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trifluoperazine + trihexyphenidyl (Fluhex forte / Fluhex / Fluhexette)

✓ Approved

A. N. Pharmacia Laboratories · CHRM1 · Small Molecule

What is trifluoperazine + trihexyphenidyl?

trifluoperazine + trihexyphenidyl is a small molecule developed by A. N. Pharmacia Laboratories. It is approved for therapeutic indications via oral (po).

Drug Profile

Brand NamesFluhex forte, Fluhex, Fluhexette
CompanyA. N. Pharmacia Laboratories
Drug ClassSmall Molecule
Molecular TargetCHRM1
RouteOral (PO)
StatusApproved
Sources: ClinicalTrials.gov, A. N. Pharmacia Laboratories

Mechanism of Action

Molecular Targets

trifluoperazine + trihexyphenidyl acts on 1 molecular target:

CHRM1cholinergic receptor muscarinic 1 (M1, HM1)
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Therapeutic Indications

trifluoperazine + trihexyphenidyl is developed for 1 unique indication across 1 therapeutic area.

Therapeutic AreaConditionPhase
Psychiatric disordersSubstance-induced psychotic disorder✓ Approved

Related Research Articles

PubMedbioRxiv : the preprint server for biology2026-06-05

A membrane-permeable small molecule biosensor accesses intractable cells and animals without genetic manipulation.

Kreider Gabriel G, MacNevin Christopher J CJ, Vairaprakash Pothiappan P, Rougie Marie M et al.

Fluorescent biosensors have proven valuable for revealing the spatio-temporal dynamics of protein conformation in live cells and animals. The great majority of biosensors are genetically encoded, but genetic encoding is difficult or impossible to apply in many cases, including cells or animals with poorly understood genomes, no DNA, or sensitive to manipulation. Using biosensors without genetic manipulation could greatly simplify studies in animals, expand the range of accessible organisms, and ultimately enable application in humans. Here we explore using a membrane-permeable small molecule as a fluorescent biosensor. The drug trifluoperazine, which binds only to the active conformation of calmodulin, was covalently linked to an environment-sensing merocyanine dye to create CaMero, a biosensor of calmodulin activation. Simple incubation of CaMero in the extracellular medium, or injection in the tail vein of mice, led to sensitive real time reporting of calmodulin activity. The dye underwent a 12-fold change in fluorescence intensity upon binding to activated calmodulin, revealing waves of activation in peristaltic intestine, localization and kinetics of calmodulin activation during serum stimulation in fibroblasts, and localized activation in the single-celled marine protist foraminifera.

PMID 42244718
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PubMedFrontiers in genetics2026-06-05

Case Report: Two siblings with a novel homozygous SLC18A2 variant causing parkinsonism-dystonia-2: a case series from Saudi Arabia.

Almutair Meshal M, Hakami Wejdan W

Monoamine neurotransmitter disorders are rare, early-onset neurological conditions that frequently mimic cerebral palsy or epileptic encephalopathies, resulting in diagnostic delay. Parkinsonism-dystonia-2 (PKDYS2), caused by biallelic variants in SLC18A2, encodes vesicular monoamine transporter 2 (VMAT2), which is essential for dopamine and serotonin vesicular storage and release. The disorder is characterized by global developmental delay, parkinsonism, dystonia, and autonomic dysfunction. This retrospective case report describes two siblings from a consanguineous family diagnosed with PKDYS2. Clinical, neuroimaging, and genetic data were collected from medical records, with longitudinal follow-up to assess disease progression and treatment response. Whole-exome sequencing (WES) was performed, and variants were analyzed using standard bioinformatics pipelines. A homozygous splice-site variant in SLC18A2 (c.1122 + 2T>C) was identified, classified as likely pathogenic according to ACMG/ClinGen criteria, and confirmed by Sanger sequencing with parental segregation. Both siblings presented in early infancy with hypotonia, developmental delay, dystonia, and oculogyric crises, with normal neuroimaging. WES identified a homozygous SLC18A2 splice-site variant (c.1122 + 2T>C) in both patients. Pramipexole resulted in partial improvement in one patient but was poorly tolerated in the other. Alternative therapies, including clonidine and trihexyphenidyl, provided limited symptomatic benefit. Both patients demonstrated severe and persistent neurodevelopmental impairment at follow-up. This case report identifies a previously unreported SLC18A2 splice-site variant (c.1122 + 2T>C) in two siblings with a severe neurodevelopmental phenotype characterized by hypotonia, dystonia, autonomic dysfunction, and parkinsonian features. These findings highlight the key role of genetic testing in establishing the diagnosis, avoiding ineffective treatments, and guiding management. Early genetic evaluation should be considered in children with early-onset movement disorders.

