Anethole trithione

Identification

Summary

Anethole trithione is a medication used to treat dry mouth associated with medication or radiotherapy of the head and neck.

Brand Names
Sialor
Generic Name
Anethole trithione
DrugBank Accession Number
DB13853
Background

Anethole trithione (ATT) appears to have a broad range of unique functions, from increasing salivary secretion to help treat xerostomia 1,6,8,9, to demonstrating an ability to inhibit carcinogenesis by increasing the activity of electrophile detoxification enzymes 7, and even being used as an adjunctive therapy for cholecystitis, gallstone, indigestion, and acute/chronic hepatitis 12 and is marketed in certain countries like France, Germany, and China 2.

Unfortunately, many of the specific mechanisms of action to these activities have yet to be formally elucidated, which means that while studies are ongoing, ATT itself is not necessarily formally indicated for many of these aforementioned functions at this time and is only used in limited regions around the world.

Type
Small Molecule
Groups
Approved, Experimental
Structure
Thumb
Weight
Average: 240.35
Monoisotopic: 239.9737284
Chemical Formula
C10H8OS3
Synonyms
  • Anetholtrithion

Pharmacology

Indication

The most typical uses for which anethol trithione is currently indicated for includes increasing salivary secretion in patients experiencing dry mouth or being used as an adjunctive therapy for cholecystitis, gallstone, indigestion, and acute/chronic hepatitis 2,4,11.

In addition, although some studies have suggested that anethol trithione also possesses a certain capacity to inhibit tumorigenesis as a potential cancer therapy medication, the specific mechanism of action for this effect remains to be elucidated 7 with certain national cancer institutes listing the agent as 'a substance that is being studied in the treatment of cancer' 10.

Pharmacology
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Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Anethol trithione (ATT) possesses a high lipophilicity (log P = 3.8) but an extremely low water solubility (0.38 ug/mL), which limits its dissolution and absorption 2,4. Furthermore, ATT is quickly metabolized into 4-hydroxy-anethole trithione (ATX, which demonstrates a similar pharmacological activity to ATT) by way of O-demethylation 2,4. As a consequence, the plasma concentration of ATT is usually fairly low, resulting in a limited oral bioavailability as well 2,4. Given this pharmacodynamic profile, there is continued interest and study in developing vehicles with which ATT can be administered in larger availabilities into the body 2,4.

Mechanism of action

Epidemiological studies demonstrate that the prevalence of xerostomia and salivary gland hypofunction (SGH) rises with age, and is largely associated with medications and health 8. In particular, anethole trithione (ATT) is believed to cause an increase in salivary secretion by upregulating the number of muscarinic receptor (whose stimulation is known to increase salivary secretion) sites on the salivary acinar cells 6,8,9. Moreover, the combination use of ATT and pilocarpine is also thought to be effective in a synergistic manner - as ATT increases the number of cell surface receptors on salivary acinar cells, the pilocarpine, which is a parasympathetic agent, stimulates the newly formed receptors 8,9.

In addition, studies have also shown that the administration of ATT can also enhance the upregulation and release of substance P and alpha-calcitonin gene-related peptide 5. As receptors for peptides like alpha-calcitonin gene-related peptide are found throughout the body, the increase in these such proteins may modulate a variety of physiological functions in various body systems, even in the gastrointestinal or salivary actions 5. Regardless, it has been shown that the use of ATT in patients can cause an increase in salivary flow rate in patients with xerostomia caused by senile hypofunction, medication side effects, and oral cancer therapy 1 and has been indicated for use in treating xerostomia associated with conditions like Sjogren's syndrome 6. Nevertheless, there exist also studies that suggest ATT is generally only effective in managing the symptoms of mild salivary gland hypofunction but is not particularly useful for treating severe salivary gland hypofunction or severe cases of Sjogren's syndrome 6,8.

ATT is also used as an adjunctive therapy for cholecystitis, gallstone, indigestion, and acute/chronic hepatitis in certain countries like France, Germany, and China 2,4. With regards to this particular indication, it is believed that ATT can facilitate raises in the level of glutathione in the liver, and raises in the activity of glutamylcysteine synthetase, glutathione reductase, and glutathione S transferase 12. All of these effects are consequently intimately involved in the cellular antioxidant activity of glutathione where glutamylcysteine synthetase is the first enzyme involved in the cellular glutathione biosynthesis pathway; where glutathione reductase is necessary for catalyzing the reduction of pathway intermediates to glutathione; and glutathione S transferase catalyze the conjugation of the reduced form of glutathione to xenobiotic substrates for the purpose of detoxification 12. Finally, glutathione itself is an important antioxidant found in plants, animals, fungi, and some bacteria where it assists in preventing damage to cellular components caused by reactive oxygen species, free radicals, etc 12. Taken altogether, these various actions are suitable for treating cholecystitis, gall stones, indigestion, and may be used in the assisting treatment of acute and chronic hepatosis.

