Succimer

{{Short description|Medication used to treat lead, mercury, and arsenic poisoning}}

{{Infobox drug

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| image = Meso-2,3-dimercaptosuccinic-acid-2D-skeletal-A-configurations-labelled.png

| image_class = skin-invert-image

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| image2 = DMSA-3D-balls.png

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| pronounce = {{IPAc-en|ˈ|s|ʌ|k|s|ᵻ|m|ər}}

| tradename = Chemet, others

| Drugs.com = {{Drugs.com|monograph|succimer}}

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| DailyMedID = Succimer

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| ATC_prefix = V03

| ATC_suffix = AB

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| legal_US = Rx-only

| legal_US_comment = {{cite web | title=Chemet- succimer capsule | work = DailyMed | publisher = U.S. National Library of Medicine | date=12 December 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=62035612-9505-3a3f-1ac8-e2dbd711d24e | access-date=19 June 2022}}{{cite web | title=Nephroscan- succimer injection, powder, lyophilized, for solution | work = DailyMed | publisher = U.S. National Library of Medicine | date=1 March 2022 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ddd90c4a-5792-49c9-837f-710d1a604742 | access-date=19 June 2022}}{{cite web | title=Rotop - DMSA- kit for the preparation of technetium tc99m succimer injection injection, powder, lyophilized, for solution | work = DailyMed | publisher = U.S. National Library of Medicine | date=9 March 2021 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fa643e8a-a8d2-4868-92ad-98dd17e92172 | access-date=19 June 2022}}

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| CAS_number = 304-55-2

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| PubChem = 2724354

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| DrugBank = DB00566

| ChemSpiderID = 2006502

| UNII = DX1U2629QE

| KEGG = D00572

| ChEBI = 63623

| ChEMBL = 1201073

| NIAID_ChemDB =

| synonyms = Dimercaptosuccinic acid
DMSA
(2R,3S)-2,3-Dimercaptosuccinic acid
meso-2,3-Dimercaptosuccinic acid
APRD01236

| IUPAC_name = (2R,3S)-2,3-disulfanylbutanedioic acid

| C=4

| H=6

| O=4

| S=2

| SMILES = O=C(O)[C@@H](S)[C@@H](S)C(=O)O

| StdInChI = 1S/C4H6O4S2/c5-3(6)1(9)2(10)4(7)8/h1-2,9-10H,(H,5,6)(H,7,8)/t1-,2+

| StdInChI_Ref = {{stdinchicite|changed|chemspider}}

| StdInChIKey = ACTRVOBWPAIOHC-XIXRPRMCSA-N

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| melting_point = 125

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Succimer, sold under the brand name Chemet among others, is a medication tool used to treat lead, mercury, and arsenic poisoning.{{cite web|title=Succimer|url=https://www.drugs.com/monograph/succimer.html|publisher=The American Society of Health-System Pharmacists|access-date=8 January 2017|url-status=live|archive-url=https://web.archive.org/web/20170116185406/https://www.drugs.com/monograph/succimer.html|archive-date=16 January 2017}} When it's radiolabeled with technetium-99m, it's used in many types of diagnostic testing.{{cite book| vauthors = Biersack HJ, Grünwald F |title=Thyroid Cancer|date=2005|publisher=Springer Science & Business Media|isbn=9783540278450|page=213|url=https://books.google.com/books?id=lncDay233rYC&pg=PA213|language=en|url-status=live|archive-url=https://web.archive.org/web/20170113131649/https://books.google.ca/books?id=lncDay233rYC&pg=PA213|archive-date=2017-01-13}}

Common side effects include vomiting, diarrhea, rash, and low blood neutrophil levels. Liver problems and allergic reactions may also occur with use. Whether use during pregnancy is safe for the baby is unclear.{{cite web|title=Succimer (Chemet) Use During Pregnancy|url=https://www.drugs.com/pregnancy/succimer.html|website=www.drugs.com|access-date=12 January 2017|url-status=live|archive-url=https://web.archive.org/web/20170116183703/https://www.drugs.com/pregnancy/succimer.html|archive-date=16 January 2017}}

Dimercaptosuccinic acid is in the chelating agent family of medications. It binds to a metal atom, leading to increased clearance from the body via the urine. A full course of Succimer lasts for 19 days of oral administration. A second course should be given when more than two weeks pass after the first course.

