Succimer

Last updated
Succimer
Meso-2,3-dimercaptosuccinic-acid-2D-skeletal-A-configurations-labelled.png
DMSA-3D-balls.png
Clinical data
Pronunciation /ˈsʌksɪmər/
Trade names Chemet, others
Other namesDimercaptosuccinic acid
DMSA
(2R,3S)-2,3-Dimercaptosuccinic acid
meso-2,3-Dimercaptosuccinic acid
APRD01236
AHFS/Drugs.com Monograph
License data
ATC code
Legal status
Legal status
Identifiers
  • (2R,3S)-2,3-disulfanylbutanedioic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.005.597 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C4H6O4S2
Molar mass 182.21 g·mol−1
3D model (JSmol)
Melting point 125 °C (257 °F)
  • O=C(O)[C@@H](S)[C@@H](S)C(=O)O
  • 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+ X mark.svgN
  • Key:ACTRVOBWPAIOHC-XIXRPRMCSA-N

Succimer, sold under the brand name Chemet among others, is a medication used to treat lead, mercury, and arsenic poisoning. [4] When radiolabeled with technetium-99m, it is used in many types of diagnostic testing. [5] A full course of Succimer lasts for 19 days of oral administration. [4] A second course should be given when more than two weeks pass after the first course. [4]

Contents

Common side effects include vomiting, diarrhea, rash, and low blood neutrophil levels. [4] Liver problems and allergic reactions may also occur with use. [4] Whether use during pregnancy is safe for the baby is unclear. [6] Dimercaptosuccinic acid is in the chelating agent family of medications. [4] It works by binding with lead and a number of other heavy metals, allowing them to leave the body in the urine. [4]

Succimer has been used medically since the 1950s. [7] [8] It is on the World Health Organization's List of Essential Medicines. [9] In the United States, no generic version was available as of 2015. [10]

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, [11] but it is not known if this is also the case in humans. [12] Even if dimercaptosuccinic acid cannot reverse the damages done to the central nervous system, it might prevent further deterioration. [13]

Succimer facilitates urinary excretion of lead, and with sufficiently aggressive treatment, can reduce lead content in the brain. [14] It also increases urinary excretion of copper and zinc. [15] 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. [14]

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.

(2R,3R)-2,3-dimercaptosuccinic-acid-2D-skeletal-A-configurations-labelled.png Meso-2,3-dimercaptosuccinic-acid-2D-skeletal-A-configurations-labelled.png (2S,3S)-2,3-dimercaptosuccinic-acid-2D-skeletal-A-configurations-labelled.png
(2R,3R)-2,3-dimercaptosuccinic-acid-2D-skeletal-B-configurations-labelled.png Meso-2,3-dimercaptosuccinic-acid-2D-skeletal-B-configurations-labelled.png (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[ clarification needed ] may be prepared by reacting acetylenedicarboxylic acid with sodium thiosulfate [16] or thioacetic acid followed by hydrolysis. The dimethyl ester is also known. [17]

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. [18] 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, providing exclusivity until 1998 which was conveyed to the successor Sanofi in 1996. [19] [20]

Related Research Articles

<span class="mw-page-title-main">Arsenic</span> Chemical element with atomic number 33 (As)

Arsenic is a chemical element with the symbol As and the atomic number 33. It is a metalloid and one of the pnictogens, and therefore shares many properties with its group 15 neighbors phosphorus and antimony. Arsenic is a notoriously toxic heavy metal. It occurs naturally in many minerals, usually in combination with sulfur and metals, but also as a pure elemental crystal. It has various allotropes, but only the grey form, which has a metallic appearance, is important to industry.

<span class="mw-page-title-main">Poison</span> Substance that causes death, injury or harm to organs

A poison is any chemical substance that is harmful or lethal to living organisms. The term is used in a wide range of scientific fields and industries, where it is often specifically defined. It may also be applied colloquially or figuratively, with a broad sense.

<span class="mw-page-title-main">Arsenic poisoning</span> Illness from ingesting arsenic

Arsenic poisoning is a medical condition that occurs due to elevated levels of arsenic in the body. If arsenic poisoning occurs over a brief period of time, symptoms may include vomiting, abdominal pain, encephalopathy, and watery diarrhea that contains blood. Long-term exposure can result in thickening of the skin, darker skin, abdominal pain, diarrhea, heart disease, numbness, and cancer.

