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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/07/17 22:32:55」(JST)

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Dimercaptosuccinic acid (DMSA), 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 meso isomer is used as a chelating agent. The acid is most often used as a treatment for heavy metal toxicity, and is a water soluble and non-toxic substance.^[2]

History

DMSA was first synthesized by V. Nirenburg in the Urals Polytechnic Institute, commissioned by one of the electrical enterprises of Sverdlovsk, which consumed many tons of mercury and was looking for a medicine to prevent poisoning of personnel. In 1957, it was found by Chinese scientists that DMSA can effectively treat antimony poisoning due to overdose of tartar emetic.^[3] Pronounced protective effect in animal poisoning with arsenic and mercury was first shown by I. Okonishnikova in 1962. In 1984 the now-defunct Bock Pharmaceutical Company requested the FDA grant approval for Orphan drug status under the trade name Chemet and the FDA approved of this in 1991 providing exclusivity until 1998 which was conveyed to the successor Sanofi in 1996.^[4]^[5]

Stereochemistry

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



(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

DMSA may be prepared by reacting acetylenedicarboxylic acid with sodium thiosulfate^[6] or thioacetic acid followed by hydrolysis. The dimethyl ester is also known.^[7]

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.

Medical use

Dimercaptosuccinic acid (CHEMET) is indicated for the treatment of lead poisoning in children with blood level measured above 45 µg/dL. The use of DMSA is not approved for prophylactic/prevention of lead poisoning in anticipation of exposure in known lead contaminated environments. Its elimination half-life is 2.5-3.5 h. DMSA can cross the blood–brain barrier of mice,^[8] but not that of humans, limiting its use to extracting heavy metals from parts of the body other than the central nervous system.^[9]^[10]

Another application for DMSA is for provocation of tissue heavy metals in anticipation of a urine test. This is sometimes called a "challenge" or "provoked" heavy metals test. DMSA is used to help mobilize heavy metals stored in body tissues (and therefore not typically present in the circulation) and increase the excretion of heavy metals in the urine. In a study by Howard Frumkin et al., this sort of test was shown to not reliably provide an indication of past chronic mercury exposure, something it was often used for.^[11] A 2004 study by GP Archbold, et al. called the results of a DMSA challenge test "misleading" for the purposes of diagnosing mercury toxicity.^[12] Moreover, DMSA share the limitation of extracellular distribution, which makes it unable to cross the cell membrane and chelate heavy metals from intracellular sites.

The relative activities of a series of novel monoalkyl esters of meso-2,3-dimercaptosuccinic acid (MiADMSA) have been examined as agents for the mobilization of cadmium,^[13] lead ^[14] and arsenic ^[15] owing to the ability of these monoesters to cross cell membranes. The monoesters were found to be more effective than the parent compound DMSA. The complexes (monoesters of DMSA) seem to penetrate cells (not possible in the case of DMSA), which helps in targeting intracellular sites in the body and aids in the removal of toxic metal ions in the cytosol and organelles inside the cell.