Succimer has been used medically since the 1950s.{{cite journal | vauthors = Miller AL | title = Dimercaptosuccinic acid (DMSA), a non-toxic, water-soluble treatment for heavy metal toxicity | journal = Alternative Medicine Review | volume = 3 | issue = 3 | pages = 199–207 | date = June 1998 | pmid = 9630737 }}{{cite book| vauthors = Chappell WR, Abernathy CO, Calderon RL |title=Arsenic Exposure and Health Effects III|date=1999|publisher=Elsevier|isbn=9780080527574|page=350|url=https://books.google.com/books?id=YMsi_gdILu4C&pg=PA350|language=en|url-status=live|archive-url=https://web.archive.org/web/20170113131749/https://books.google.ca/books?id=YMsi_gdILu4C&pg=PA350|archive-date=2017-01-13}} It is on the World Health Organization's List of Essential Medicines.{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }} In the United States, no generic version was available as of 2015.{{cite book| vauthors = Hamilton R |title=Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition|date=2015|publisher=Jones & Bartlett Learning|isbn=9781284057560|page=472}}

Medical uses

Succimer is indicated for the treatment of lead poisoning in children with blood level measured above 45 μg/dL. The use of dimercaptosuccinic acid is not approved for prevention of lead poisoning in anticipation of exposure in known lead-contaminated environments. Dimercaptosuccinic acid can cross the blood–brain barrier of mice,{{cite journal | vauthors = Aaseth J, Jacobsen D, Andersen O, Wickstrøm E | title = Treatment of mercury and lead poisonings with dimercaptosuccinic acid and sodium dimercaptopropanesulfonate. A review | journal = The Analyst | volume = 120 | issue = 3 | pages = 853–854 | date = March 1995 | pmid = 7741240 | doi = 10.1039/an9952000853 | bibcode = 1995Ana...120..853A }} but it is not known if this is also the case in humans.{{cite journal | vauthors = Guzzi G, La Porta CA | title = Molecular mechanisms triggered by mercury | journal = Toxicology | volume = 244 | issue = 1 | pages = 1–12 | date = February 2008 | pmid = 18077077 | doi = 10.1016/j.tox.2007.11.002 | bibcode = 2008Toxgy.244....1G }} Even if dimercaptosuccinic acid cannot reverse the damages done to the central nervous system, it might prevent further deterioration.{{cite journal | vauthors = Clarkson TW, Magos L, Myers GJ | title = The toxicology of mercury--current exposures and clinical manifestations | journal = The New England Journal of Medicine | volume = 349 | issue = 18 | pages = 1731–1737 | date = October 2003 | pmid = 14585942 | doi = 10.1056/nejmra022471 }}

Succimer facilitates urinary excretion of lead, and with sufficiently aggressive treatment, can reduce lead content in the brain.{{cite journal | vauthors = Smith D, Strupp BJ | title = The scientific basis for chelation: animal studies and lead chelation | journal = Journal of Medical Toxicology | volume = 9 | issue = 4 | pages = 326–338 | date = December 2013 | pmid = 24113857 | pmc = 3846979 | doi = 10.1007/s13181-013-0339-2 }} It also increases urinary excretion of copper and zinc.{{cite journal | vauthors = Bradberry S, Sheehan T, Vale A | title = Use of oral dimercaptosuccinic acid (succimer) in adult patients with inorganic lead poisoning | journal = QJM | volume = 102 | issue = 10 | pages = 721–732 | date = October 2009 | pmid = 19700440 | doi = 10.1093/qjmed/hcp114 | doi-access = free }} Dimercaptosuccinic acid improved cognitive function in rats that had been exposed to lead, but reduced cognitive function in rats that had not been exposed to lead.

Chemistry

Succimer is an isomer of 2,3-dimercaptosuccinic acid. 2,3-dimercaptosuccinic acid is the organosulfur compound with the formula HO₂CCH(SH)CH(SH)CO₂H. This colorless solid contains two carboxylic acid and two thiol groups, the latter being responsible for its mildly unpleasant odour. It occurs in two diastereomers, meso and the chiral dl forms.