Chelation is a type of bonding of ions and the molecules to metal ions. It involves the formation or presence of two or more separate coordinate bonds between a polydentate ligand and a single central metal atom. These ligands are called chelants, chelators, chelating agents, or sequestering agents. They are usually organic compounds, but this is not a necessity.

<span class="mw-page-title-main">Mercury poisoning</span> Poisoning caused by mercury chemicals

Mercury poisoning is a type of metal poisoning due to exposure to mercury. Symptoms depend upon the type, dose, method, and duration of exposure. They may include muscle weakness, poor coordination, numbness in the hands and feet, skin rashes, anxiety, memory problems, trouble speaking, trouble hearing, or trouble seeing. High-level exposure to methylmercury is known as Minamata disease. Methylmercury exposure in children may result in acrodynia in which the skin becomes pink and peels. Long-term complications may include kidney problems and decreased intelligence. The effects of long-term low-dose exposure to methylmercury are unclear.

<span class="mw-page-title-main">Chelation therapy</span> Medical procedure to remove heavy metals from the body

Chelation therapy is a medical procedure that involves the administration of chelating agents to remove heavy metals from the body. Chelation therapy has a long history of use in clinical toxicology and remains in use for some very specific medical treatments, although it is administered under very careful medical supervision due to various inherent risks, including the mobilization of mercury and other metals through the brain and other parts of the body by the use of weak chelating agents that unbind with metals before elimination, exacerbating existing damage. To avoid mobilization, some practitioners of chelation use strong chelators, such as selenium, taken at low doses over a long period of time.

<span class="mw-page-title-main">Dimercaprol</span> Chemical compound

Dimercaprol, also called British anti-Lewisite (BAL), is a medication used to treat acute poisoning by arsenic, mercury, gold, and lead. It may also be used for antimony, thallium, or bismuth poisoning, although the evidence for those uses is not very strong. It is given by injection into a muscle.

<span class="mw-page-title-main">Penicillamine</span> Chemical compound

Penicillamine, sold under the brand name of Cuprimine among others, is a medication primarily used for the treatment of Wilson's disease. It is also used for people with kidney stones who have high urine cystine levels, rheumatoid arthritis, and various heavy metal poisonings. It is taken by mouth.

<span class="mw-page-title-main">Arsanilic acid</span> Chemical compound

Arsanilic acid, also known as aminophenyl arsenic acid or aminophenyl arsonic acid, is an organoarsenic compound, an amino derivative of phenylarsonic acid whose amine group is in the 4-position. A crystalline powder introduced medically in the late 19th century as Atoxyl, its sodium salt was used by injection in the early 20th century as the first organic arsenical drug, but it was soon found prohibitively toxic for human use.

<span class="mw-page-title-main">2,3-Dimercapto-1-propanesulfonic acid</span> Chemical compound

2,3-Dimercapto-1-propanesulfonic acid and its sodium salt are chelating agents that form complexes with various heavy metals. They are related to dimercaprol, which is another chelating agent.

<span class="mw-page-title-main">Metal toxicity</span> Harmful effects of certain metals

Metal toxicity or metal poisoning is the toxic effect of certain metals in certain forms and doses on life. Some metals are toxic when they form poisonous soluble compounds. Certain metals have no biological role, i.e. are not essential minerals, or are toxic when in a certain form. In the case of lead, any measurable amount may have negative health effects. It is often thought that only heavy metals can be toxic, but lighter metals such as beryllium and lithium may also be in certain circumstances. Not all heavy metals are particularly toxic, and some are essential, such as iron. The definition may also include trace elements when abnormally high doses may be toxic. An option for treatment of metal poisoning may be chelation therapy, a technique involving the administration of chelation agents to remove metals from the body.

<span class="mw-page-title-main">Delafloxacin</span> Chemical compound

Delafloxacin sold under the brand name Baxdela among others, is a fluoroquinolone antibiotic used to treat acute bacterial skin and skin structure infections.

