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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/09/13 04:56:06」(JST)

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The structure of Arsphenamine has been proposed to be akin to the azobenzene (A), but mass spectral studies published in 2005 suggest^[1] it is actually a mixture of the trimer B and the pentamer C.

Arsphenamine, also known as Salvarsan or compound 606, is a drug that was introduced at the beginning of the 1910s as the first effective treatment for syphilis, and was also used to treat trypanosomiasis.^[2] This organoarsenic compound was the first modern chemotherapeutic agent.

History

First synthesized in 1907 in Paul Ehrlich's lab by Alfred Bertheim,^[3] the antisyphilitic activity of this compound was discovered by Sahachiro Hata in 1909, during a survey of hundreds of newly synthesized organic arsenical compounds. Ehrlich had theorized that by screening many compounds, a drug could be discovered with antimicrobial activity without killing the human patient. Ehrlich's team began their search for such a "magic bullet" among chemical derivatives of the dangerously toxic drug atoxyl. This project was the first organized team effort to optimize the biological activity of a lead compound through systematic chemical modifications, the basis for nearly all modern pharmaceutical research.

Arsphenamine was used to treat the disease syphilis because it is toxic to the bacterium Treponema pallidum, a spirochete that causes syphilis.

Arsphenamine was originally called "606" because it was the sixth in the sixth group of compounds synthesized for testing; it was marketed by Hoechst AG under the trade name Salvarsan in 1910.^[4]^[5] Salvarsan was the first organic antisyphilitic, and a great improvement over the inorganic mercury compounds that had been used previously. It was distributed as a yellow, crystalline, hygroscopic powder that was highly unstable in air.^[6] This significantly complicated administration, as the drug had to be dissolved in several hundred milliliters of distilled, sterile water with minimal exposure to air to produce a solution suitable for injection. Some of the side effects attributed to Salvarsan, including rashes, liver damage, and risks of life and limb,^[7] were thought to be caused by improper handling and administration, causing Ehrlich, who worked assiduously to standardize practices, to observe, "the step from the laboratory to the patient's bedside ... is extraordinarily arduous and fraught with danger." ^[4]

Ehrlich's laboratory developed a more soluble (but slightly less effective) arsenical compound, Neosalvarsan (neoarsphenamine), which was easier to prepare, and it became available in 1912. Less severe side-effects such as nausea and vomiting were still common. An additional problem was that both Salvarsan and Neosalvarsan had to be stored in sealed vials under a nitrogen atmosphere to prevent oxidation. These arsenical compounds were supplanted as treatments for syphilis in the 1940s by penicillin.^[8]

After leaving Ehrlich's laboratory, Hata continued parallel investigation of the new medicines in Japan.^[9]

Structure

Salvarsan has long been assumed to have an As=As double bond, akin to the N=N linkage in azobenzene. However, in 2005, an extensive mass spectral analysis Salvarsan was shown to have As-As single bonds, not As=As double bonds. The drug was also found to be a mixture consisting of cyclo-As₃ and cyclo-As₅ species.^[1]^[4]^[10]

