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Cell May 2020Swelling of the brain or spinal cord (CNS edema) affects millions of people every year. All potential pharmacological interventions have failed in clinical trials,...
Swelling of the brain or spinal cord (CNS edema) affects millions of people every year. All potential pharmacological interventions have failed in clinical trials, meaning that symptom management is the only treatment option. The water channel protein aquaporin-4 (AQP4) is expressed in astrocytes and mediates water flux across the blood-brain and blood-spinal cord barriers. Here we show that AQP4 cell-surface abundance increases in response to hypoxia-induced cell swelling in a calmodulin-dependent manner. Calmodulin directly binds the AQP4 carboxyl terminus, causing a specific conformational change and driving AQP4 cell-surface localization. Inhibition of calmodulin in a rat spinal cord injury model with the licensed drug trifluoperazine inhibited AQP4 localization to the blood-spinal cord barrier, ablated CNS edema, and led to accelerated functional recovery compared with untreated animals. We propose that targeting the mechanism of calmodulin-mediated cell-surface localization of AQP4 is a viable strategy for development of CNS edema therapies.
Topics: Animals; Aquaporin 4; Astrocytes; Brain; Brain Edema; Calmodulin; Central Nervous System; Edema; Male; Rats; Rats, Sprague-Dawley; Spinal Cord; Spinal Cord Injuries; Trifluoperazine
PubMed: 32413299
DOI: 10.1016/j.cell.2020.03.037 -
Dermatology Online Journal Nov 2018Morgellons disease is a disfiguring and distressing condition. Patients commonly present with multiple, non-healing, cutaneous wounds. Patients report protruding fibers... (Review)
Review
Morgellons disease is a disfiguring and distressing condition. Patients commonly present with multiple, non-healing, cutaneous wounds. Patients report protruding fibers or other objects as the source and often provide samples to the clinician. Originally the etiology of this condition was broad and debated ranging from infectious to psychiatric. This article reviews current treatments and details our approach to treatment, aiming to aid clinicians with useful pharmacotherapy and adherence techniques when treating patients with Morgellons disease. Although current opinions have consolidated to the psychiatric spectrum, Morgellons treatment remains difficult and unstandardized with most evidence from retrospective reviews and a handful of case reports. Having considerable overlap with delusions of parasitosis, treatments have consisted of various antipsychotics and antibacterial wound care. Many antipsychotics have been selected owing to additional antipruritic or analgesic benefits. Generally, low-doses are used to minimize the risk of side effects. Risperidone or trifluoperazine can provide relief to patients especially when paired with adjuvant therapies, strong doctor-patient relationships, and a multidisciplinary approach.
Topics: Anti-Bacterial Agents; Antipsychotic Agents; Humans; Medication Adherence; Morgellons Disease; Physician-Patient Relations; Risperidone; Trifluoperazine; Wound Infection
PubMed: 30695970
DOI: No ID Found -
The Cochrane Database of Systematic... 2004Trifluoperazine is an inexpensive accessible 'high potency' antipsychotic drug, widely used to treat schizophrenia or related psychoses. (Review)
Review
BACKGROUND
Trifluoperazine is an inexpensive accessible 'high potency' antipsychotic drug, widely used to treat schizophrenia or related psychoses.
OBJECTIVES
To estimate the effects of trifluoperazine compared with placebo and other drugs.
SEARCH STRATEGY
Searches of the Cochrane Schizophrenia Group's register of trials (March 2002), supplemented with hand searching, reference searching, personal communication and contact with industry.
SELECTION CRITERIA
All clinical randomised trials involving people with schizophrenia and comparing trifluoperazine with any other treatment.
DATA COLLECTION AND ANALYSIS
Studies were reliably selected and quality rated and data was extracted. For dichotomous data, relative risks (RR) were estimated, with 95% confidence intervals (CI). Where possible, we undertook intention-to-treat analyses. For statistically significant results, the number needed to treat (NNT) was calculated. We estimated heterogeneity (I-square technique) and publication bias.
