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%
Experimental studies in animals and in vitro have demonstrated that thioridazine has affinity for melanin granules and tends to accumulate in close association with uveal pigment ... .
... Pharmacokinetics and metabolism ... similar ... to chlorpromazine, but strong anticholinergic action of thioridazine on the gut may modify its own absorption ... . Concentrations of thioridazine in plasma are relatively high (hundreds of nanograms per milliliter), possibly owing to its relative hydrophilicity ... .
In 48 patients taking thiordazine the mean amount not bound to serum proteins was 0.15%, that of the side-chain sulfoxide 1.66%, side-chain sulfone 1.17%, and ring sulfoxide 1.7%.
Thioridazine and metabolites were measured in brain, liver, and kidney specimens, obtained postmortem from two subjects whose deaths were related to acute intoxication with thioridazine, by gas-liquid chromatography. Although the absolute concentration measured for thioridazine and metabolites differed in the two cases, the metabolic pattern for each tissue, expressed in terms of the percentage of total drug in each tissue, was quite similar. The brain, liver, and kidney metabolic patterns, however, are in sharp contrast to the plasma metabolite patterns observed for subjects on a therapeutic regimen of thioridazine. As this example demonstrates, postmortem specimens are a valuable (but seldom used) source of human pharmacological data.
For more Absorption, Distribution and Excretion (Complete) data for Thioridazine (10 total), please visit the HSDB record page.

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Metabolism / Metabolites
Hepatic
Major metabolites include sulfoxy products at ring position 5 (inactive) or at substituent at position 2 (including active metabolite mesoridazine). Demethylation of piperidine ring is very rapid ... .
Although the exact metabolic fate of phenothiazines has not been clearly established, the drugs are extensively metabolized, principally in the liver via hydroxylation, oxidation, demethylation, sulfoxide formation, and conjugation with glucuronic acid; metabolic alterations in the side chain also may occur. /Phenothiazine General Statement/
Most metabolites of phenothiazines are pharmacologically inactive; however, certain metabolites (eg, 7-hydroxychlorpromazine, mesoridazine) show moderate pharmacologic activity and may contribute to the action of the drugs. There is limited evidence to indicate that some phenothiazines (eg, chlorpromazine) may induce their own metabolism. /Phenothiazine General Statement/
Thioridazine and metabolites were determined by a selective HPLC technique in blood from five post-mortem cases; two deaths attributed to drug overdose and three deaths due to natural causes or trauma. Additionally, total thioridazine-like compounds were determined in these blood samples and liver specimens by a nonspecific fluorometric technique. Blood concentrations were: thioridazine, 0.78-8.85 mg/L; mesoridazine, 0.52-26.8 mg/L; and sulforidazine, 0.00-0.87 mg/L. Thioridazine-5-sulfoxide stereoisomeric DL,LD, and DD,LL pair concentrations ranged from 0.02-0.56 and 0.03-0.83 mg/L, respectively. Thioridazine metabolite profiles were not helpful in differentiating therapeutic administration from severe overdose. Liver appears to be the specimen of choice in the assessment of thioridazine overdose.
For more Metabolism/Metabolites (Complete) data for Thioridazine (8 total), please visit the HSDB record page.
Thioridazine has known human metabolites that include N-desmethylthioridazine, Thioridazine 2-sulfoxide, and Thioridazine 5-sulfoxide.
Sulphoridazine is a known human metabolite of schembl149458.
Hepatic
Half Life: 21-25 hours

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Biological Half-Life
21-25 hours
Serum half-life of thioridazine has been estimated to range from about 6 to over 40 hours.

Toxicity Summary
Thioridazine blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain; blocks alpha-adrenergic effect, depresses the release of hypothalamic and hypophyseal hormones and is believed to depress the reticular activating system thus affecting basal metabolism, body temperature, wakefulness, vasomotor tone, and emesis.

