(Z)-Thiothiene has the ability to prevent cell death and/or increase cell survival and/or plasticity, especially in situations where toxic agents are present in cells, including neural cells [1]. The Z (cis) isomer of thiothixene is known as (Z)-Thiothixene, and it functions as a synthetic precursor and degrader [2].

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- (Z)-Thiothixene exhibits cell death inhibitory activity. In vitro experiments using multiple mammalian cell lines (including neuronal, cardiac, and epithelial cells) showed that it dose-dependently protected cells from stress-induced death (e.g., oxidative stress, toxin-induced damage). At concentrations of 1-10 μM, it increased cell viability by 30-60% compared with the vehicle control group (detected by MTT assay and lactate dehydrogenase (LDH) release assay) [1]

- Cell death protection assay: Mammalian cells were seeded in 96-well plates at a density of 5×10³ cells/well and cultured overnight. (Z)-Thiothixene (0.1-20 μM) was added 2 hours before inducing cell stress (e.g., hydrogen peroxide for oxidative stress, doxorubicin for toxin-induced damage). After 24-48 hours of stress exposure, cell viability was measured by MTT assay; LDH release in the supernatant was quantified to assess cell membrane integrity and death rate [1]

Absorption, Distribution and Excretion
As part of routine therapeutic drug monitoring, 59 plasma thiothoxane concentration measurements were performed in 42 patients. Data collection included concomitant medications, smoking history, and demographic variables. A retrospective analysis was conducted to assess the impact of these parameters on oral thiothoxane clearance. After grouping patients according to concomitant medications (i.e., no-interaction drugs, enzyme/clearance inducers, and enzyme/clearance inhibitors), enzyme inducers (e.g., anticonvulsants) significantly increased thiothoxane clearance, while clearance inhibitors (e.g., cimetidine) decreased it. Smoking significantly increased hepatic clearance of thiothoxane in the no-interaction and inhibitor groups, but this was not observed in the inducer group. The inducer group had significantly more patients with plasma thiothoxane concentrations below the detection limit than other groups. When all patients were divided into two groups by age, the mean clearance rate was significantly higher in patients under 50 years of age (48.2 ± 37.8 L/min) than in patients 50 years of age and older (20.0 ± 12.6 L/min). The clearance rate in male patients (49.2 ± 38.7 L/min) was significantly higher than that in female patients (22.0 ± 13.5 L/min). A more appropriate thiothoxane dosage may be achieved by considering these potential sources of pharmacokinetic variation when monitoring plasma thiothoxane concentrations. Controlled prospective studies are needed to validate these findings. Thiothione is widely distributed throughout the body and can remain in the body for several weeks after administration. Thiothione is readily absorbed from the gastrointestinal tract. Treatment response may occur within days to weeks after oral administration. The required plasma concentration for therapeutic effect is currently unknown. This article reports two studies on the correlation between acute single-dose thiothoxane (Navane) and age. In the first study, 28 male subjects received an oral dose of 20 mg, and serum samples were collected 2 hours later. The mean age of the subjects was 30 years, and the correlation coefficient between serum concentration and age was 0.43 (P < 0.02). In the second study, 25 subjects (mean age 41 years) received an oral dose of 10 mg. The results showed that the correlation coefficient between serum concentration and age was 0.41 (P<0.05). Previous studies have found that this acute dose level is associated with steady-state serum concentration and the clinical efficacy of the drug. ...

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Metabolism/Metabolites
Hepatic metabolism.
Thiothoxane is metabolized in the liver and mainly excreted via bile, in the form of the original drug and demethylated, sulfoxide, demethyl sulfoxide, and hydroxylated thiothoxane derivatives in feces.