BDTH<sub>2</sub> Chemical compound

BDTH2 (also called BDET and BDETH2; trade names B9, MetX, and OSR#1) is an organosulfur compound that is used as a chelation agent. It is a colourless solid. The molecule consists of two thiol groups and linked via a pair of amide groups.

<span class="mw-page-title-main">DMSA scan</span> Radionuclide scan

A DMSA scan is a radionuclide scan that uses dimercaptosuccinic acid (DMSA) in assessing renal morphology, structure and function. Radioactive technetium-99m is combined with DMSA and injected into a patient, followed by imaging with a gamma camera after 2-3 hours. A DMSA scan is usually static imaging, while other radiotracers like DTPA and MAG3 are usually used for dynamic imaging to assess renal excretion.

<span class="mw-page-title-main">Zamfara State lead poisoning outbreak</span> 2010 lead poisoning incidents in Nigeria

A series of lead poisonings in Zamfara State, Nigeria, led to the deaths of at least 163 people between March and June 2010, including 111 children. Nigerian Federal Ministry of Health figures, state the discovery of 355 cases with 46 percent proving fatal. It was one of the many lead poisoning epidemics with low and middle income countries. By 2022, Médecins Sans Frontières stated that conditions had greatly improved after years of a lead poisoning intervention programme.

<span class="mw-page-title-main">Dithiol</span> Organosulfur compound with two –SH groups

In organic chemistry, a dithiol is a type of organosulfur compound with two thiol functional groups. Their properties are generally similar to those of monothiols in terms of solubility, odor, and volatility. They can be classified according to the relative location of the two thiol groups on the organic backbone.

Arsenic biochemistry refers to biochemical processes that can use arsenic or its compounds, such as arsenate. Arsenic is a moderately abundant element in Earth's crust, and although many arsenic compounds are often considered highly toxic to most life, a wide variety of organoarsenic compounds are produced biologically and various organic and inorganic arsenic compounds are metabolized by numerous organisms. This pattern is general for other related elements, including selenium, which can exhibit both beneficial and deleterious effects. Arsenic biochemistry has become topical since many toxic arsenic compounds are found in some aquifers, potentially affecting many millions of people via biochemical processes.

<span class="mw-page-title-main">Jeffrey Brent</span> Medical toxicologist

Jeffrey A. Brent is a medical toxicologist who is a distinguished clinical professor of medicine and emergency medicine at the University of Colorado, School of Medicine. In addition, he is a professor at the Department of Environmental and Occupational Health at the Colorado School of Public Health. He is also the past president of the American Academy of Clinical Toxicology, was editor in chief of the journal Toxicological Reviews, and was a member of the board of directors of the American College of Medical Toxicology. Previously, most of Brent's research focused on the use of fomepizole as a treatment for both methanol and ethylene glycol poisoning, and he led a trial of this drug which resulted in the FDA approving it in December 1997. Currently, Brent serves as Director of the Toxicology Investigators Consortium, an NIH and FDA supported multi center research and surveillance group. Brent is also a senior editor of "Critical Care Toxicology: Diagnosis and Management of the Critically Poisoned Patient," originally published in 2005, and now in its second edition, which was published in 2017.

Hurair Vasken Aposhian was a Ph.D. toxicologist and an emeritus professor of molecular and cell biology at the University of Arizona, a post he held beginning in 1975. He is also a former professor of pharmacology at the medical school at said university. He received his bachelor's degree in chemistry, at Brown University, 1948. He received a master's degree and a PhD in physiological chemistry at the University of Rochester, where he published some scientific studies about the synthesis of isoalloxazine ring-containing compounds. He did a postdoctoral with Nobel Laureate Arthur Kornberg in the department of biochemistry at Stanford University School of Medicine. He has done sabbatical scholar-in-residence at MIT and at the University of California at San Diego. He is best known for his pioneering work on Succimer and Unithiol in the treatment of arsenic, mercury, lead and other heavy metals leading to FDA approval of succimer in childhood lead poisoning at levels over 40 ug/dl. Previous posts he had held include at Vanderbilt, Tufts University, and the University of Maryland. His views about mercury in vaccines and in dental amalgams go against the consensus of the medical community and are controversial.