The 2,3-dimercaptosuccinic acid molecule has two stereocentres (two asymmetric carbon atoms), and can exist as three different stereoisomers. The 2S,3S and 2R,3R isomers are a pair of enantiomers, whereas the 2R,3S isomer (succimer) is a meso compound and thus optically inactive.

class="wikitable" style="text-align:center;"

| File:(2R,3R)-2,3-dimercaptosuccinic-acid-2D-skeletal-A-configurations-labelled.png

File:Meso-2,3-dimercaptosuccinic-acid-2D-skeletal-A-configurations-labelled.png

File:(2S,3S)-2,3-dimercaptosuccinic-acid-2D-skeletal-A-configurations-labelled.png

File:(2R,3R)-2,3-dimercaptosuccinic-acid-2D-skeletal-B-configurations-labelled.png

File:Meso-2,3-dimercaptosuccinic-acid-2D-skeletal-B-configurations-labelled.png

File:(2S,3S)-2,3-dimercaptosuccinic-acid-2D-skeletal-B-configurations-labelled.png

(2R,3R)-2,3-dimercaptosuccinic acid

(2R,3S)-2,3-dimercaptosuccinic acid
(meso-2,3-dimercaptosuccinic acid)

(2S,3S)-2,3-dimercaptosuccinic acid

Preparation and reactivity

Dimercaptosuccinic acid{{clarify|reason=which isomer or a mix?|date=April 2023}} may be prepared by reacting acetylenedicarboxylic acid with sodium thiosulfate{{ref patent | country =US | title = Process for the preparation of 2,3-dimercaptosuccinic acid and its lower alkyl esters | number = 4550193 | inventor = Lindemann MK, Lukenbach ER | assign1 = Johnson & Johnson Baby Products | gdate = 29 October 1985 }} or thioacetic acid followed by hydrolysis. The dimethyl ester is also known.{{cite journal | vauthors = Gerecke M, Friedheim EA, Brossi A | title = Zur Kenntnis der 2,3-Dimercapto-bernsteinsäuren | journal = Helvetica Chimica Acta | year = 1961 | volume =44 | issue = 4 | pages = 955–960 | doi = 10.1002/hlca.19610440410}}

Meso 2,3-dimercaptosuccinic acid binds to "soft" heavy metals such as Hg²⁺ and Pb²⁺, mobilizing these ions for excretion. It binds to metal cations through the thiol groups, which ionize upon complexation.

History

Dimercaptosuccinic acid was first synthesized by V. L. Nirenburg in the Urals Polytechnic Institute, commissioned by one of the electrical enterprises of Sverdlovsk, Russia, which consumed many tons of mercury and was looking for a medicine to prevent poisoning of personnel. In 1957, Chinese scientists found that dimercaptosuccinic acid can effectively treat antimony poisoning due to overdose of tartar emetic.{{cite journal| vauthors = Liang Y, Chu C, Tsen Y, Ting K |year= 1957|title= Studies on antibilharzial drugs. Vl. The antidotal effects of sodium dimercaptosuccinate and BAL-glucoside against tartar emetic.|journal= Acta Physiol. Sin.|volume= 21|pages=24–32}} Pronounced protective effect in animal poisoning with arsenic and mercury was first shown by I. E. Okonishnikova in 1962. In 1984, the now-defunct Bock Pharmaceutical Company requested the FDA grant approval for orphan drug status under the brand name Chemet and the FDA approved of this in 1991. It provided exclusivity until 1998 which was conveyed to the successor Sanofi in 1996.{{cite web |url=http://www.accessdata.fda.gov/scripts/opdlisting/oopd/OOPD_Results_2.cfm?Index_Number=001984 |title=Search Orphan Drug Designations and Approvals |author= |date=2013 |website=Searchable database for Orphan Designated and or Approved Products. |publisher=FDA |access-date=5 November 2014 |url-status=dead |archive-url=https://web.archive.org/web/20141106095648/http://www.accessdata.fda.gov/scripts/opdlisting/oopd/OOPD_Results_2.cfm?Index_Number=001984 |archive-date=6 November 2014 }}{{cite news |author= |date=July 17, 1996 |title=Sanofi Buying An American Drug Concern |url=https://www.nytimes.com/1996/07/17/business/sanofi-buying-an-american-drug-concern.html |newspaper=The New York Times |access-date=5 November 2014 |url-status=live |archive-url=https://web.archive.org/web/20141106085741/http://www.nytimes.com/1996/07/17/business/sanofi-buying-an-american-drug-concern.html |archive-date=6 November 2014 }}

Succimer

Medical uses

Chemistry

Preparation and reactivity

History

References

Further reading