(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].

Absorption, Distribution and Excretion
Fifty-nine plasma thiothixene concentrations were measured in 42 patients as part of routine therapeutic drug monitoring. Data collection included concomitant medications, smoking history, and demographic variables. A retrospective analysis was performed to assess the effect of these parameters on oral thiothixene clearance. When groups of patients were categorized by concomitant medications (i.e., no interacting drugs, enzyme/clearance inducers, and enzyme/clearance inhibitors), thiothixene clearance was found to be significantly increased by enzyme inducing drugs (e.g., anticonvulsants) and decreased by clearance inhibiting agents (e.g., cimetidine). Tobacco smoking significantly increased the hepatic clearance of thiothixene within the no interactions and inhibitor groups, but not in the inducer group. Significantly more patients in the inducer group had nondetectable plasma concentrations of thiothixene than the other groups. When the entire patient population was dichotomized by age, patients less than 50 years old had a significantly greater mean clearance (48.2 +/- 37.8 liters/min) versus those greater than or equal to 50 (20.0 +/- 12.6 liters/min). Men in this cohort exhibited a significantly higher clearance (49.2 +/- 38.7 liters/min) than did the women (22.0 +/- 13.5 liters/min). By taking into account these potential sources of pharmacokinetic variability when monitoring plasma thiothixene concentrations, more appropriate dosing of thiothixene may be achieved. Controlled, prospective studies are needed to validate these findings.
Thiothixene is widely distributed into body tissues and may remain in the body for several weeks following administration.
Thiothixene is well absorbed from the GI tract. Therapeutic response may occur within a few days to several weeks following oral administration of the drug. Plasma concentrations required for therapeutic effects are not known.
Two experiments are reported in which acute single test dose levels of thiothixene (Navane) were correlated with age. In the first study 20 mg oral doses were given to 28 male subjects and serum levels were drawn 2 hr later. Mean age was 30 and correlation of serum level with age was 0.43, P less than 0.02. In a second older group with a mean age of 41, 10 mg oral doses were given to 25 subjects. A correlation with age of 0.41, P less than 0.05 was obtained with age. In prior work such acute levels have been found to correlate with steady-state serum levels and with clinical response to the medication. ...

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Metabolism / Metabolites
Hepatic.
Thiothixene is metabolized in the liver and is excreted mainly in feces via biliary elimination as unchanged drug and as the demethyl, sulfoxide, demethylated sulfoxide, and hydroxylated thiothixene derivatives.

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Biological Half-Life
10-20 hours

Toxicity Summary
IDENTIFICATION AND USE: Thiothixene is a solid. It is antipsychotic agent and dopamine antagonist. Thiothixene capsules are effective in the management of schizophrenia. HUMAN STUDIES: Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs, including thiothixene. A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs, including thiothixene. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Manifestations of overdose include muscular twitching, drowsiness and dizziness. Symptoms of gross overdosage may include CNS depression, rigidity, weakness, torticollis, tremor, salivation, dysphagia, hypotension, disturbances of gait, or coma. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Thiothixene may be additive with or may potentiate the action of other CNS depressants (including alcohol), anticholinergics, or hypotensive agents. ANIMAL STUDIES: In animal reproduction studies with thiothixene, there was some decrease in conception rate and litter size, and an increase in resorption rate in rats and rabbits. After repeated oral administration of thiothixene to rats (5 to 15 mg/kg/day), rabbits (3 to 50 mg/kg/day), and monkeys (1 to 3 mg/kg/day) before and during gestation, no teratogenic effects were seen.

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Because there is no published experience with thiothixene during breastfeeding, other antipsychotic agents are preferred.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Thiothixene has caused galactorrhea. Hyperprolactinemia appears to be the cause of the galactorrhea. The hyperprolactinemia is caused by the drug's dopamine-blocking action in the tuberoinfundibular pathway. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

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Interactions
Hepatic microsomal enzyme inducing agents, such as carbamazepine, were found to significantly increase the clearance of thiothixene. Patients receiving these drugs should be observed for signs of reduced thiothixene effectiveness.
In this study healthy volunteers received thiothixene with and without a 3-day pretreatment with paroxetine to determine if paroxetine decreased the clearance of thiothixene. Ten healthy medication-free volunteers (4 women and 6 men, mean age 38 +/- 12 years) were randomized to receive a single 20 mg oral dose of thiothixene on two separate occasions. On one occasion thiothixene was given concurrently, and following 3 days of pre-treatment with oral paroxetine (20 mg/day). On the other occasion thiothixene was given without paroxetine pre-treatment. The two study days were separated by a minimum period of 2 weeks. On both study days, after the administration of thiothixene, 10 mL blood samples were collected over the next 72 hr. None of the pharmacokinetic parameters of thiothixene were significantly altered by a 3-day treatment with paroxetine. It is likely that the CYP2D6 isoenzyme is not responsible for a high proportion of thiothixene clearance, but one cannot exclude the possibility that a longer paroxetine pretreatment might have caused some inhibition of thiothixene clearance.
Thiothixene may be additive with or may potentiate the action of other CNS depressants (including alcohol), anticholinergics, or hypotensive agents.
Due to a possible additive effect with hypotensive agents, patients receiving these drugs should be observed closely for signs of excessive hypotension when thiothixene is added to their drug regimen.