MAIN RESULTS
1162 people from 13 studies were randomised to trifluoperazine or placebo. For global improvement, small short-term studies favoured trifluoperazine (n=95, 3 RCTs, RR 0.62 CI 0.49 to 0.78 NNT 3 CI 2 to 4). Loss to follow up was about 12% in both groups (n=280, 7 RCTs, RR 0.99 CI 0.62 to 1.57) and more people allocated trifluoperazine used antiparkinson drugs to alleviate movements disorders compared with placebo (n=195, 4 RCTs, RR 5.06 CI 2.49 to 10.27, NNH 4 CI 2 to 9). 2230 people from 49 studies were randomised to trifluoperazine or another older generation antipsychotic. Trifluoperazine was not clearly different in terms of 'no substantial improvement' (n=1016, 27 RCTs, RR 1.06 CI 0.98 to 1.14) or leaving the study early (n=930, 22 RCTs, RR 1.15 CI 0.83 to 1.58). Almost identical numbers of people reported at least one adverse event (60%) in each group (n=585, 14 RCTs, RR 0.99 CI 0.87 to 1.13), although trifluoperazine was more likely to cause extrapyramidal adverse effects overall when compared to low potency antipsychotics such as chlorpromazine (n=130, 3 RCTs, RR 1.66 CI 1.03 to 2.67, NNH 6 CI 3 to 121). One small study (n=38) found no clear differences between trifluoperazine and the atypical drug, sulpiride.
REVIEWER'S CONCLUSIONS
Although there are shortcomings and gaps in the data, there appears to be enough consistency over different outcomes and periods to confirm that trifluoperazine is an antipsychotic of similar efficacy to other commonly used neuroleptics for people with schizophrenia. Its adverse events profile is similar to that of other drugs. It has been claimed that trifluoperazine is effective at low doses for patients with schizophrenia but this does not appear to be based on good quality trial based evidence.
Topics: Antipsychotic Agents; Humans; Randomized Controlled Trials as Topic; Schizophrenia; Trifluoperazine
PubMed: 14974020
DOI: 10.1002/14651858.CD003545.pub2 -
The Cochrane Database of Systematic... Jan 2014Trifluoperazine is a long-established high potency typical antipsychotic drug used in the treatment of schizophrenia and schizophrenia-like illnesses. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Trifluoperazine is a long-established high potency typical antipsychotic drug used in the treatment of schizophrenia and schizophrenia-like illnesses.
OBJECTIVES
To determine absolute effects of trifluoperazine for schizophrenia and schizophrenia-like illnesses compared with placebo.To critically appraise and summarise current evidence on the resource use, cost and economic evaluation of trifluoperazine compared with placebo for schizophrenia.
SEARCH METHODS
Searches of the Cochrane Schizophrenia Group's register of trials (July 2012), supplemented with handsearching, reference searching, personal communication and contact with industry. Two review authors undertook a search for economic studies using the Cochrane Schizophrenia Group's Health Economic Database (CSzGHED) on the 9th April 2013.
SELECTION CRITERIA
All available clinical randomised trials involving people with schizophrenia and schizophrenia-like illnesses that compare trifluoperazine with placebo.
DATA COLLECTION AND ANALYSIS
Studies for the effects of interventions were reliably selected by a review team and data were doubly independently extracted to reduce bias. We only used dichotomous data, using intention-to-treat analysis when possible. Data were estimated using risk ratio (RR) with 95% confidence intervals (CI). A 'Summary of findings' table was produced, where possible, for each primary outcome using GRADE. Economic studies were searched and reliably selected by review authors (VF and SS) to provide an economic summary of available data. Where no relevant economic studies were eligible for inclusion, the economic review team valued the already-included effectiveness outcome data to provide a rudimentary economic summary.
