his time. To achieve that aim, he plowed through hundreds of compounds, battled back against criticism and doubt of colleagues, and made countless adjustments in mid-air to optimize the drug and its delivery.
In the end, perhaps his dream of the silver bullet was larger than his actual achievement; we still struggle to cure syphilis, and antibiotics have proven anything but perfect. But surely we must forgive Ehrlich his enthusiasm: without his boundless optimism, that cornerstone of all scientific inquiry, we might still be injecting mercury salts.
References
1 Jones HW Report of a series of cases of syphilis treated by Ehrlich's arsenobenzol at the Walter Reed General Hospital, District of Columbia. Boston Med Surg J 1911;164:381-383
2 French HC Salvarsan (“606”) and mercury in the treatment of syphilis. Lancet 1911;178:326-327
3 Schwartz RS Paul Ehrlich's magic bullets. N Engl J Med 2004;350:1079-1080
4 Riethmiller S From Atoxyl to Salvarsan: searching for the magic bullet. Chemotherapy 2005;51:234-242
5 Unfortunate connotation of "606 “ Boston Med Surg J 1911;164:591-591
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By Kent A. Sepkowitz, from the Memorial Sloan-Kettering Cancer Center, New York
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