Editing Arsphenamine

{{Short description|Antibiotic drug introduced in the 1910s}}
[[File:Salvarsan-montage (cropped).png|thumb|right|170px|The structure of arsphenamine has been proposed to be akin to [[azobenzene]] (top). Salvarsan is now assumed to be a mixture of the trimer (middle) and the pentamer (bottom).<ref name="pmid15624113"/>]]
'''Arsphenamine''', also known as '''Salvarsan''' or '''compound 606''', is an [[antibiotic]] [[medication|drug]] that was introduced at the beginning of the 1910s as the first effective treatment for the deadly [[infectious disease]]s [[syphilis]], [[relapsing fever]], and [[African trypanosomiasis]].<ref name='ITOM'>{{cite book |last1=Gibaud |first1=Stéphane |last2=Jaouen |first2=Gérard |title=Medicinal Organometallic Chemistry |chapter=Arsenic-Based Drugs: From Fowler's Solution to Modern Anticancer Chemotherapy |year=2010 |volume=32 |pages=1–20 |series=Topics in Organometallic Chemistry |bibcode=2010moc..book....1G |isbn=978-3-642-13184-4 |doi=10.1007/978-3-642-13185-1_1}}</ref><ref>{{cite book |last1=Ehrlich |first1=Paul |last2=Hata |first2=Sahachiro |last3=Newbold |first3=A. |last4=Felkin |first4=Robert W. |oclc=3225081 |title=The Experimental Chemotherapy of Spirilloses |publisher=Rebman |location=New York |year=1911 |language=en}}</ref>
This [[organoarsenic chemistry|organoarsenic compound]] was the first modern [[antimicrobial agent]].<ref name=Williams/>

==History==
{{Main|Magic bullet (medicine)}}
[[File:Salvarsan treatment kit for syphilis, Germany, 1909-1912 Wellcome L0057814.jpg|thumb|right|Salvarsan treatment kit for syphilis, Germany, 1909–1912<ref>{{cite web |title=Salvarsan treatment kit for syphilis, Germany, 1909–1912 – Wellcome Collection |website=Wellcome Collection |url=https://wellcomecollection.org/works/dvfqcxyz|access-date=26 October 2018}}</ref>]]
Arsphenamine was first synthesized in 1907 in [[Paul Ehrlich]]'s lab by [[Alfred Bertheim]].<ref name=Williams>{{cite journal |volume=102 |issue=8 |title=The introduction of 'chemotherapy' using arsphenamine - the first magic bullet |year=2009 |journal=J R Soc Med |pages=343–48 |author=Williams KJ |pmid=19679737 |doi=10.1258/jrsm.2009.09k036 |pmc=2726818}}</ref> The antisyphilitic activity of this compound was discovered by [[Sahachiro Hata]] in 1909, during a survey of hundreds of newly synthesized organic [[arsenic]]al compounds. Ehrlich had theorized that by screening many compounds, a drug could be discovered that would have anti-microbial activity but not kill the human patient. Ehrlich's team began their search for such a "[[magic bullet (medical)|magic bullet]]" among chemical derivatives of the dangerously toxic drug [[atoxyl]].

Arsphenamine was used to treat the disease [[syphilis]] because it is toxic to the [[bacterium]] ''[[Treponema pallidum]]'', a [[spirochete]] that causes syphilis.<ref>{{cite journal |last=Abraham |first=J. Johnston |title=Some Account of the History of the Treatment of Syphilis* |date=December 1948 |journal=British Journal of Venereal Diseases |volume=24 |issue=4 |pages=153–160 |issn=0007-134X |pmid=18099878 |doi=10.1136/sti.24.4.153 |pmc=1053609}}</ref>

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.<ref name=acs>{{cite magazine |title=Salvarsan |magazine=[[Chemical & Engineering News]] |last=Yarnell |first=Amanda |volume=83 |issue=25 |date=20 June 2005 |url=http://pubs.acs.org/cen/coverstory/83/8325/8325salvarsan.html |access-date=2010-02-01}}</ref><ref>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 a search for insecticides. It is commonly known as [[E605]] (E stands for ''Entwicklungsnummer'', German for "development number").</ref> Salvarsan was the first organic antisyphilitic, and a great improvement over the inorganic [[mercury (element)|mercury]] compounds that had been used previously. It was distributed as a yellow, crystalline, [[hygroscopy|hygroscopic]] powder that was highly unstable in air.<ref name=":0">{{cite book |chapter-url=http://chestofbooks.com/health/materia-medica-drugs/American-Medical-Association/A-Handbook-of-Useful-Drugs/Salvarsan-Salvarsan-N-N-R.html |title=A Handbook of Useful Drugs |chapter=Salvarsan, N. N. R. |author=State Medical Examining and Licensing Boards |publisher=Press of the [[American Medical Association]] |year=1913 |access-date=17 August 2010}}</ref> 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, were thought to be caused by improper handling and administration.<ref>{{cite magazine |title=Paul Ehrlich and the Salvarsan Wars |date=Spring 2010 |magazine=[[Proto (magazine)|Proto]] |url=http://archive.protomag.com/assets/paul-ehrlich-and-the-salvarsan-wars |access-date=21 February 2015 |url-status=dead |archive-url=https://web.archive.org/web/20150221234212/http://archive.protomag.com/assets/paul-ehrlich-and-the-salvarsan-wars |archive-date=21 February 2015}}</ref> This caused 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."<ref name=acs/>

