Thiosulfuric acid

Identification

Summary

Thiosulfuric acid is a sulfur donor used sequentially with sodium nitrite for the reversal of life-threatening acute cyanide poisoning. Also used to reduce the risk of ototoxicity associated with cisplatin.

Brand Names
Nithiodote, Pedmark, Seacalphyx
Generic Name
Thiosulfuric acid
DrugBank Accession Number
DB09499
Background

Thiosulfuric acid is available in its salt forms sodium thiosulfate and sodium thiosulfate pentahydrate. Sodium thiosulfate is part of the World Health Organization’s list of essential medicines, and it has a variety of industrial uses, including food preservative, water de-chlorinator and paper pulp bleaching agent.1 Sodium thiosulfate is rapidly degraded in the stomach; therefore, it is normally administered through other routes, such as intravenous or topical.1 Sodium thiosulfate is approved for the treatment of acute cyanide poisoning5,6,2 and it is frequently used in conjunction with sodium nitrite (a salt form of nitrous acid). Sodium thiosulfate is also used to reduce the risk of ototoxicity associated with cisplatin.7 When administered 6 hours after cisplatin chemotherapy, Sodium thiosulfate leads to a lower incidence of cisplatin-induced hearing loss among children without affecting its effectiveness.3,4

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 114.144
Monoisotopic: 113.94453531
Chemical Formula
H2O3S2
Synonyms
  • Monosulfanemonosulfonic acid
  • Sulfurothioic S-acid

Pharmacology

Indication

Thiosulfuric acid (as sodium thiosulfate) is indicated for sequential intravenous use with sodium nitrite for the treatment of acute cyanide poisoning that is judged to be life-threatening.6 Sodium thiosulfate is also indicated to reduce the risk of ototoxicity associated with cisplatin in pediatric patients 1 month of age and older with localized, non-metastatic solid tumors in the US.7 In Europe, it is indicated for the same prevention of ototoxicity for patients 1 month of age to < 18 years old.8

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Prevention ofCisplatin ototoxicity•••••••••••••••••••••••••••••••••• ••••••••• ••••• •••••••••••••••
Used in combination to treatCyanide poisoningCombination Product in combination with: Nitrous acid (DB09112)•••••••••••••••••••••
Prevention ofOtotoxicity from cisplatin chemotherapy••••••••••••••••••••••••• ••••••••• ••••• ••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Sodium thiosulfate doses of 20, 15 and 10 g/m2 deliver sodium loads of 162, 121 and 81 mmol/m2. One hour after infusion, the administration of sodium thiosulfate causes a transient increase in sodium of approximately 6 mmol/L; however, levels return to baseline 18 to 24 hours after infusion.7 The pharmacodynamics of sodium thiosulfate as an antidote for the treatment of acute cyanide poisoning were evaluated by measuring the rate of conversion of cyanide to thiocyanate. Pretreatment with sodium thiosulfate to achieve a steady state level of 2 µmol/mL increased the rate of conversion of cyanide to thiocyanate over 30-fold in dogs.6 The use of sodium thiosulfate may cause hypersensitivity reactions and lead to hypernatremia and hypokalemia. It may also lead to nausea and vomiting.7

Mechanism of action

When administered with sodium nitrate, sodium thiosulfate acts as an antidote for the treatment of acute cyanide poisoning.6 Cyanide has a high affinity for cytochrome a3, a component of the cytochrome c oxidase complex in mitochondria. By binding and inhibiting cytochrome a3, cyanide prevents cells from using oxygen and forces anaerobic metabolism, inhibiting cellular respiration and resulting in lactic acidosis and cytotoxic hypoxia. Sodium nitrite reacts with hemoglobin to form methemoglobin, which competes with cytochrome a3 for the cyanide ion. Cyanide binds to methemoglobin to form cyanmethemoglobin, a nontoxic compound, and restore cytochrome oxidase activity. When cyanide dissociates from methemoglobin, sodium thiosulfate acts as a sulfur donor for the endogenous sulfur transferase enzyme and facilitates its conversion to thiocyanate, a less toxic ion.6

