NCI-N87 and AGS cell viability is lowered by thioridazine (0.01-100 μM; 48 h) in a concentration-dependent manner [2]. Cell viability of endometrial cancer cells (HEC-1-A and KLE) and cervical cancer cells (HeLa, Caski, and C33A) is decreased by thioridazine (15 μM; 24 hours) [4]. Through both the mitochondrial pathway and the mitochondrial apoptotic pathway, thioridazine (1–15 μM; 24-48 h) causes the death of gastric cancer cells [2]. In cervical and endometrial cancer cells, thioridazine (15 μM; 24 hours) promotes G1 cell cycle arrest and interferes with the PI3K/Akt pathway to regulate cell cycle progression [4]. Acinetobacter baumannii strains that are both multidrug resistant and susceptible to antibiotics cannot develop when thioridazine is used [3].

Tumor-bearing mice's survival is extended when thioridazine (25 mg/kg; intraperitoneally every 3 days for 3 weeks) is administered, and the amount of pluripotent embryonal carcinoma cells (ECs) inside the tumors is decreased [5]. Subcutaneous injection of thioridazine (1.0-5.0 mg/kg) lowers oral habits and inhibits repetitive head bobbing selectively [1].

Cell viability assay[1]
Cell Types: NCI-N87 and AGS cells.
Tested Concentrations: 0.01, 0.1, 0.5, 1, 5, 10, 20, 50, 100 μM.
Incubation Duration: 48 hrs (hours).
Experimental Results: demonstrated cytotoxicity to gastric cancer cells.

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Western Blot Analysis[1]
Cell Types: NCI-N87 and AGS Cell
Tested Concentrations: 1, 5, 10, 15 μM.
Incubation Duration: 24, 48 hrs (hours).
Experimental Results: Down-regulation of caspase-9, caspase-8 and caspase-3 precursor proteins.

Animal/Disease Models: Nude mice and Rag2KO mice were injected with iPS cells or NT2D1 cells [5].
Doses: 25 mg/kg.
Route of Administration: IP every 3 days for 3 weeks.
Experimental Results: The number of OCT4-expressing cells in malignant teratocarcinoma was diminished and the survival period of tumor-bearing mice was prolonged. Has no effect on fertility.

Absorption, Distribution and Excretion
60%
Animal and in vitro studies have shown that thioridazine has an affinity for melanin granules and tends to accumulate by tightly binding with uveal pigment…
…Pharmacokinetics and Metabolism…Similar to chlorpromazine…However, the strong anticholinergic effect of thioridazine on the intestine may alter its absorption…The concentration of thioridazine in plasma is relatively high (hundreds of nanograms/mL), which may be related to its relative hydrophilicity…
In 48 patients who took thioridazine, the average content of thioridazine not bound to serum proteins was 0.15%, side-chain sulfoxides 1.66%, side-chain sulfones 1.17%, and cyclic sulfoxides 1.7%.
Gas chromatography was used to determine thioridazine and its metabolites in brain, liver, and kidney tissue specimens from two patients who died from acute thioridazine poisoning. Although the absolute concentrations of thioridazine and its metabolites differed between the two patients, the metabolic patterns of the drug in various tissues (expressed as a percentage of the total drug in each tissue) were very similar. However, the metabolic patterns in the brain, liver, and kidneys were distinctly different from the plasma metabolite patterns in subjects treated with thioridazine. As this example illustrates, autopsy specimens are a valuable (but rarely used) source of human pharmacological data. For more complete data on the absorption, distribution, and excretion of thioridazine (10 in total), please visit the HSDB record page. Metabolism/Metabolites Liver Major metabolites include sulfoxide products at the 5-position (inactive) or 2-position substituents (including the active metabolite mesoliridazine) of the ring. Demethylation of the piperidine ring is very rapid… Although the exact metabolic pathways of phenothiazines are not fully understood, these drugs are extensively metabolized in the liver primarily through hydroxylation, oxidation, demethylation, sulfoxide formation, and glucuronide conjugation; side-chain metabolic alterations may also occur. /Overview of Phenothiazines/
Most metabolites of phenothiazines are pharmacologically inactive; however, some metabolites (e.g., 7-hydroxychlorpromazine, mesorizine) have moderate pharmacological activity and may participate in the drug's action. Limited evidence suggests that some phenothiazines (e.g., chlorpromazine) may induce their own metabolism. /Overview of Phenothiazines/
Thioridazine and its metabolites were determined in five autopsy blood samples using selective high-performance liquid chromatography (HPLC); two deaths were attributed to drug overdose, and three deaths were attributed to natural causes or trauma. Furthermore, the total amount of thioridazine compounds in these blood samples and liver specimens was determined using a nonspecific fluorescence method. Blood concentrations were: thioridazine 0.78–8.85 mg/L; mesorizine 0.52–26.8 mg/L; Sulfasymazine 0.00–0.87 mg/L. The concentration ranges of the stereoisomers thioridazine-5-sulfoxide (DL, LD and DD, LL) are 0.02–0.56 mg/L and 0.03–0.83 mg/L, respectively. The metabolite profile of thioridazine is not helpful in distinguishing between therapeutic and severe overdose. The liver appears to be the preferred specimen for assessing thioridazine overdose. For more complete metabolite/metabolite data on thioridazine (8 metabolites in total), please visit the HSDB record page. Known human metabolites of thioridazine include N-demethylthioridazine, thioridazine-2-sulfoxide, and thioridazine-5-sulfoxide. Sulfaridazine is a known human metabolite listed in schembl149458.
Liver
Half-life: 21-25 hours

