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
- 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.
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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
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Sialor Tablet 25.0 mg Oral Pharmascience Inc 2000-08-02 Not applicable Canada Sialor Tab 25mg Tablet 25 mg / tab Oral Solvay Pharma Inc 1992-12-31 2000-07-28 Canada - Over the Counter Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Sulfarlem Tab 12.5mg Tablet 12.5 mg / tab Oral Solvay Pharma Inc 1993-12-31 1999-08-30 Canada
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
- 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]
- 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]
- 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]
- 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]
- 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]
- Fox PC: Salivary enhancement therapies. Caries Res. 2004 May-Jun;38(3):241-6. doi: 10.1159/000077761. [Article]
- 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]
- 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]
- Gupta A, Epstein JB, Sroussi H: Hyposalivation in elderly patients. J Can Dent Assoc. 2006 Nov;72(9):841-6. [Article]
- NIH National Cancer Institute Dictionary of Cancer Terms: Anetholtrithione [Link]
- The Medicine Shoppe Pharmacy: Sialor, 25MG, Tablet (anethole trithione) Monograph [Link]
- Anethole trithione liposome and its prepn [Link]
- External Links
- KEGG Drug
- D01584
- PubChem Compound
- 2194
- PubChem Substance
- 347829320
- ChemSpider
- 2109
- 820
- ChEBI
- 31221
- ChEMBL
- CHEMBL178862
- ZINC
- ZINC000000000949
- Wikipedia
- Anethole_trithione
- MSDS
- Download (72.5 KB)
Clinical Trials
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet Oral 25.0 mg Tablet Oral 25 mg / tab Tablet Oral 12.5 mg / tab - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Not Available
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.00879 mg/mL ALOGPS logP 3.58 ALOGPS logP 3.29 Chemaxon logS -4.4 ALOGPS pKa (Strongest Basic) -4.8 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 1 Chemaxon Hydrogen Donor Count 0 Chemaxon Polar Surface Area 9.23 Å2 Chemaxon Rotatable Bond Count 2 Chemaxon Refractivity 70.15 m3·mol-1 Chemaxon Polarizability 24.78 Å3 Chemaxon Number of Rings 2 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule Yes Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not Available
Drug created at June 23, 2017 20:49 / Updated at May 31, 2023 00:21