References

^ Merck Index, 11th Edition, 8854.
^ Miller, Alan (June 1998). "Dimercaptosuccinic acid (DMSA), a non-toxic, water-soluble treatment for heavy metal toxicity.". Alternative Medicine Review 3 (3): 199–207. PMID 9630737.
^ Liang, Y., Chu. C, Tsen, Y., Ting, K. (1957). "Studies on antibilharzial drugs. Vl. The antidotal effects of sodium dimercaptosuccinate and BAL-glucoside against tartar emetic.". Acta Physiol. Sin. 21: 24–32.
^ "Search Orphan Drug Designations and Approvals". Searchable database for Orphan Designated and or Approved Products. FDA. 2013. Retrieved 5 November 2014.
^ "Sanofi Buying An American Drug Concern". New York Times (New York, NY). July 17, 1996. Retrieved 5 November 2014.
^ US 4550193, Lindemann, Martin K. O. & Lukenbach, Elvin R., "Process for the preparation of 2,3-dimercaptosuccinic acid and its lower alkyl esters", assigned to Johnson & Johnson Baby Products
^ M. Gerecke, E. A. H. Friedheim, A. Brossi (1961). "Zur Kenntnis der 2,3-Dimercapto-bernsteinsäuren". Helvetica Chimica Acta 44 (4): 955–960. doi:10.1002/hlca.19610440410.
^ Aasath, Jan; Dag Jacobsen; Ole Andersen; Elsa Wickstrøm (March 1995). "Treatment of Mercury and Lead Poisonings with Dimercaptosuccinic Acid (DMSA) and Sodium Dimercaptopropanesulfonate (DMPS)". Analyst 120: 853ff. doi:10.1039/an9952000853.
^ Rooney, James (2007). "The role of thiols, dithiols, nutritional factors and interacting ligands in the toxicology of mercury". Toxicology 234 (3): 145–156. doi:10.1016/j.tox.2007.02.016. PMID 17408840.
^ Guzzi, GianPaolo; Caterina A.M. La Porta (2008). "Molecular mechanisms triggered by mercury". Toxicology 244 (1): 1–12. doi:10.1016/j.tox.2007.11.002. PMID 18077077.
^ Frumkin H, Manning CC, Williams PL et al. (February 2001). "Diagnostic chelation challenge with DMSA: a biomarker of long-term mercury exposure?". Environ. Health Perspect. 109 (2): 167–71. doi:10.1289/ehp.01109167. PMC 1240638. PMID 11266328. Retrieved 2010-12-20.
^ Archbold GP, McGuckin RM, Campbell NA (May 2004). "Dimercaptosuccinic acid loading test for assessing mercury burden in healthy individuals". Ann. Clin. Biochem. 41 (Pt 3): 233–6. doi:10.1258/000456304323019622. PMID 15117439. Retrieved 2010-12-20.
^ Jones MM, Singh PK, Gale GR, Smith AB and Atkins LM. (May 1992). "Cadmium mobilization in vivo by intraperitoneal or oral administration of monoalkyl esters of meso-2,3-dimercaptosuccinic acid in the mouse". Pharmacology & Toxicology 70 (5 Pt 1): 336–343. doi:10.1111/j.1600-0773.1992.tb00483.x. PMID 1319053.
^ Walker EM Jr, Stone A, Milligan LB, Gale GR, Atkins LM, Smith AB, Jones MM, Singh PK and Basinger MA. (Nov 1992). "Mobilization of lead in mice by administration of monoalkyl esters of meso-2,3-dimercaptosuccinic acid". Toxicology 76 (1): 79–87. doi:10.1016/0300-483x(92)90020-f. PMID 1335621.
^ Kreppel H, Reichl FX, Kleine A, Szinicz L, Singh PK and Jones MM. (Jul 1995). "Antidotal efficacy of newly synthesized dimercaptosuccinic acid (DMSA) monoesters in experimental arsenic poisoning in mice". Fundamental & Applied Toxicology 26 (2): 239–245. doi:10.1093/toxsci/26.2.239. PMID 7589912.

UpToDate Contents

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English Journal

High-Salinity Growth Conditions Promote Tat-Independent Secretion of Tat Substrates in Bacillus subtilis.

van der Ploeg R, Monteferrante CG, Piersma S, Barnett JP, Kouwen TR, Robinson C, van Dijl JM.SourceDepartment of Medical Microbiology, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands.
Applied and environmental microbiology.Appl Environ Microbiol.2012 Nov;78(21):7733-44. doi: 10.1128/AEM.02093-12. Epub 2012 Aug 24.
The Gram-positive bacterium Bacillus subtilis contains two Tat translocases, which can facilitate transport of folded proteins across the plasma membrane. Previous research has shown that Tat-dependent protein secretion in B. subtilis is a highly selective process and that heterologous proteins, suc
PMID 22923407

Rotavirus capsid surface protein VP4-coated Fe(3)O(4) nanoparticles as a theranostic platform for cellular imaging and drug delivery.

Chen W, Cao Y, Liu M, Zhao Q, Huang J, Zhang H, Deng Z, Dai J, Williams DF, Zhang Z.SourceDivision of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, PR China.
Biomaterials.Biomaterials.2012 Nov;33(31):7895-902. doi: 10.1016/j.biomaterials.2012.07.016. Epub 2012 Jul 28.
The development of a theranostic nanoplatform based on rotavirus structural protein VP4-coated Fe(3)O(4) nanoparticles (NPs) for dual modality magnetic resonance/fluorescence cellular imaging and drug delivery is reported. VP4 protein was obtained from Escherichia coli approach, and then chemically
PMID 22841921

Japanese Journal

Rapid estimation of split renal function in kidney donors using software developed for computed tomographic renal volumetry

Kato Fumi,Kamishima Tamotsu,Morita Ken,Muto Natalia S.,Okamoto Syozou,Omatsu Tokuhiko,Oyama Noriko,Terae Satoshi,Kanegae Kakuko,Nonomura Katsuya,Shirato Hiroki
European Journal of Radiology 79(1), 15-20, 2011-07
… The correlation with split renal function (SRF) using 99mTc-DMSA scintigraphy was also investigated. …
NAID 120003118165