References

^ ^a ^b Lloyd NC, Morgan HW, Nicholson BK, Ronimus RS (2005). "The composition of Ehrlich's salvarsan: resolution of a century-old debate". Angew. Chem. Int. Ed. Engl. 44 (6): 941–4. doi:10.1002/anie.200461471. PMID 15624113.
^ Gibaud, Stéphane; Jaouen, Gérard (2010). "Arsenic - based drugs: from Fowler's solution to modern anticancer chemotherapy". Topics in Organometallic Chemistry. Topics in Organometallic Chemistry. 32: 1–20. doi:10.1007/978-3-642-13185-1_1. ISBN 978-3-642-13184-4.
^ Williams KJ (2009). "The introduction of 'chemotherapy' using arsphenamine - the first magic bullet". J R Soc Med. 102: 343–8. doi:10.1258/jrsm.2009.09k036. PMC 2726818. PMID 19679737.
^ ^a ^b ^c "Salvarsan". Chemical & Engineering News. Retrieved 2010-02-01.
^ In Germany, it was the practice to designate compounds by their development number. Another compound known commonly in Germany by its number is parathion, which was the 605th compound to be developed in search for insecticide. It is commonly known as E605 (E stands for Entwicklungsnummer (German for "development number"))
^ "A Handbook of Useful Drugs". American Medical Association. 1913. Retrieved 2010-08-17.
^ http://archive.protomag.com/assets/paul-ehrlich-and-the-salvarsan-wars
^ Bosch F, Rosich L (2008). "The contributions of Paul Ehrlich to pharmacology: a tribute on the occasion of the centenary of his Nobel Prize". Pharmacology. 82: 171–9. doi:10.1159/000149583. PMC 2790789. PMID 18679046.
^ Izumi, Yoshio; Isozumi, Kazuo (2001). "Modern Japanese medical history and the European influence" (free download pdf). Keio Journal of Medicine. 50 (2): 91–99. doi:10.2302/kjm.50.91. PMID 11450598.
^ http://www.rsc.org/chemistryworld/2013/04/salvarsan-podcast

UpToDate Contents

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1. ヒ素曝露と中毒 arsenic exposure and poisoning

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The treatment of syphilis with salvarsan.

Dufty NE, Leverton D.
Journal of the Royal Army Medical Corps.J R Army Med Corps.2014 Jun;160 Suppl 1:i21-3. doi: 10.1136/jramc-2014-000288.
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Metalloid compounds as drugs.

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The six elements commonly known as metalloids are boron, silicon, germanium, arsenic, antimony, and tellurium. Metalloid containing compounds have been used as antiprotozoal drugs. Boron-based drugs, the benzoxaboroles have been exploited as potential treatments for neglected tropical diseases. Arse
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[Dawn of the antibiotic era and some consequences for the present].

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The beginning of antibiotic era is traditionally ascribed to Fleming's discovery of penicillin in 1928. From the modern view, however, the term "antibiotic" includes all antibacterial drugs for oral or parenteral administration, regardless of their origin (microbial products or chemical compounds).
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Japanese Journal

症例 Arsphenamine(サルバルサン)の皮下注射による皮膚石灰沈着症の1例

千代丸康治,山田陽三
皮膚科の臨床 51(6), 785-787, 2009-06
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日本における薬物性肝障害の実態-過去70年間の薬物性肝障害症例-

鮫島美子,塩崎安子,水野孝子,笹川美年子
日本消化器病学会雑誌 81(1), 37-45, 1984
… 1223, chemotherapeutic drugs 1174, cardiovascular drugs 879, carcinostatic agents 604, hormones and hormone antagonists 452, diagnostic aids 370, and other drugs 725.Ten of the most common drugs which caused hepatic injury were chephalosporins, penicillins, thorium dioxide, arsphenamine, aminoglycosides, ethionamide, refampicine, macrolides, 4, 4'-diethylaminoethoxy hexestrol, cholrpromazine in descending order of frequency.The common clinical symptoms were gastrointestinal complaints, jaundice, fever, hepatomegaly and less frequently skin eruption.Approxim …
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Drug-induced Hepatic Injury:A Review of the Japanese Articles for the Past 50 Years

鮫島美子,水野孝子,笹川美年子,塩崎安子,龍見幸二
日本消化器病学会雑誌 73(10), 1214-1221, 1976
… of the most common drugs which caused hepatic injury were arsphenamine sodium, thorium dioxide, 4, 4'-diethylaminoethoxy hexestrol, ethionamide, chlorpromazine, erythromycin estolate, sulfonamide, PAS, rifampicin, ajmaline in descending order of frequency.Most of the cases were diagnosed on the basis of clinical history, however, in some cases, readministration test, skin test, macrophage migration inhibitory test and lymphocyte transformation test of suspected drug was also performed as diagnostic aid.The most common drugs reported to have high …
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