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]].<ref>{{cite journal |volume=82 |issue=3 |title=The contributions of Paul Ehrlich to pharmacology: a tribute on the occasion of the centenary of his Nobel Prize |year=2008 |vauthors=Bosch F, Rosich L |journal=Pharmacology |pages=171–79 |pmid=18679046 |doi=10.1159/000149583 |pmc=2790789}}</ref>

After leaving Ehrlich's laboratory, Hata continued parallel investigation of the new medicines in [[Japan]].<ref>{{cite journal |author1=Izumi, Yoshio |author2=Isozumi, Kazuo |year=2001 |format=free download pdf |title=Modern Japanese medical history and the European influence |journal=Keio Journal of Medicine |volume=50 |pages=91–99 |issue=2 |pmid=11450598 |doi=10.2302/kjm.50.91 |doi-access=free |url=http://www.kjm.keio.ac.jp/past/50/2/91.pdf |url-status=live |archive-url=https://web.archive.org/web/20050329181525/http://www.kjm.keio.ac.jp/past/50/2/91.pdf |archive-date=2005-03-29}}</ref>

==Structure==
Salvarsan has long been assumed to have an As=As [[double bond]], akin to the N=N linkage in [[azobenzene]]. However, in 2005, in an extensive [[mass spectrometry|mass spectrometric analysis]], the arsenic–arsenic bonds in Salvarsan were shown to be single bonds rather than double bonds. Presumed to consist of RAs=AsR molecules, i.e. (RAs)<sub>2</sub>, Salvarsan was found to actually contain a mixture of cyclo-(RAs)<sub>3</sub> and cyclo-(RAs)<sub>5</sub> species, where R is the 3-amino-4-hydroxyphenyl [[moiety (chemistry)|moiety]].<ref name="pmid15624113">{{cite journal |vauthors=Lloyd NC, Morgan HW, Nicholson BK, Ronimus RS |title=The composition of Ehrlich's salvarsan: resolution of a century-old debate |journal=Angew. Chem. Int. Ed. Engl. |volume=44 |issue=6 |pages=941–944 |year=2005 |pmid=15624113 |doi=10.1002/anie.200461471 |doi-access=free |hdl=10289/207 |url=https://researchcommons.waikato.ac.nz/bitstream/10289/207/1/content.pdf |url-status=live |archive-url=https://web.archive.org/web/20170506105634/http://researchcommons.waikato.ac.nz/bitstream/10289/207/1/content.pdf |archive-date=2017-05-06}}</ref><ref>{{cite web |title=Salvarsan (podcast) |date=22 December 2010 |work=[[Chemistry World]] |publisher=[[Royal Society of Chemistry]] |last=Robinson |first=Philip |url=https://www.chemistryworld.com/podcasts/salvarsan/3005937.article |access-date=16 December 2019}}</ref> According to Nicholson,<ref name="pmid15624113">{{cite journal |vauthors=Lloyd NC, Morgan HW, Nicholson BK, Ronimus RS |title=The composition of Ehrlich's salvarsan: resolution of a century-old debate |journal=Angew. Chem. Int. Ed. Engl. |volume=44 |issue=6 |pages=941–944 |year=2005 |pmid=15624113 |doi=10.1002/anie.200461471 |doi-access=free |hdl=10289/207 |url=https://researchcommons.waikato.ac.nz/bitstream/10289/207/1/content.pdf |url-status=live |archive-url=https://web.archive.org/web/20170506105634/http://researchcommons.waikato.ac.nz/bitstream/10289/207/1/content.pdf |archive-date=2017-05-06}}</ref> these cyclic species slowly release an oxidised species, RAs(OH)<sub>2</sub>, that is likely responsible for Salvarsan's antisyphilis properties.<ref name=acs/>

==See also==
* ''[[Dr. Ehrlich's Magic Bullet]]'', the 1940 film about Ehrlich's quest to find a cure for syphilis.
* [[Arsenicin A]], an organoarsenic molecule found in nature with similar activity.

==References==
{{Reflist}}

[[Category:Amines]]
[[Category:Antibiotics]]
[[Category:Antiparasitic agents]]
[[Category:German inventions]]
[[Category:Organoarsenic compounds]]
[[Category:Paul Ehrlich]]
[[Category:Phenols]]
[[Category:Syphilis]]
[[Category:1907 in biology]]
[[Category:1907 in Germany]]