Carcinoma Infection and Immune Systems of Ehrlich Ascites Carcinoma-Bearing Mice Treated with Structurally Similar Sulfonium Compounds

NAKAJIMA Kenji,NAKAJIMA Yoshiki
Bioscience, biotechnology, and biochemistry 75(4), 808-811, 2011-04-23
… The effects of intraperitoneal administration of dimethylsulfonioacetate (DMSA), dimethlsulfoniopropionate (DMSP), and methylmethionine (MeMet) solutions (10 mM each) on the body weights and the hematological parameters (red and white blood cells) of Ehrlich ascites carcinoma (EAC)-bearing mice were examined for up to 10 d. … Body weights significantly increased in the EAC-bearing mice treated with and without MeMet in contrast to those with DMSA and DMSP. …
NAID 10028272068

Related Pictures

★リンクテーブル★

リンク元	「鉛中毒」「ジメルカプトコハク酸」「succimer」「2,3-dimercaptosuccinic acid」「キドニーシンチ」
拡張検索	「99mTc-DMSA」
関連記事	「DM」「DMS」

「鉛中毒」

Dimercaptosuccinic acid^[1]
Names
	IUPAC name meso-2,3-dimercaptosuccinic acid
	Other names succimer, APRD01236 (Drugbank), Chemet
Identifiers
CAS Registry Number	304-55-2
ChEMBL	ChEMBL1201073
ChemSpider	2006502
EC number	259-952-2
	InChI InChI=1S/C4H6O4S2/c5-3(6)1(9)2(10)4(7)8/h1-2,9-10H,(H,5,6)(H,7,8)/t1-,2+ ; Key: ACTRVOBWPAIOHC-XIXRPRMCSA-N ; InChI=1/C4H6O4S2/c5-3(6)1(9)2(10)4(7)8/h1-2,9-10H,(H,5,6)(H,7,8)/t1-,2+; Key: ACTRVOBWPAIOHC-XIXRPRMCBX ;
Jmol-3D images	Image
PubChem	2724354
	SMILES O=C(O)[C@@H](S)[C@@H](S)C(=O)O ;
UNII	DX1U2629QE
Properties
Chemical formula	C4H6O4S2
Molar mass	182.22 g/mol
Melting point	125 °C (257 °F; 398 K)
Related compounds
Related	Tartaric acid
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
	verify (what is: /?)
	Infobox references

　　[★]

英: lead poisoning
同: 鉛化合物中毒
関: 鉛、鉛中毒予防規則

first aid step1 2006 p.103,206,298

sulfhydryl groupを持つ酵素に結合

pyruvate dehydrogenase, α-ketoglutarate dehydrogenase

病態生理

酵素活性を阻害

ポルフィリン合成系路の障害

アミノレブリン酸デヒドラターゼ　→　赤血球プロトポルフィリン増加、尿中コプロポルフィリン増加
フェロケラターゼの阻害　→　尿中ALA増加

症状

貧血、悪心・嘔吐、唾液分泌亢進、腹痛、下痢、知覚異常、疼痛、血圧低下、運動失調、血尿、腎障害、呼吸麻痺など

検査

血液検査

網赤血球：増加
赤血球寿命：短縮

治療

CaNa2-EDTAの筋注、D-ペニシラミン経口投与 (SUB12.389)
DMSA経口投与、CaNa2-EDTA経口投与。エビデンスが弱いがアスコルビン酸も血中の鉛濃度を下げるので、治療の選択肢となるかもしれない。 (参考1)

参考

1. [charged] Adult lead poisoning - uptodate [1]

国試

103E047

「ジメルカプトコハク酸」

　　[★]

英: dimercaptosuccinic acid, DMSA, 2,3-dimercaptosuccinic acid
同: サクシマー succimer
関: テクネチウム99m-DMSA

商品名？：CHEMET
鉛中毒の際のキレート剤として使われる。日本で使われているかは不明。
http://www.chelation.org/ja/chelating-agents/

「succimer」

　　[★]

関: dimercaptosuccinic acid、DMSA、succimer, DMSA, Chemet、2,3-dimercaptosuccinic acid

「2,3-dimercaptosuccinic acid」

　　[★] 2,3-ジメルカプトコハク酸

同: succimer, DMSA, Chemet

「キドニーシンチ」

　　[★] 2,3-ジメルカプトコハク酸(DMSA)

関: 放射性医薬品

「99mTc-DMSA」

　　[★]

英: technetium-99m-DMSA
同: テクネチウム99m-DMSA、ジメルカプトコハク酸テクネチウム(99mTc) technetium(99mTc) dimercaptosuccinic acid
関: ジメルカプトコハク酸, dimercaptosuccinic acid, DMSA、腎シンチグラフィ

「DM」

　　[★]

「DMS」

　　[★]

dimethyl sulfate
diffuse mesangial sclerosis

[1] Merck Index, 11th Edition, 8854.