Sodium thiosulfate can also reduce the risk of ototoxicity associated with cisplatin. Pediatric patients treated with cisplatin have a high risk of developing ototoxicity, possibly due to a combination of reactive oxygen species (ROS) production and direct alkylation of DNA that leads to cell death.7 Sodium thiosulfate interacts with cisplatin to form inactive platinum species. It can also enter cells via the sodium sulfate cotransporter 2 to increase antioxidant glutathione levels and inhibit intracellular oxidative stress. Although a mechanism of action has not been fully elucidated, both activities are thought to reduce the risk of ototoxicity.7

Absorption

Sodium thiosulfate taken orally is not systemically absorbed. Most of the thiosulfate is oxidized to sulfate or is incorporated into endogenous sulphur compounds; a small proportion is excreted through the kidneys.6 In pediatric patients given the recommended intravenous dose of sodium thiosulfate, the Cmax of thiosulfate was 13 ± 1.2 mM, and increased proportionally to dose over the range of 4 g/m2 to 20 g/m2. Thiosulfate accumulation is not expected following the intravenous administration of sodium thiosulfate on 2 consecutive days.7

Volume of distribution

Thiosulfate has a mean volume of distribution of 0.23 L/kg.7

Protein binding

Sodium thiosulfate does not bind to human plasma proteins.7

Metabolism

Thiosulfate sulfur transferase and thiosulfate reductase metabolize thiosulfate to form sulfite, which is oxidized to sulfate.7

Route of elimination

Approximately 20-50% of exogenously administered sodium thiosulfate is eliminated by the kidneys.6,7 More than 95% of the thiosulfate eliminated in urine is excreted within the first 4 hours after administration.7 When used as an antidote to cyanide poisoning, sodium thiosulfate is eliminated as thiocyanate, a relatively nontoxic compound. Thiocyanate is also excreted in urine at a rate inversely proportional to creatinine clearance.6

Half-life

The half-life of thiosulfate administered intravenously (1 g sodium thiosulfate) was approximately 20 minutes. However, higher doses may increase this value. In healthy men given 150 mg/kg of sodium thiosulfate, the elimination half-life was 182 minutes.6

Clearance

In patients with fully developed renal function (1 year old approximately), the mean total clearance of thiosulfate is 2.2 mL/min/kg.7

Adverse Effects
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Toxicity

The effects in humans of large doses of sodium thiosulfate have not been thoroughly studied. Sodium thiosulfate administered orally (3 g per day) for 1-2 weeks resulted in reductions in room air arterial oxygen saturation to as low as 75%. One week after discontinuation, subjects returned to baseline oxygen saturations. A single dose of 20 mL of 10% sodium thiosulfate administered intravenously did not have an effect on oxygen saturation.6

In rats, the oral LD50 of sodium thiosulfate pentahydrate is 5000 mg/kg.[L43327] The carcinogenic activity of sodium thiosulfate has not been evaluated. An in vitro bacterial reverse mutation assay showed that sodium thiosulfate was not mutagenic in the absence nor presence of metabolic activation.7