Although the specific mechanism of action for which ATT is seemingly capable of inhibiting tumorigenesis to a certain degree remains to be elucidated, some potential plausible mechanisms have been discussed. One such potential mechanism suggests that ATT has the capability to alter the metabolism of carcinogens by increasing the rate of detoxification of carcinogens in target organs like the liver and colon, thereby decreasing the generation of carcinogen metabolites and reducing parent-carcinogen induced carcinogenesis by way of those agents 7. And finally, a second potential mechanism proposes that ATT can strikingly increase the antioxidant activities of colonic and liver GST, NAD(P)H:QR, and UDP-GT, therefore eliciting a chemoprotective action 7.

Absorption

Although anethole trithione (ATT) has a high lipophilicity (log P = 3.8) and a high intestinal permeability, it has an extremely low water solubility (0.38 ug/ml). This low solubility limits ATT dissolution and bioavailability 2,4.

Regardless, after ATT was administered to twenty-two healthy Chinese volunteers, the Cmax observed was about 0.98 +/- 0.49 ng/mL and the recorded Tmax was 2.2 +/- 1.9 h 3.

Volume of distribution

Despite the medication being studied and discussed as early as the 1980s, detailed pharmacokinetic information about it is not readily accessible and limited new pharmacokinetic data has only been determined for the drug for the first time only very recently (as recently as 2007) 3.

Nevertheless, the poor absorption and bioavailability of anethole trithione suggests any kind of volume of distribution measurement may not be entirely accurate.

Protein binding

Despite the medication being studied and discussed as early as the 1980s, detailed pharmacokinetic information about it is not readily accessible and limited new pharmacokinetic data has only been determined for the drug for the first time only very recently (as recently as 2007) 3.

Metabolism

Anethole trithione (ATT) is metabolized rapidly into 4-hydroxy-anethole trithione via O-demethylation 2,4. This metabolite demonstrates similar pharmacological activities to its parent, ATT 2,4. It is proposed that such metabolism occurs in liver microsomes, although neither this proposal or by what specific hepatic cytochrome P450 isoform(s) are involved in such metabolism has been formally elucidated 2.

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Route of elimination

Despite the medication being studied and discussed as early as the 1980s, detailed pharmacokinetic information about it is not readily accessible and limited new pharmacokinetic data has only been determined for the drug for the first time only very recently (as recently as 2007) 3.

Half-life

Despite the medication being studied and discussed as early as the 1980s, detailed pharmacokinetic information about it is not readily accessible and limited new pharmacokinetic data has only been determined for the drug for the first time only very recently (as recently as 2007) 3.

Consequently, after anethole trithione was administered to twenty-two healthy Chinese volunteers, the half-life observed was about 3.78 +/- 2.12 hours 3.

Clearance

Despite the medication being studied and discussed as early as the 1980s, detailed pharmacokinetic information about it is not readily accessible and limited new pharmacokinetic data has only been determined for the drug for the first time only very recently (as recently as 2007) 3.

Regardless, data about the estimated clearance of anethole trithione in the rat model after administration of anethole trithione oral aqueous suspension was observed to be approximately 113.20 +/- 52.37 L/h/kg 2.

Adverse Effects
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Toxicity

Data regarding the overdosage and toxicity of anethole trithione (ATT) is not readily accessible. Nevertheless, some common side effects associated with taking ATT include softening of stool and/or discoloration of the urine to a bright yellow 11.

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.
Not Available
Food Interactions
  • Take before a meal.

Products

Products
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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
SialorTablet25.0 mgOralPharmascience Inc2000-08-02Not applicableCanada flag
Sialor Tab 25mgTablet25 mg / tabOralSolvay Pharma Inc1992-12-312000-07-28Canada flag
Over the Counter Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Sulfarlem Tab 12.5mgTablet12.5 mg / tabOralSolvay Pharma Inc1993-12-311999-08-30Canada flag