[2] Miller, Alan (June 1998). "Dimercaptosuccinic acid (DMSA), a non-toxic, water-soluble treatment for heavy metal toxicity.". Alternative Medicine Review 3 (3): 199–207. PMID 9630737.

[3] Liang, Y., Chu. C, Tsen, Y., Ting, K. (1957). "Studies on antibilharzial drugs. Vl. The antidotal effects of sodium dimercaptosuccinate and BAL-glucoside against tartar emetic.". Acta Physiol. Sin. 21: 24–32.

[4] "Search Orphan Drug Designations and Approvals". Searchable database for Orphan Designated and or Approved Products. FDA. 2013. Retrieved 5 November 2014.

[5] "Sanofi Buying An American Drug Concern". New York Times (New York, NY). July 17, 1996. Retrieved 5 November 2014.

[6] US 4550193, Lindemann, Martin K. O. & Lukenbach, Elvin R., "Process for the preparation of 2,3-dimercaptosuccinic acid and its lower alkyl esters", assigned to Johnson & Johnson Baby Products

[7] M. Gerecke, E. A. H. Friedheim, A. Brossi (1961). "Zur Kenntnis der 2,3-Dimercapto-bernsteinsäuren". Helvetica Chimica Acta 44 (4): 955–960. doi:10.1002/hlca.19610440410.

[8] Aasath, Jan; Dag Jacobsen; Ole Andersen; Elsa Wickstrøm (March 1995). "Treatment of Mercury and Lead Poisonings with Dimercaptosuccinic Acid (DMSA) and Sodium Dimercaptopropanesulfonate (DMPS)". Analyst 120: 853ff. doi:10.1039/an9952000853.

[9] Rooney, James (2007). "The role of thiols, dithiols, nutritional factors and interacting ligands in the toxicology of mercury". Toxicology 234 (3): 145–156. doi:10.1016/j.tox.2007.02.016. PMID 17408840.

[10] Guzzi, GianPaolo; Caterina A.M. La Porta (2008). "Molecular mechanisms triggered by mercury". Toxicology 244 (1): 1–12. doi:10.1016/j.tox.2007.11.002. PMID 18077077.

[pmid11266328-11] Frumkin H, Manning CC, Williams PL et al. (February 2001). "Diagnostic chelation challenge with DMSA: a biomarker of long-term mercury exposure?". Environ. Health Perspect. 109 (2): 167–71. doi:10.1289/ehp.01109167. PMC 1240638. PMID 11266328. Retrieved 2010-12-20.

[pmid15117439-12] Archbold GP, McGuckin RM, Campbell NA (May 2004). "Dimercaptosuccinic acid loading test for assessing mercury burden in healthy individuals". Ann. Clin. Biochem. 41 (Pt 3): 233–6. doi:10.1258/000456304323019622. PMID 15117439. Retrieved 2010-12-20.

[pmid1319053-13] Jones MM, Singh PK, Gale GR, Smith AB and Atkins LM. (May 1992). "Cadmium mobilization in vivo by intraperitoneal or oral administration of monoalkyl esters of meso-2,3-dimercaptosuccinic acid in the mouse". Pharmacology & Toxicology 70 (5 Pt 1): 336–343. doi:10.1111/j.1600-0773.1992.tb00483.x. PMID 1319053.

[pmid1335621-14] Walker EM Jr, Stone A, Milligan LB, Gale GR, Atkins LM, Smith AB, Jones MM, Singh PK and Basinger MA. (Nov 1992). "Mobilization of lead in mice by administration of monoalkyl esters of meso-2,3-dimercaptosuccinic acid". Toxicology 76 (1): 79–87. doi:10.1016/0300-483x(92)90020-f. PMID 1335621.

[pmid7589912-15] Kreppel H, Reichl FX, Kleine A, Szinicz L, Singh PK and Jones MM. (Jul 1995). "Antidotal efficacy of newly synthesized dimercaptosuccinic acid (DMSA) monoesters in experimental arsenic poisoning in mice". Fundamental & Applied Toxicology 26 (2): 239–245. doi:10.1093/toxsci/26.2.239. PMID 7589912.

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案内

案内

DMSA