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AmitriptylineThe metabolism of Amitriptyline can be increased when combined with Thiosulfuric acid.
AntipyrineThe metabolism of Antipyrine can be increased when combined with Thiosulfuric acid.
ApomorphineThe metabolism of Apomorphine can be increased when combined with Thiosulfuric acid.
ArtemetherThe metabolism of Artemether can be increased when combined with Thiosulfuric acid.
AsunaprevirThe metabolism of Asunaprevir can be increased when combined with Thiosulfuric acid.
Food Interactions
No interactions found.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Sodium thiosulfateL0IYT1O31N7772-98-7AKHNMLFCWUSKQB-UHFFFAOYSA-L
Sodium thiosulfate pentahydrateHX1032V43M10102-17-7PODWXQQNRWNDGD-UHFFFAOYSA-L
International/Other Brands
Pedmark (Fennec Pharmaceuticals,)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
PedmarkInjection, solution12.5 g/100mLIntravenousFennec Pharmaceuticals Inc.2022-10-03Not applicableUS flag
PedmarqsiInjection, solution80 mg/mlIntravenousFennec Pharmaceuticals (Eu) Limited2023-06-09Not applicableEU flag
SeacalphyxSolution250 mg / mLIntravenousSeaford Pharmaceuticals Inc2013-01-08Not applicableCanada flag
Sodium ThiosulfateInjection, solution250 mg/1mLIntravenousHope Pharmaceuticals2012-02-14Not applicableUS flag
Sodium Thiosulfate Inj 25% USPLiquid250 mg / mLIntravenousDavid Bull Laboratories (Pty) Ltd.1991-12-311998-08-13Canada flag
Over the Counter Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Oligostim SoufreTablet0.015 mgOralDolisos Laboratoires S.A.1998-06-112007-08-01Canada flag
วีเนียPowder15 gบริษัท วิทยาศรม จำกัด1991-10-18Not applicableThailand flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
Adasept Acne GelSodium thiosulfate (8 %) + Salicylic acid (2 %) + Triclosan (0.5 %)LotionTopicalOdan Laboratories Ltd1974-12-31Not applicableCanada flag
NithiodoteSodium thiosulfate pentahydrate (250 mg/1mL) + Sodium nitrite (30 mg/1mL)Injection, solution; KitIntravenousHope Pharmaceuticals2011-01-14Not applicableUS flag
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
Sodium polysulthionate and folic acidSodium thiosulfate pentahydrate (1.8 mg/1) + Folic acid (1 mg/1) + Octasulfur (388 mg/1) + Sodium sulfate decahydrate (8 mg/1)CapsuleOralSolubiomix2016-08-242017-10-16US flag
Sodium polysulthionate, 5-methyltetrahydrofolateSodium thiosulfate pentahydrate (.45 g/100g) + Levomefolic acid (.125 g/100g) + Octasulfur (97 g/100g) + Sodium sulfate decahydrate (2 g/100g)PowderOral; TopicalSolubiomix2015-07-212016-01-12US flag
Sodium Polysulthionate, 5-mthfSodium thiosulfate pentahydrate (1.8 mg/1) + 5-methyltetrahydrofolic acid (.5 mg/1) + Octasulfur (388 mg/1) + Sodium sulfate decahydrate (8 mg/1)CapsuleOralSolubiomix2016-01-092016-01-12US flag
Sodum ThiosulfateSodium thiosulfate pentahydrate (250 mg/1mL)Injection, solutionIntravenousAmerican Regent1990-09-302012-11-28US flag
Sodum ThiosulfateSodium thiosulfate pentahydrate (100 mg/1mL)Injection, solutionIntravenousAmerican Regent1990-09-302012-11-28US flag

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of inorganic compounds known as non-metal thiosulfates. These are inorganic non-metallic compounds containing a thiosulfate as its largest oxoanion.
Kingdom
Inorganic compounds
Super Class
Homogeneous non-metal compounds
Class
Non-metal oxoanionic compounds
Sub Class
Non-metal thiosulfates
Direct Parent
Non-metal thiosulfates
Alternative Parents
Inorganic sulfides / Inorganic oxides
Substituents
Inorganic oxide / Inorganic sulfide / Non-metal thiosulfate
Molecular Framework
Not Available
External Descriptors
thiosulfuric acid (CHEBI:29279)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
7K79Y2EKKP
CAS number
13686-28-7
InChI Key
DHCDFWKWKRSZHF-UHFFFAOYSA-N
InChI
InChI=1S/H2O3S2/c1-5(2,3)4/h(H2,1,2,3,4)
IUPAC Name
dihydroxy-1lambda6-disulfen-1-one
SMILES
OS(O)(=O)=S

References

Synthesis Reference

Sherman, C., et al. (2016). Sodium thiosulfate-containing pharmaceutical compositions (U.S. Patent No. 2016/0235782 A1). U.S. Patent and Trademark Office. https://patentimages.storage.googleapis.com/0c/2a/58/edc43adab43077/US20160235782A1.pdf