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Biological half-life
10-20 hours

Toxicity Summary
Identification and Uses: Thiothioxane is a solid. It is an antipsychotic and dopamine antagonist. Thiothioxane capsules are effective in treating schizophrenia. Human Studies: Patients receiving antipsychotic medications, including thiothiooxane, may experience tardive dyskinesia, a syndrome consisting of potentially irreversible involuntary motor disorders. Antipsychotic medications, including thiothiooxane, have also been reported to cause a potentially fatal symptom cluster, sometimes referred to as neuroleptic malignancy (NMS). Clinical manifestations of NMS include high fever, muscle rigidity, altered mental status, and evidence of autonomic dysfunction (irregular pulse or blood pressure, tachycardia, excessive sweating, and arrhythmias). Overdose symptoms include muscle twitching, drowsiness, and dizziness. Symptoms of severe overdose may include central nervous system depression, muscle rigidity, weakness, torticollis, tremor, drooling, dysphagia, hypotension, gait abnormalities, or coma. Elderly patients with dementia-related psychosis receiving antipsychotic medications have an increased risk of death. Thiothioxan may have additive or synergistic effects with other central nervous system depressants (including alcohol), anticholinergic drugs, or antihypertensive drugs. Animal studies: In animal reproductive studies of thiothiooxan, conception rates and litter sizes were decreased in rats and rabbits, while embryo resorption rates were increased. No teratogenic effects were observed after repeated oral administration of thiothiooxan to rats (5–15 mg/kg/day), rabbits (3–50 mg/kg/day), and monkeys (1–3 mg/kg/day) before and during pregnancy.

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Effects during pregnancy and lactation
◉ Overview of use during lactation
Since there is no published experience with the use of thiothiooxan during lactation, it is recommended to prioritize other antipsychotic drugs.
◉ Effects on breastfed infants
As of the revision date, no relevant published information was found.
◉ Effects on lactation and breast milk
Thiothiooxan can cause galactorrhea. Hyperprolactinemia appears to be the cause of galactorrhea. Hyperprolactinemia is caused by the drug's dopamine blockade effect on the tuberous-infundibulum pathway. For established lactating mothers, prolactin levels may not affect their ability to breastfeed. Drug Interactions: Studies have found that hepatic microsomal enzyme inducers, such as carbamazepine, can significantly increase the clearance of thiothoxane. Patients taking such drugs should be closely monitored for signs of decreased efficacy of thiothoxane. In this study, healthy volunteers received thiothoxane either with or without a 3-day pretreatment with paroxetine to determine whether paroxetine reduces the clearance of thiothoxane. Ten healthy, drug-free volunteers (4 women and 6 men, mean age 38 ± 12 years) were randomly assigned to receive a single 20 mg oral dose of thiothoxane at two different time points. In one instance, thiothoxane was administered concurrently with a 3-day pretreatment with paroxetine (20 mg/day). In the other instance, thiothoxane was administered without paroxetine pretreatment. The two studies were spaced at least 2 weeks apart. On both study days, 10 mL blood samples were collected within the next 72 hours after administration of thiothoxane. No significant changes were observed in any pharmacokinetic parameters of thiothoxane after 3 days of paroxetine treatment. The CYP2D6 isoenzyme may not be the primary enzyme for thiothoxane clearance, but the possibility that prolonged paroxetine pretreatment may have inhibited thiothoxane clearance to some extent cannot be ruled out. Thiothione may have synergistic or synergistic effects with other central nervous system depressants (including alcohol), anticholinergic drugs, or antihypertensive drugs. Due to the potential synergistic effect with antihypertensive drugs, patients taking these medications should be closely monitored for signs of excessive hypotension when thiothoxane is added to their regimen.

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Non-human toxicity values
Oral LD50 in rats: 720 mg/kg
Subcutaneous LD50 in rats: 2 g/kg
Oral LD50 in mice: 400 mg/kg
Subcutaneous LD50 in mice: 4 g/kg

[1]. Novel compounds and methods for inhibiting cell death. US 20150141345 A1.

[2]. Severin G. Comprehensive high-performance liquid chromatographic methodology for the determination of thiothixene in bulk drug, finished product, and dissolution testing samples. J Pharm Sci. 1987 Mar;76(3):231-4.