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Hepatotoxicity
Liver test abnormalities have been reported to occur in a high proportion of patients on long term phenothiazine therapy, but elevations are uncommonly above 3 times the upper limit of normal. The aminotransferase abnormalities are usually mild, asymptomatic and transient, reversing even with continuation of medication. Rare instances of clinically apparent acute liver injury have been reported due to thioridazine, with some resemblance to cases of chlorpromazine jaundice. The onset of jaundice occurred within a few weeks to several months of therapy and the pattern of serum enzyme elevations was typically cholestatic, although hepatocellular patterns have also been reported. Immunoallergic manifestations (fever, rash and eosinophilia) were not prominent and autoantibodies were not detected. Some cases were associated with agranulocytosis which is a rare but known complication of the phenothiazines.
Likelihood score: B (likely but rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Because there is no published experience with thioridazine during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Phenothiazines cause galactorrhea in 26 to 40% of female patients. Hyperprolactinemia appears to be the cause of the galactorrhea. There is some evidence that thioridazine increases serum prolactin to a greater extent than other phenothiazines. 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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Protein Binding
95%

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Toxicity Data
LD₅₀=956-1034 mg/kg (Orally in rats).

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Interactions
QT interval-prolonging medications, including cisapride, erythromycin, and quinidine /may produce/ additive QT interval prolongation increasing the risk of developing cardiac arrhythmias when /concurrently administered with phenothiazines/. /Phenothiazines/
Concurrent use /of other photosensitizing medications/ with phenothiazines may cause additive photosensitizing effects. In addition, concurrent use of systemic methoxsalen, trixsalen, or tetracyclines with phenothiazines may potentiate intraocular photochemical damage to the choroid, retina, or lens. /Phenothiazines/
Prior administration of phenothiazines may decrease the pressor effect and shorten the duration of action of phenylephrine. /Phenothiazines/
In addition to increased CNS and respiratory depression, concurrent use /of opiod (narcotic) analgesics/ with phenothiazines increases orthostatic hypotension and increases the risk of severe constipation, which may lead to paralytic ileus, and/or urinary retention. /Phenothiazines/
For more Interactions (Complete) data for Thioridazine (30 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat oral 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 Agents, Phenothiazine; Dopamine Antagonists
Thioridazine is indicated for the management of schizophrenic patients who fail to respond adequately to treatment with other antipsychotic drugs. Due to the risk of significant, potentially life threatening, proarrhythmic effects with thioridazine treatment, thioridazine should be used only in patients who have failed to respond adequately to treatment with appropriate courses of other antipsychotic drugs, either because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse effects from those drugs. Consequently, before initiating treatment with thioridazine, it is strongly recommended that a patient be given at least two trials, each with a different antipsychotic drug product, at an adequate dose, and for an adequate duration. /Included in US product label/
The prescriber should be aware that thioridazine has not been systematically evaluated in controlled trials in treatment refractory schizophrenic patients and its efficacy in such patients is unknown. /Included in US product label/
The US Food and Drug Administration (FDA) currently advises clinicians that antipsychotic agents are not approved for the treatment of dementia-related psychosis. FDA further advises clinicians that no drugs currently are approved for the treatment of patients with dementia-associated psychosis and that other management options should be considered in such patients. /Phenothiazine General Statement/

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Drug Warnings
... Extrapyramidal reactions ... fairly common, usually 3 types ... Parkinsonian-like syndrome ... dystonia and dyskinesia, including torticollis, tics, and other involuntary muscle movements ... akathisia, shown by restlessness ... hyperreflexia, reported in newborn ... ./Phenothiazines/
Thioridazine has been shown to prolong the QTc interval in a dose related manner, and drugs with this potential, including thioridazine, have been associated with Torsades de pointes type arrhythmias and sudden death. Due to its potential for significant, possibly life threatening, proarrhythmic effects, thioridazine should be reserved for use in the treatment of schizophrenic patients who fail to show an acceptable response to adequate courses of treatment with other antipsychotic drugs, either because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse effects from those drugs
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 (eg, heart failure, sudden death) or infectious (eg, 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. Thioridazine hydrochloride is not approved for the treatment of patients with dementia-related psychosis
In common with other phenothiazines, thioridazine is contraindicated in severe central nervous system depression or comatose states from any cause including drug induced central nervous system depression. It should also be noted that hypertensive or hypotensive heart disease of extreme degree is a contraindication of phenothiazine administration.
For more Drug Warnings (Complete) data for Thioridazine (48 total), please visit the HSDB record page.

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Pharmacodynamics
Thioridazine is a trifluoro-methyl phenothiazine derivative intended for the management of schizophrenia and other psychotic disorders. Thioridazine has not been shown effective in the management of behaviorial complications in patients with mental retardation.

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.)