General References
  1. Zhang MY, Dugbartey GJ, Juriasingani S, Sener A: Hydrogen Sulfide Metabolite, Sodium Thiosulfate: Clinical Applications and Underlying Molecular Mechanisms. Int J Mol Sci. 2021 Jun 16;22(12). pii: ijms22126452. doi: 10.3390/ijms22126452. [Article]
  2. Bebarta VS, Brittain M, Chan A, Garrett N, Yoon D, Burney T, Mukai D, Babin M, Pilz RB, Mahon SB, Brenner M, Boss GR: Sodium Nitrite and Sodium Thiosulfate Are Effective Against Acute Cyanide Poisoning When Administered by Intramuscular Injection. Ann Emerg Med. 2017 Jun;69(6):718-725.e4. doi: 10.1016/j.annemergmed.2016.09.034. Epub 2016 Dec 29. [Article]
  3. Freyer DR, Chen L, Krailo MD, Knight K, Villaluna D, Bliss B, Pollock BH, Ramdas J, Lange B, Van Hoff D, VanSoelen ML, Wiernikowski J, Neuwelt EA, Sung L: Effects of sodium thiosulfate versus observation on development of cisplatin-induced hearing loss in children with cancer (ACCL0431): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2017 Jan;18(1):63-74. doi: 10.1016/S1470-2045(16)30625-8. Epub 2016 Dec 1. [Article]
  4. Brock PR, Maibach R, Childs M, Rajput K, Roebuck D, Sullivan MJ, Laithier V, Ronghe M, Dall'Igna P, Hiyama E, Brichard B, Skeen J, Mateos ME, Capra M, Rangaswami AA, Ansari M, Rechnitzer C, Veal GJ, Covezzoli A, Brugieres L, Perilongo G, Czauderna P, Morland B, Neuwelt EA: Sodium Thiosulfate for Protection from Cisplatin-Induced Hearing Loss. N Engl J Med. 2018 Jun 21;378(25):2376-2385. doi: 10.1056/NEJMoa1801109. [Article]
  5. Medsafe New Zealand Approved Drug Products: DBL sodium thiosulfate solution for injection [Link]
  6. FDA Approved Drug Products: NITHIODOTE (sodium nitrite and sodium thiosulfate) injection for intravenous infusion [Link]
  7. FDA Approved Drug Products: PEDMARK (sodium thiosulfate) injection for intravenous use [Link]
  8. EMA Approved Drug Products: Pedmarqsi (sodium thiosulfate) injection for intravenous injection [Link]
Human Metabolome Database
HMDB0000257
KEGG Compound
C05529
PubChem Compound
24478
PubChem Substance
347827866
ChemSpider
22886
ChEBI
5587
ChEMBL
CHEMBL1208642
ZINC
ZINC000008214573
Wikipedia
Thiosulfuric_acid