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Biological half-life
21-25 hours
The serum half-life of thioridazine is estimated to be more than 6 to 40 hours.

Toxicity Summary
Thioridazine blocks postsynaptic mesolimbic dopamine D1 and D2 receptors in the brain; it blocks alpha-adrenergic effects, inhibits the release of hypothalamic and pituitary hormones, and is thought to inhibit the reticular activating system, thereby affecting basal metabolism, body temperature, arousal, vasomotor activity, and vomiting. Hepatotoxicity
Liver dysfunction has been reported in patients taking phenothiazines long-term, but elevations exceeding three times the upper limit of normal are uncommon. Transaminase abnormalities are usually mild, asymptomatic, and transient, and are reversible with continued use. Thioridazine can cause rare, clinically significant acute liver injury with symptoms similar to jaundice caused by chlorpromazine. Jaundice usually appears weeks to months after treatment, with serum enzyme elevations typically cholestatic, although hepatocellular patterns have been reported. Immune allergic reactions (fever, rash, and eosinophilia) are not prominent, and no autoantibodies have been detected. Some cases are associated with agranulocytosis, a rare but known complication of phenothiazines.
Probability Score: B (Possibly but rarely causes clinically significant liver damage).

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Effects during Pregnancy and Lactation
◉ Overview of Use During Lactation
Since there is no published experience with thioridazine during lactation, alternative medications may be preferred, especially when breastfeeding newborns or preterm infants.
◉ Effects on Breastfed Infants
As of the revision date, no relevant published information was found.
◉ Effects on Lactation and Breast Milk
Phenothiazines can cause galactorrhea in 26% to 40% of female patients. Hyperprolactinemia appears to be the cause of galactorrhea. There is evidence that thioridazine raises serum prolactin levels more than other phenothiazines. Hyperprolactinemia is caused by the drug's dopamine blocking effect on the tuberous-infundibular pathway. Prolactin levels in established lactating mothers may not affect their lactation capacity. Protein binding rate: 95% Toxicity data: LD50 = 956-1034 mg/kg (oral administration in rats). Interactions: QT prolonging drugs, including cisapride, erythromycin, and quinidine, may produce additive QT prolongation when used in combination with phenothiazines, increasing the risk of arrhythmias. Phenothiazines: Phenothiazines may produce additive photosensitizing effects when used in combination with other photosensitizing drugs. Furthermore, concomitant use of systemic methoxsalen, triamcinolone, or tetracyclines with phenothiazines may exacerbate intraocular photochemical damage to the choroid, retina, or lens. Prior use of phenothiazines may reduce the pressor effect of phenylephrine and shorten its duration of action. /Phenothiazines/
In addition to increasing central nervous system and respiratory depression, concomitant use of /opioid (narcotic) analgesics/ phenothiazines can increase orthostatic hypotension and the risk of severe constipation, which may lead to paralytic ileus and/or urinary retention. /Phenothiazines/
For more complete data on interactions of thioridazines (30 in total), please visit the HSDB record page.

