5-(4-Methoxyphenyl)-3H-1,2-dithiole-3-thione

240.36

240.36

208-528-5

QUY32964DJ

DTXSID9046651

C246

A16AX02|A - Alimentary tract and metabolism

2930909090

91.9

2.8

Powder

1.4±0.1 g/cm3

111 °C

398.1°C at 760 mmHg

194.6±30.7 °C

1.732

Oral-mouse LD50: 3850 mg/kg; peritoneal-mouse LD50: 1780 mg/kg

Flammable; burning produces toxic sulfur oxide fumes

Warehouse ventilated, low temperature and dry

P273, P391, P501

H400

moderately toxic

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.

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).

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. 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 with certain national cancer institutes listing the agent as 'a substance that is being studied in the treatment of cancer'.

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. Furthermore, ATT is quickly metabolized into 4-hydroxy-anethole trithione (ATX, which demonstrates a similar pharmacological activity to ATT) by way of O-demethylation. As a consequence, the plasma concentration of ATT is usually fairly low, resulting in a limited oral bioavailability as well. 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.

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

Anethole trithione (ATT) is metabolized rapidly into 4-hydroxy-anethole trithione via O-demethylation. This metabolite demonstrates similar pharmacological activities to its parent, ATT. 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.

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

Epidemiological studies demonstrate that the prevalence of xerostomia and salivary gland hypofunction (SGH) rises with age, and is largely associated with medications and health. 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. 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. 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. 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. 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 and has been indicated for use in treating xerostomia associated with conditions like Sjogren's syndrome. 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. ATT is also used as an adjunctive therapy for cholecystitis, gallstone, indigestion, and acute/chronic hepatitis in certain countries like France, Germany, and China. 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. 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. 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. 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. 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.

Anethol Dithiolthione