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4TerminatedTreatmentCutaneous calcification1
3Active Not RecruitingTreatmentMedulloblastomas1
3CompletedSupportive CareBrain Neoplasm / Central Nervous System Neoplasm / Extragonadal Germ Cell Tumor / Liver Cancer / Neuroblastoma (NB) / Ototoxicity / Ovarian Cancer / Pediatric Germ Cell Tumor / Sarcomas1
3CompletedTreatmentLiver Cancer / Ototoxicity1
3RecruitingTreatmentCalciphylaxis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
LotionTopical
Injection, solution; kitIntravenous
TabletOral0.015 mg
Injection, solutionIntravenous12.5 g/100mL
Injection, solutionIntravenous80 mg/ml
SolutionIntravenous250 mg / mL
Injection, solution, concentrateIntravenous
LiquidIntravenous250 mg / mL
Injection, solutionIntravenous100 mg/1mL
Injection, solutionIntravenous250 mg/1mL
PowderOral
SolutionIntravenous200 mg
CapsuleOral
PowderOral; Topical
Powder15 g
Injection, solutionIntravenous262.5 mg/1ml
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8496973No2013-07-302031-03-29US flag
US8568793No2013-10-292031-12-24US flag
US9585912No2017-03-072031-03-29US flag
US9345724No2016-05-242031-03-29US flag
US9687506No2017-06-272031-12-24US flag
US10479686No2019-11-192031-03-29US flag
US10596190No2020-03-242038-01-05US flag
US11291728No2019-07-012039-07-01US flag
US11510984No2019-07-012039-07-01US flag
US11617793No2019-07-012039-07-01US flag
US11753301No2010-02-102030-02-10US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)48 °C Sigma-Aldrich: Sodium thiosulfate SDS (https://www.sigmaaldrich.com/CA/en/sds/SIGALD/217263)
boiling point (°C)100°CScholAR Chemistry: Sodium thiosulfate SDS (https://www.mccsd.net/cms/lib/NY02208580/Centricity/Shared/Material%20Safety%20Data%20Sheets%20_MSDS_/MSDS%20Sheets_Sodium_Thiosulfate_Anhydrous_703_00.pdf)
water solubility210 g/LSigma-Aldrich: Sodium thiosulfate SDS (https://www.sigmaaldrich.com/CA/en/sds/SIGALD/217263)
Predicted Properties
PropertyValueSource
logP0.048Chemaxon
pKa (Strongest Acidic)2.7Chemaxon
Physiological Charge-1Chemaxon
Hydrogen Acceptor Count3Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area57.53 Å2Chemaxon
Rotatable Bond Count0Chemaxon
Refractivity21.76 m3·mol-1Chemaxon
Polarizability8.51 Å3Chemaxon
Number of Rings0Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-03di-2900000000-0340aa179a944cddc03f
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-03di-0900000000-9b392ce35f8d17472a4f
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-03di-0900000000-8713d6562312e043b633
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-03di-2900000000-354647bf0c281581f176
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-03di-0900000000-2c260178b79a63eadae6
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0002-9300000000-2fd3cffde331cad1dd43
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-03di-0900000000-bfc4d410b67f38a234f9
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-101.8675725
predicted
DarkChem Lite v0.1.0
[M-H]-101.8686725
predicted
DarkChem Lite v0.1.0
[M-H]-126.323906
predicted
DeepCCS 1.0 (2019)
[M+H]+129.12137
predicted
DeepCCS 1.0 (2019)
[M+Na]+137.25946
predicted
DeepCCS 1.0 (2019)

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Substrate
Curator comments
Processed as sodium thiosulfate.
General Function
Thiosulfate sulfurtransferase activity
Specific Function
Formation of iron-sulfur complexes, cyanide detoxification or modification of sulfur-containing enzymes. Other thiol compounds, besides cyanide, can act as sulfur ion acceptors. Also has weak merca...
Gene Name
TST
Uniprot ID
Q16762
Uniprot Name
Thiosulfate sulfurtransferase
Molecular Weight
33428.69 Da
References
  1. FDA Approved Drug Products: PEDMARK (sodium thiosulfate) injection for intravenous use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Curator comments
Processed as sodium thiosulfate.
General Function
Thiosulfate:glutathione sulfurtransferase (TST) required to produce S-sulfanylglutathione (GSS(-)), a central intermediate in hydrogen sulfide metabolism (PubMed:24981631). Provides the link between the first step in mammalian H(2)S metabolism performed by the sulfide:quinone oxidoreductase (SQOR) which catalyzes the conversion of H(2)S to thiosulfate, and the sulfur dioxygenase (SDO) which uses GSS(-) as substrate (PubMed:24981631). The thermodynamic coupling of the irreversible SDO and reversible TST reactions provides a model for the physiologically relevant reaction with thiosulfate as the sulfane donor (PubMed:24981631).
Specific Function
Dna-binding transcription factor activity, rna polymerase ii-specific
Gene Name
TSTD1
Uniprot ID
Q8NFU3
Uniprot Name
Thiosulfate:glutathione sulfurtransferase
Molecular Weight
12530.1 Da
References
  1. FDA Approved Drug Products: PEDMARK (sodium thiosulfate) injection for intravenous use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inducer
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. FDA Approved Drug Products: PEDMARK (sodium thiosulfate) injection for intravenous use [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
General Function
Sodium/sulfate cotransporter that mediates sulfate reabsorption in the high endothelial venules (HEV).
Specific Function
Sodium
Gene Name
SLC13A4
Uniprot ID
Q9UKG4
Uniprot Name
Solute carrier family 13 member 4
Molecular Weight
69357.885 Da
References
  1. FDA Approved Drug Products: PEDMARK (sodium thiosulfate) injection for intravenous use [Link]

Drug created at November 30, 2015 19:10 / Updated at March 18, 2024 16:48