Categories

ATC Codes
A16AX02 — Anethole trithione
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as anisoles. These are organic compounds containing a methoxybenzene or a derivative thereof.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Phenol ethers
Sub Class
Anisoles
Direct Parent
Anisoles
Alternative Parents
Phenoxy compounds / Methoxybenzenes / Alkyl aryl ethers / 1,2-dithiole-3-thiones / Heteroaromatic compounds / Organosulfur compounds / Hydrocarbon derivatives
Substituents
1,2-dithiole / 1,2-dithiole-3-thione / Alkyl aryl ether / Anisole / Aromatic heteromonocyclic compound / Dithiole / Ether / Heteroaromatic compound / Hydrocarbon derivative / Methoxybenzene
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
QUY32964DJ
CAS number
532-11-6
InChI Key
KYLIZBIRMBGUOP-UHFFFAOYSA-N
InChI
InChI=1S/C10H8OS3/c1-11-8-4-2-7(3-5-8)9-6-10(12)14-13-9/h2-6H,1H3
IUPAC Name
5-(4-methoxyphenyl)-3H-1,2-dithiole-3-thione
SMILES
COC1=CC=C(C=C1)C1=CC(=S)SS1

References

General References
  1. Hamada T, Nakane T, Kimura T, Arisawa K, Yoneda K, Yamamoto T, Osaki T: Treatment of xerostomia with the bile secretion-stimulating drug anethole trithione: a clinical trial. Am J Med Sci. 1999 Sep;318(3):146-51. [Article]
  2. Yu HZ, Han SF, Li P, Zhu CL, Zhang XX, Gan L, Gan Y: An examination of the potential effect of lipids on the first-pass metabolism of the lipophilic drug anethol trithione. J Pharm Sci. 2011 Nov;100(11):5048-58. doi: 10.1002/jps.22702. Epub 2011 Jul 15. [Article]
  3. Li T, Zhang Z, Jiao H, Zhang L, Tian Y, Chen Y, Pang X, Zhuang J: Determination of anethole trithione in human plasma using high performance liquid chromatography coupled with tandem mass spectrometric detection. Anal Chim Acta. 2007 Jul 2;594(2):274-8. doi: 10.1016/j.aca.2007.05.038. Epub 2007 May 26. [Article]
  4. Han SF, Yao TT, Zhang XX, Gan L, Zhu C, Yu HZ, Gan Y: Lipid-based formulations to enhance oral bioavailability of the poorly water-soluble drug anethol trithione: effects of lipid composition and formulation. Int J Pharm. 2009 Sep 8;379(1):18-24. doi: 10.1016/j.ijpharm.2009.06.001. Epub 2009 Jun 7. [Article]
  5. Nagano T, Takeyama M: Enhancement of salivary secretion and neuropeptide (substance P, alpha-calcitonin gene-related peptide) levels in saliva by chronic anethole trithione treatment. J Pharm Pharmacol. 2001 Dec;53(12):1697-702. [Article]
  6. Fox PC: Salivary enhancement therapies. Caries Res. 2004 May-Jun;38(3):241-6. doi: 10.1159/000077761. [Article]
  7. Reddy BS, Rao CV, Rivenson A, Kelloff G: Chemoprevention of colon carcinogenesis by organosulfur compounds. Cancer Res. 1993 Aug 1;53(15):3493-8. [Article]
  8. Anil S, Vellappally S, Hashem M, Preethanath RS, Patil S, Samaranayake LP: Xerostomia in geriatric patients: a burgeoning global concern. J Investig Clin Dent. 2016 Feb;7(1):5-12. doi: 10.1111/jicd.12120. Epub 2014 Sep 1. [Article]
  9. Gupta A, Epstein JB, Sroussi H: Hyposalivation in elderly patients. J Can Dent Assoc. 2006 Nov;72(9):841-6. [Article]
  10. NIH National Cancer Institute Dictionary of Cancer Terms: Anetholtrithione [Link]
  11. The Medicine Shoppe Pharmacy: Sialor, 25MG, Tablet (anethole trithione) Monograph [Link]
  12. Anethole trithione liposome and its prepn [Link]
KEGG Drug
D01584
PubChem Compound
2194
PubChem Substance
347829320
ChemSpider
2109
RxNav
820
ChEBI
31221
ChEMBL
CHEMBL178862
ZINC
ZINC000000000949
Wikipedia
Anethole_trithione
MSDS
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Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral25.0 mg
TabletOral25 mg / tab
TabletOral12.5 mg / tab
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00879 mg/mLALOGPS
logP3.58ALOGPS
logP3.29ChemAxon
logS-4.4ALOGPS
pKa (Strongest Basic)-4.8ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count1ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area9.23 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity70.15 m3·mol-1ChemAxon
Polarizability24.78 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Drug created on June 23, 2017 20:49 / Updated on July 29, 2021 06:27