PMID 42245405
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PubMedIdeggyogyaszati szemle2026-06-03

[Case report: VPS16 - a new cause of generalized dystonia].

Salamon András A, Zádori Dénes D, Szpisjak László L, Maróti Zoltán Z et al.

Introduction - Dystonia is the third most common movement disorder, which is highly diverse, both clinically and genetically. With the rise of next-generation sequencing, the number of genes associated with dystonia is increasing. Genetic testing is particularly important to predict the effectiveness of widely used therapeutic approaches (e.g., deep brain stimulation/DBS).Case report - The symptoms of a 69-yearold female patient began at the age of 18 years. Her symptoms developed gradually, i.e., cervical abnormal postures and movements first, followed by tongue movement problems, writer's cramp and speech difficulty. At the age of 38, she became severely disabled. During the neurological examination, generalized dystonia as well as occasional choreoathetoid movement elements on the upper limbs were observed. We noticed dysphagia, dysarthria and occasional oro-facial and cervical dyskinesia. Brain magnetic resonance imaging demonstrated minimal cortical atrophy. The whole exome sequencing analysis detected a heterozygous pathogenic nonsense mutation in the VPS16 gene. The patient is currently receiving clonazepam therapy with moderate symptom relief. Trihexyphenidyl treatment has not been attempted because the significant side effects of the previously tried anticholinergic drug. Although DBS was offered, the patient refused this treatment.Conclusion - Dystonia caused by mutation of the VPS16 gene (autosomal dominant) is a recently recognized new form of hereditary dystonia. The disease is characterized by early-onset progressive, generalized dystonia, with the predominant involvement of orofacial, bulbar, cervical and upper limb regions. Currently there is no clear recommendation for treatment, however, beneficial effects of DBS as well as botulinum toxin have been reported.

PMID 42233462
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PubMedBiomolecules2026-05-27

Trihexyphenidyl Ameliorates Depression-like Behaviors in Adult Zebrafish Exposed to Chronic Unpredictable Stress, Consistent with Regulation of the MAPK Signaling Pathway.

Hu Siqi S, Yao Yedong Y, Li Siyuan S, Zhan Leqing L et al.

Depression is a complex mental and neurological disorder and has become one of the most serious public health issues in modern society. Trihexyphenidyl (THY) is a traditional drug used to treat Parkinson's disease. Recent studies have suggested that it may play a role in regulating neurotransmitters and protecting neurons, but its potential for treating depression has not been fully explored, and how it works remains unclear. Therefore, we examined the effects of THY on depression-like behaviors in zebrafish caused by chronic unpredictable stress (CUS). Our results showed that THY significantly attenuated the CUS-induced decrease in exploratory behavior and shortened the CUS-induced increase in latency time. At the tissue level, THY effectively attenuated the thinning of the optic tectum and the loss of Nissl bodies caused by CUS. In addition, THY reversed the CUS-induced increase in stress hormone levels and reduction in neurotransmitter content. Through network pharmacology and transcriptome sequencing analysis, we found that the mechanisms underlying depression-like behaviors and the antidepressant effects of THY might be related to the MAPK signaling pathway. Further experiments showed that THY regulated the CUS-induced activation of the MAPK signaling pathway, improved the abnormal activation of microglia and damage to astrocytes, and reduced the expression of pro-inflammatory factors, thereby easing neuroinflammation and improving depression-like behaviors. In summary, this study explored the potential mechanism of THY ameliorating depressive-like behaviors and provided basic theoretical evidence.