MAIN RESULTS
This review included 10 studies with a total number of 686 participants featuring in 20 different outcomes of interest. Overall, there was significant clinical improvement in clinical global state at medium term amongst people receiving trifluoperazine (3 RCTs, n = 417, RR 4.61, CI 1.54 to 13.84, low quality evidence) and significantly fewer people receiving trifluoperazine left the studies early due to relapse or worsening at medium term (2 RCTs, n = 381, RR 0.34, CI 0.23 to 0.49, low quality evidence). However, results were equivocal for leaving the study early at medium term for any reason (2 RCTs, n = 391, RR 0.80, CI 0.17 to 3.81, very low quality evidence) and due to severe adverse effects (2 RCTs, n = 391, RR 1.54, CI 0.56 to 4.24, very low quality evidence). Equivocal data were also found for intensified symptoms at medium term (2 RCTs, n = 80, RR 1.05, CI 0.54 to 2.05, very low quality evidence) and rates of agitation or distress again at medium term (1 RCT, n = 52, RR 2.00, CI 0.19 to 20.72, very low quality evidence). Comparison between low and high-dose trifluoperazine with placebo from a single study provided equivocal evidence of effects. For economic outcomes, we valued outcomes in GBP terms and presented them in additional tables; there was an estimated saving of £3488.3 in favour of trifluoperazine. However, numerous assumptions were made and these savings need to be interpreted in light of those assumptions.
AUTHORS' CONCLUSIONS
Our results agree with existing evidence that compared to placebo, trifluoperazine is an effective antipsychotic for people with schizophrenia. Furthermore, our review provides supportive evidence that trifluoperazine increases the risk of extrapyramidal adverse effects. Although the effect sizes against placebo are similar to those observed with other agents, they are based on data from many small, pre-CONSORT trials with generally either a low or very low GRADE evidence that has limited implication for clinical practice. Large, independent trials are needed that adhere to the CONSORT statement to compare trifluoperazine with placebo used in the treatment of schizophrenia and schizophrenia-like illnesses.
Topics: Antipsychotic Agents; Dyskinesia, Drug-Induced; Humans; Randomized Controlled Trials as Topic; Schizophrenia; Trifluoperazine
PubMed: 24414883
DOI: 10.1002/14651858.CD010226.pub2 -
Science Advances Oct 2023Cancers in the central nervous system resist therapies effective in other cancers, possibly due to the unique biochemistry of the human brain microenvironment composed...
Cancers in the central nervous system resist therapies effective in other cancers, possibly due to the unique biochemistry of the human brain microenvironment composed of cerebrospinal fluid (CSF). However, the impact of CSF on cancer cells and therapeutic efficacy is unknown. Here, we examined the effect of human CSF on glioblastoma (GBM) tumors from 25 patients. We found that CSF induces tumor cell plasticity and resistance to standard GBM treatments (temozolomide and irradiation). We identified nuclear protein 1 (NUPR1), a transcription factor hampering ferroptosis, as a mediator of therapeutic resistance in CSF. NUPR1 inhibition with a repurposed antipsychotic, trifluoperazine, enhanced the killing of GBM cells resistant to chemoradiation in CSF. The same chemo-effective doses of trifluoperazine were safe for human neurons and astrocytes derived from pluripotent stem cells. These findings reveal that chemoradiation efficacy decreases in human CSF and suggest that combining trifluoperazine with standard care may improve the survival of patients with GBM.
Topics: Humans; Glioblastoma; Trifluoperazine; Brain Neoplasms; Temozolomide; Chemoradiotherapy; Cell Line, Tumor; Tumor Microenvironment
PubMed: 37878712
DOI: 10.1126/sciadv.adf1332 -
Asian Pacific Journal of Cancer... Aug 2022The aim of this study was to investigate the effects of CaM antagonist, PTZ, and TFP on cell proliferation and migration of colon cancer cells and its impact on POPDC...
OBJECTIVE
The aim of this study was to investigate the effects of CaM antagonist, PTZ, and TFP on cell proliferation and migration of colon cancer cells and its impact on POPDC protein expression.
METHODS
The 50% inhibitory concentration (IC50) of PTZ and TFP in SW1116, SW480, HCT-15, and COLO205 colon cancer cell lines are measured using MTT. Western blot and immunocytochemistry were used to determine the expression of PCNA, cyclin D1 (CD1), and POPDC proteins. Cell migration was observed using a scratch wound-healing assay.