Thiothiazine is an N-methylpiperazine compound with anticoronavirus activity. It is a thioxanthracene compound used as an antipsychotic, with effects similar to phenothiazine antipsychotics. Thiothiazine is a typical antipsychotic. It is a thioxanthracene derivative and also a dopamine antagonist with antipsychotic activity. Thiothiazine blocks postsynaptic dopamine receptors in the mesolimbic system and medullary chemoreceptor trigger zones, thereby reducing dopamine activity, thus reducing stimulation of the vomiting center and alleviating psychotic symptoms such as hallucinations and delusions. Furthermore, the drug blocks D2 cell body dendritic autoreceptors, thereby increasing dopamine metabolism. Thiothiazine has a weak affinity for histamine H1 receptors and α-adrenergic receptors. Thiothiazine hydrochloride is the hydrochloride form of thioxanthine, a thioxanthate derivative and also a dopamine antagonist with antipsychotic activity. Thiothiazol blocks postsynaptic dopamine receptors in the mesolimbic system and medullary chemoreceptor trigger zones, thereby reducing dopamine activity, leading to decreased stimulation of the vomiting center and psychotic symptoms such as hallucinations and delusions. In addition, the drug blocks D2 cell body dendritic autoreceptors, thereby increasing dopamine metabolism. Thiothiazol has a weak affinity for histamine H1 receptors and α-adrenergic receptors.
A thioxanthracene compound used as an antipsychotic. Its effects are similar to those of phenothiazine antipsychotics.
See also: Thiothiazol hydrochloride (salt form).
Drug Indications
For the treatment of schizophrenia.

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Mechanism of Action
Thiaxoxane acts as an antagonist (blocker) on different postsynaptic receptors—dopaminergic receptors (D1, D2, D3, and D4 subtypes—with different antipsychotic properties for productive and nonproductive symptoms), serotonergic receptors (5-HT1 and 5-HT2, which have anti-anxiety, antidepressant, and anti-aggressive properties and can reduce extrapyramidal side effects, but can also cause weight gain, decreased blood pressure, sedation, and ejaculatory dysfunction), and histaminergic receptors (H1... It acts on receptors (sedative, antiemetic, dizzy, blood pressure lowering, and weight gain), α1/α2 receptors (antisympathetic effects, blood pressure lowering, reflex tachycardia, dizziness, sedation, excessive salivation and urinary incontinence, and sexual dysfunction, but may also alleviate pseudo-Parkinsonian syndrome—controversial), and finally acts on muscarinic (cholinergic) M1/M2 receptors (causing anticholinergic symptoms such as dry mouth, blurred vision, constipation, difficulty/inability to urinate, sinus tachycardia, ECG changes, and memory loss, but anticholinergic effects may reduce extrapyramidal side effects).

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Therapeutic Uses
Anthemistry; Dopamine antagonists
/Clinical Trials/ ClinicalTrials.gov is a registry and results database that includes human clinical studies funded by public and private institutions worldwide. This website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov includes a summary of the study protocol, including: the disease or condition; the intervention (e.g., the medical product, behavior, or procedure being investigated); the title, description, and design of the study; participation requirements (eligibility criteria); the location of the study; contact information for the study location; and links to other relevant health websites, such as NLM's MedlinePlus (which provides patient health information) and PubMed (which provides citations and abstracts of academic articles in the medical field). Thiothioxane is listed in this database.
Thiothiooxane capsules are effective in treating schizophrenia. /US product label contains/
Limited experience with this drug in treating neurosis does not suggest that thiothiooxane may be superior to anti-anxiety medications, butyrophenones, phenothiazines, or chlorprothiooxane (which is discontinued in the US). Thiothioxane has not been evaluated for the treatment of behavioral complications in patients with intellectual disabilities.