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Non-human toxicity values
Oral LD50 in rats: 995 mg/kg

[1]. Tschanz JT, et, al. Atypical antipsychotic drugs block selective components of amphetamine-induced stereotypy. Pharmacol Biochem Behav. 1988 Nov;31(3):519-22.
[2]. Mu J, et, al. Thioridazine, an antipsychotic drug, elicits potent antitumor effects in gastric cancer. Oncol Rep. 2014 May;31(5):2107-14.
[3]. Kang S, et, al. Thioridazine induces apoptosis by targeting the PI3K/Akt/mTOR pathway in cervical and endometrial cancer cells. Apoptosis. 2012 Sep;17(9):989-97.
[4]. Loehr AR, et, al. Targeting Cancer Stem Cells with Differentiation Agents as an Alternative to Genotoxic Chemotherapy for the Treatment of Malignant Testicular Germ Cell Tumors. Cancers (Basel). 2021 Apr 23;13(9):2045.

Therapeutic Uses

Antipsychotic, phenothiazines; dopamine antagonist
Thioridazine is indicated for patients with schizophrenia who have not responded adequately to other antipsychotic medications. Because thioridazine treatment carries a significant and potentially life-threatening risk of arrhythmias, it should only be used in patients who have not responded adequately to other antipsychotic medications for an appropriate duration, and who may not be able to reach an effective dose due to inadequate efficacy or intolerable adverse reactions. Therefore, it is strongly recommended that patients undergo a trial of at least two different antipsychotic medications, each at an adequate dose and duration, before initiating treatment with thioridazine. /US product label includes/
Prescribing physicians should note that thioridazine has not been systematically evaluated in controlled trials in patients with treatment-resistant schizophrenia, and its efficacy in these patients is unclear. /US product label includes/
The US Food and Drug Administration (FDA) currently advises clinicians that antipsychotic medications are not approved for the treatment of dementia-related psychosis. The FDA also advises clinicians that, since no drugs are currently approved for the treatment of dementia-related psychosis, alternative treatment options should be considered. /Phenothiazines General Statement/

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Drug Warnings
...Extrapyramidal reactions...Quite common, usually of three types...Parkinsonian syndrome...Dystonia and movement disorders, including torticollis, tics, and other involuntary muscle movements...Akasoriatic disorder, manifested as restlessness...Hyperreflexia has been reported in newborns... /Phenothiazines/
Thioridazine has been shown to prolong the QTc interval in a dose-dependent manner. Drugs with this potential, including thioridazine, have been associated with torsades de pointes and sudden cardiac death. Because thioridazine can produce significant, even life-threatening, arrhythmic effects, it should only be used to treat patients with schizophrenia who have not responded adequately to other antipsychotic medications for a full course, and who may not be able to reach an effective dose due to inadequate efficacy or intolerance to adverse drug reactions.
The risk of death is increased in patients with dementia-related psychosis who receive antipsychotic medication. 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 the medication group than in the placebo group. These trials primarily involved patients taking atypical antipsychotics. In typical 10-week controlled trials, 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 characteristics of the patients, is currently unclear. Thioridazine hydrochloride is not approved for the treatment of patients with dementia-related psychosis. As with other phenothiazines, thioridazine is contraindicated in severe central nervous system depression or coma from any cause, including drug-induced central nervous system depression. It should also be noted that extremely high blood pressure or hypotensive heart disease are contraindications for phenothiazines. For more complete data on drug warnings for thioridazine (48 in total), please visit the HSDB records page.

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Pharmacodynamics
Thioridazine is a trifluoromethylphenothiazine derivative used to treat schizophrenia and other psychotic disorders. Thioridazine has not been shown to be effective in treating behavioral complications in patients with intellectual disability.

C21H26N2S2

370.573

370.153

50-52-2

Thioridazine hydrochloride;130-61-0;Thioridazine-d3 hydrochloride;1189928-36-6

5452

Crystals from acetone
Colorless crystals

1.2±0.1 g/cm3

515.7±50.0 °C at 760 mmHg

72-74°

265.7±30.1 °C

0.0±1.3 mmHg at 25°C

1.677

6.13

0

4

4

25

432

0

KLBQZWRITKRQQV-UHFFFAOYSA-N

InChI=1S/C21H26N2S2/c1-22-13-6-5-7-16(22)12-14-23-18-8-3-4-9-20(18)25-21-11-10-17(24-2)15-19(21)23/h3-4,8-11,15-16H,5-7,12-14H2,1-2H3

10-[2-(1-methylpiperidin-2-yl)ethyl]-2-methylsulfanylphenothiazine

Thioridazine Melleril Mellaril

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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