PMID 42194028
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PubMedEuropean journal of pharmacology2026-05-25

Trifluoperazine induces ferroptosis in acute myeloid leukemia by suppressing the Nrf2/SLC7A11/GPX4 axis.

Xu Jing J, Yang Wanfang W, Zhang Yaofang Y, Liu Jianbing J et al.

Acute myeloid leukemia (AML) remains a therapeutic challenge due to high relapse rates and limited treatment options. Drug repurposing offers a promising strategy to accelerate clinical translation. In this study, we investigated the anti-AML potential of the FDA-approved antipsychotic drug trifluoperazine (TFP) and explored its underlying mechanisms. We found that TFP markedly inhibits AML cell proliferation by inducing cell cycle arrest and apoptosis, while exhibiting minimal toxicity to normal human umbilical vein endothelial cells and bone marrow stromal cells. Mechanistically, TFP triggers impairments in mitochondrial activity and promotes the accumulation of reactive oxygen species (ROS), and induces ferroptosis, a form of iron-dependent cell death characterized by iron overload, glutathione depletion, and lipid peroxidation. The ferroptosis inhibitor ferrostatin-1 (Fer-1) effectively rescued TFP-induced cell death. Moreover, TFP synergized with the ferroptosis inducer erastin to enhance ferroptotic cell death. At the molecular level, TFP suppressed the Nrf2/SLC7A11/GPX4 antioxidant axis, an effect that was reversible by the Nrf2 activator ML334. In an AML xenograft model, TFP monotherapy significantly inhibited tumor growth and alleviated hepatosplenomegaly. Importantly, TFP synergized with venetoclax, a standard AML therapy, to enhance antileukemic efficacy both in vitro and in vivo. Collectively, our findings identify TFP as a potent ferroptosis inducer in AML and suggest its potential as a repurposed therapeutic agent, either as monotherapy or in combination with venetoclax.

PMID 42178012
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PubMedEuropean journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences2026-05-18

A phenothiazine analog, PTF, suppresses breast cancer growth by inhibiting YAP signaling.

Weng Jing-Ru JR, Bai Li-Yuan LY, Hu Jing-Lan JL, Wu Chia-Hsien CH et al.

Phenothiazines, a class of compounds originally developed for the treatment of psychotic disorders, exert antitumor activity by targeting multiple signaling pathways. In this study, we evaluated the anticancer potential of a modified phenothiazine analogue (PTF) in breast carcinoma models. Compared with its precursor trifluoperazine, PTF exhibited markedly improved efficacy in inhibiting the proliferation of MCF-7 and MDA-MB-231 breast cancer cells, while sparing non-tumorigenic mammary epithelial cells (H184B5F/M10), which showed minimal sensitivity to the compound. PTF triggered programmed cell death, accompanied by caspase activation and reduced levels of the anti-apoptotic protein Mcl-1. Immunoblot analyses demonstrated that PTF altered the activity of the Akt/mTOR/NF-κB axis and MAPK cascades, provoked endoplasmic reticulum stress, and elevated the ERβ-to-ERα expression ratio. In addition, transmission electron microscopy, confocal imaging, and immunoblotting analyses collectively demonstrated that PTF induces autophagy in OSCC cells. Importantly, enforced expression of YAP attenuated PTF-induced cytotoxic effects, whereas blocking proteasomal function prevented PTF-driven degradation of YAP, implying that YAP destabilization contributes to the cytotoxic mechanism. Collectively, these results identify PTF as a potential therapeutic lead for breast cancer, acting through coordinated induction of apoptosis and autophagy, disruption of oncogenic signaling networks, and modulation of YAP protein stability.

PMID 42144082
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