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Non-Human Toxicity Values
LD50 Rat oral 720 mg/kg
LD50 Rat sc 2 g/kg
LD50 Mouse oral 400 mg/kg
LD50 Mouse sc 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.

Thiothixene is a N-methylpiperazine. It has a role as an anticoronaviral agent.
A thioxanthine used as an antipsychotic agent. Its effects are similar to the phenothiazine antipsychotics.
Thiothixene is a Typical Antipsychotic.
Thiothixene is a thioxanthene derivative and a dopamine antagonist with antipsychotic property. Thiothixene blocks postsynaptic dopamine receptors in the mesolimbic system and medullary chemoreceptor trigger zone, thereby decreasing dopamine activity leading to decreased stimulation of the vomiting center and psychotic effects, such as hallucinations and delusions. In addition, this agent blocks the D2 somatodendritic autoreceptor, thereby increasing dopamine turnover. Thiothixene possesses weak affinity for the histamine H1 and alpha-adrenergic receptors.
Thiothixene Hydrochloride is the hydrochloride salt form of thiothixene, a thioxanthene derivative and a dopamine antagonist with antipsychotic property. Thiothixene blocks postsynaptic dopamine receptors in the mesolimbic system and medullary chemoreceptor trigger zone, thereby decreasing dopamine activity leading to decreased stimulation of the vomiting center and psychotic effects, such as hallucinations and delusions. In addition, this agent blocks the D2 somatodendritic autoreceptor, thereby increasing dopamine turnover. Thiothixene possesses weak affinity for the histamine H1 and alpha-adrenergic receptors.
A thioxanthine used as an antipsychotic agent. Its effects are similar to the phenothiazine antipsychotics.
See also: Thiothixene Hydrochloride (has salt form).

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Drug Indication
For the management of schizophrenia.

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Mechanism of Action
Thiothixene acts as an antagonist (blocking agent) on different postsysnaptic receptors -on dopaminergic-receptors (subtypes D1, D2, D3 and D4 - different antipsychotic properties on productive and unproductive symptoms), on serotonergic-receptors (5-HT1 and 5-HT2, with anxiolytic, antidepressive and antiaggressive properties as well as an attenuation of extrapypramidal side-effects, but also leading to weight gain, fall in blood pressure, sedation and ejaculation difficulties), on histaminergic-receptors (H1-receptors, sedation, antiemesis, vertigo, fall in blood pressure and weight gain), alpha1/alpha2-receptors (antisympathomimetic properties, lowering of blood pressure, reflex tachycardia, vertigo, sedation, hypersalivation and incontinence as well as sexual dysfunction, but may also attenuate pseudoparkinsonism - controversial) and finally on muscarinic (cholinergic) M1/M2-receptors (causing anticholinergic symptoms like dry mouth, blurred vision, obstipation, difficulty/inability to urinate, sinus tachycardia, ECG-changes and loss of memory, but the anticholinergic action may attenuate extrapyramidal side-effects).

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Therapeutic Uses
Antipsychotic Agents; Dopamine Antagonists
/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Thiothixene is included in the database.
Thiothixene capsules are effective in the management of schizophrenia. /Included in US product label/
Experience with the drug in treating neurotic conditions is limited and does not indicate that thiothixene is likely to have advantages over anxiolytic agents, butyrophenones, phenothiazines, or chlorprothixene (no longer commercially available in the US). Thiothixene has not been evaluated in the management of behavioral complications in mentally retarded patients.

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Drug Warnings
/BOXED WARNING/ Increased Mortality in Elderly Patients with Dementia-Related Psychosis: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Thiothixene is not approved for the treatment of patients with dementia-related psychosis.
Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs, including thiothixene. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs, including thiothixene. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias).
The most frequent adverse effects of thiothixene are drowsiness (which usually is mild and subsides with continuation of therapy) and extrapyramidal symptoms. Like propylpiperazine phenothiazines, thiothixene is more likely to produce akathisia and dystonia than parkinson-like syndromes. Generally, extrapyramidal effects can be controlled by reducing the dosage of thiothixene and/or administering an antiparkinsonian drug.
For more Drug Warnings (Complete) data for Thiothixene (21 total), please visit the HSDB record page.

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Pharmacodynamics
Thiothixene is an antipsychotic of the thioxanthene series. Navane possesses certain chemical and pharmacological similarities to the piperazine phenothiazines and differences from the aliphatic group of phenothiazines. Although widely used in the treatment of schizophrenia for several decades, thiothixene is seldom used today in favor of atypical antipsychotics such as risperidone.

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.)