<span class="mw-page-title-main">Sodium thiosulfate (medical use)</span>

Sodium thiosulfate, also spelled sodium thiosulphate, is used as a medication to treat cyanide poisoning, pityriasis versicolor, and to decrease side effects from cisplatin. For cyanide poisoning, it is often used after the medication sodium nitrite and is typically only recommended for severe cases. It is either given by injection into a vein or applied to the skin.

References

  1. "Chemet- succimer capsule". DailyMed. U.S. National Library of Medicine. 12 December 2019. Retrieved 19 June 2022.
  2. "Nephroscan- succimer injection, powder, lyophilized, for solution". DailyMed. U.S. National Library of Medicine. 1 March 2022. Retrieved 19 June 2022.
  3. "Rotop - DMSA- kit for the preparation of technetium tc99m succimer injection injection, powder, lyophilized, for solution". DailyMed. U.S. National Library of Medicine. 9 March 2021. Retrieved 19 June 2022.
  4. 1 2 3 4 5 6 7 "Succimer". The American Society of Health-System Pharmacists. Archived from the original on 16 January 2017. Retrieved 8 January 2017.
  5. Biersack HJ, Grünwald F (2005). Thyroid Cancer. Springer Science & Business Media. p. 213. ISBN   9783540278450. Archived from the original on 2017-01-13.
  6. "Succimer (Chemet) Use During Pregnancy". www.drugs.com. Archived from the original on 16 January 2017. Retrieved 12 January 2017.
  7. Miller AL (June 1998). "Dimercaptosuccinic acid (DMSA), a non-toxic, water-soluble treatment for heavy metal toxicity". Alternative Medicine Review. 3 (3): 199–207. PMID   9630737.
  8. Chappell WR, Abernathy CO, Calderon RL (1999). Arsenic Exposure and Health Effects III. Elsevier. p. 350. ISBN   9780080527574. Archived from the original on 2017-01-13.
  9. World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  10. Hamilton R (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 472. ISBN   9781284057560.
  11. Aaseth J, Jacobsen D, Andersen O, Wickstrøm E (March 1995). "Treatment of mercury and lead poisonings with dimercaptosuccinic acid and sodium dimercaptopropanesulfonate. A review". The Analyst. 120 (3): 853–854. Bibcode:1995Ana...120..853A. doi:10.1039/an9952000853. PMID   7741240.
  12. Guzzi G, La Porta CA (February 2008). "Molecular mechanisms triggered by mercury". Toxicology. 244 (1): 1–12. Bibcode:2008Toxgy.244....1G. doi:10.1016/j.tox.2007.11.002. PMID   18077077.
  13. Clarkson TW, Magos L, Myers GJ (October 2003). "The toxicology of mercury--current exposures and clinical manifestations". The New England Journal of Medicine. 349 (18): 1731–1737. doi:10.1056/nejmra022471. PMID   14585942.
  14. 1 2 Smith D, Strupp BJ (December 2013). "The scientific basis for chelation: animal studies and lead chelation". Journal of Medical Toxicology. 9 (4): 326–338. doi:10.1007/s13181-013-0339-2. PMC   3846979 . PMID   24113857.
  15. Bradberry S, Sheehan T, Vale A (October 2009). "Use of oral dimercaptosuccinic acid (succimer) in adult patients with inorganic lead poisoning". QJM. 102 (10): 721–732. doi: 10.1093/qjmed/hcp114 . PMID   19700440.
  16. US 4550193,Lindemann MK, Lukenbach ER,"Process for the preparation of 2,3-dimercaptosuccinic acid and its lower alkyl esters",issued 29 October 1985, assigned to Johnson & Johnson Baby Products
  17. Gerecke M, Friedheim EA, Brossi A (1961). "Zur Kenntnis der 2,3-Dimercapto-bernsteinsäuren". Helvetica Chimica Acta . 44 (4): 955–960. doi:10.1002/hlca.19610440410.
  18. 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.
  19. "Search Orphan Drug Designations and Approvals". Searchable database for Orphan Designated and or Approved Products. FDA. 2013. Archived from the original on 6 November 2014. Retrieved 5 November 2014.
  20. "Sanofi Buying An American Drug Concern". The New York Times. July 17, 1996. Archived from the original on 6 November 2014. Retrieved 5 November 2014.

Further reading