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Drug Warning
/Black Box Warning/ Increased Mortality in Alzheimer's Disease-Related Psychosis: The risk of death is increased in patients with Alzheimer's disease-related psychosis who are receiving antipsychotic medications. An analysis of 17 placebo-controlled trials (mean duration 10 weeks) showed that the risk of death was 1.6 to 1.7 times higher in patients treated with medication compared to those treated with placebo. These trials primarily involved patients taking atypical antipsychotics. In a typical 10-week controlled trial, the mortality rate was approximately 4.5% in the medication group and approximately 2.6% in the placebo group. Although the causes of death varied, most deaths appeared to be related to cardiovascular diseases (e.g., heart failure, sudden death) or infectious diseases (e.g., pneumonia). Observational studies suggest that, similar to atypical antipsychotics, treatment with conventional antipsychotics may increase mortality. The extent to which the increased mortality observed in observational studies is attributable to the antipsychotics themselves, rather than certain patient characteristics, is currently unclear. Thiothioxine is not approved for the treatment of dementia-related psychosis. Tardive dyskinesia is a syndrome characterized by potentially irreversible, involuntary movement disorders that can occur in patients receiving antipsychotic medications, including thiothhioxine. Although the syndrome appears to have the highest incidence in older populations, particularly older women, prevalence estimates cannot be used to predict which patients are likely to develop the syndrome at the onset of antipsychotic medication. It remains unclear whether there are differences in the likelihood of different antipsychotic drugs causing tardive dyskinesia. Antipsychotic drugs, including thiothixanol, have been reported to cause a potentially fatal symptom cluster, sometimes referred to as neuroleptic malignant syndrome (NMS). Clinical manifestations of NMS include high fever, muscle rigidity, altered mental status, and autonomic dysfunction (irregular pulse or blood pressure, tachycardia, excessive sweating, and arrhythmias). The most common adverse reactions to thiothixanol are somnolence (usually mild and resolving with continued treatment) and extrapyramidal symptoms. Similar to propylpiperazine phenothiazines, thiothixanol is more likely to cause akathisia and dystonia than Parkinsonian-like syndromes. Extrapyramidal reactions are usually controlled by reducing the dose of thiothixanol and/or taking anti-Parkinsonian medications.
For more complete data on drug warnings for thiothoxane (21 in total), please visit the HSDB record page.

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Pharmacodynamics
Thiothoxane is a thioxanthidine antipsychotic. Thiothione is chemically and pharmacologically similar to piperazine phenothiazines, but differs from aliphatic phenothiazines. Although thiothoxane was widely used for the treatment of schizophrenia for decades, it is now rarely used, replaced by atypical antipsychotics such as risperidone.

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-(Z)-thiothoxane is a synthetic compound whose potential to inhibit cell death has been disclosed in patents [1].
-This paper establishes a high-performance liquid chromatography (HPLC) method for its quantitative analysis. The method uses a reversed-phase column and a mobile phase consisting of an organic solvent and a buffer, and can accurately determine the content of (Z)-thiothoxane in active pharmaceutical ingredients, formulations, and dissolution test samples. This method has good linearity (correlation coefficient > 0.999), precision (RSD < 2%) and recovery (98-102%), and is suitable for quality control and dissolution curve evaluation [2].

C23H29N3O2S2

443.62526

443.17

3313-26-6

Thiothixene hydrochloride;49746-04-5

941651

White to off-white solid powder

1.269 g/cm3

599ºC at 760 mmHg

114-118ºC

316.1ºC

1.643

4.427

0

6

5

30

711

0

CN1CCN(CC1)CC/C=C\2/C3=CC=CC=C3SC4=C2C=C(C=C4)S(=O)(=O)N(C)C

GFBKORZTTCHDGY-UWVJOHFNSA-N

InChI=1S/C23H29N3O2S2/c1-24(2)30(27,28)18-10-11-23-21(17-18)19(20-7-4-5-9-22(20)29-23)8-6-12-26-15-13-25(3)14-16-26/h4-5,7-11,17H,6,12-16H2,1-3H3/b19-8-

(9Z)-N,N-dimethyl-9-[3-(4-methylpiperazin-1-yl)propylidene]thioxanthene-2-sulfonamide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~10 mg/mL (~22.54 mM)

Solubility in Formulation 1: ≥ 1 mg/mL (2.25 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 1 mg/mL (2.25 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 1 mg/mL (2.25 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)