RESULTS
Treatment with PTZ and TFP inhibited colon cancer cells growth in a dose-dependent manner. PTZ and TFP significantly inhibited the activation of proliferation markers, PCNA and CD1, and the migration of colon cancer cells. Furthermore, POPDC protein was significantly suppressed in all cell types of colon cancer, particularly in SW480. Finally, the CaM antagonist upregulates the POPDC1 expression in colon cancer cells.
CONCLUSION
These findings suggest that CaM antagonists suppress colon cancer cells proliferation via downregulation of CD1 and PCNA. In addition, POPDC protein could be used as a biomarker in colon cancer, and CaM antagonist could be used to regulate POPDC1 expression. This study suggests that targeting POPDC1 with CaM inhibition could be a potential therapeutic strategy for colon cancer treatment.
.Topics: Cell Movement; Cell Proliferation; Colonic Neoplasms; Humans; Proliferating Cell Nuclear Antigen; Trifluoperazine
PubMed: 36037145
DOI: 10.31557/APJCP.2022.23.8.2863 -
International Journal of Medical... 2023Currently, no specific and standard treatment for traumatic brain injury (TBI) has been developed. Therefore, studies on new therapeutic drugs for TBI treatment are...
Currently, no specific and standard treatment for traumatic brain injury (TBI) has been developed. Therefore, studies on new therapeutic drugs for TBI treatment are urgently needed. Trifluoperazine (TFP) is a therapeutic agent for the treatment of psychiatric disorders that reduces edema of the central nervous system. However, the specific working mechanism of TFP is not fully understood in TBI. In this study, the immunofluorescence co-localization analysis revealed that the area and intensity covered by Aquaporin4 (AQP4) on the surface of brain cells (astrocyte endfeet) increased significantly after TBI. In contrast, TFP treatment reversed these phenomena. This finding showed that TFP inhibited AQP4 accumulation on the surface of brain cells (astrocyte endfeet). The tunel fluorescence intensity and fluorescence area were lower in the TBI+TFP group compared to the TBI group. Additionally, the brain edema, brain defect area, and modified neurological severity score (mNSS) were lower in the TBI+TFP. The RNA-seq was performed on the cortical tissues of rats in the Sham, TBI, and TBI+TFP groups. A total of 3774 genes differently expressed between the TBI and the Sham group were identified. Of these, 2940 genes were up-regulated and 834 genes were down-regulated. A total of 1845 differently expressed genes between the TBI+TFP and TBI group were also identified, in which 621 genes were up-regulated and 1224 genes were down-regulated. Analysis of the common differential genes in the three groups showed that TFP could reverse the expression of apoptosis and inflammation genes. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that the differentially expressed genes (DEGs) were highly enriched in the signaling pathways regulating inflammation. In conclusion, TFP alleviates brain edema after TBI by preventing the accumulation of AQP4 on the surface of brain cells. Generally, TFP alleviates apoptosis and inflammatory response induced by TBI, and promotes the recovery of nerve function in rats after TBI. Thus, TFP is a potential therapeutic agent for TBI treatment.
Topics: Animals; Rats; Apoptosis; Aquaporin 4; Brain; Brain Edema; Brain Injuries, Traumatic; Inflammation; Trifluoperazine
PubMed: 37213674
DOI: 10.7150/ijms.82677 -
International Microbiology : the... Mar 2015Historically, multiplicity of actions in synthetic compounds is a rule rather than exception. The science of non-antibiotics evolved in this background. From the... (Review)
Review
Historically, multiplicity of actions in synthetic compounds is a rule rather than exception. The science of non-antibiotics evolved in this background. From the antimalarial and antitrypanosomial dye methylene blue, chemically similar compounds, the phenothiazines, were developed. The phenothiazines were first recognised for their antipsychotic properties, but soon after their antimicrobial functions came to be known and then such compounds were designated as non-antibiotics. The emergence of highly drug-resistant bacteria had initiated an urgent need to search for novel affordable compounds. Several phenothiazines awakened the interest among scientists to determine their antimycobacterial activity. Chlorpromazine, trifluoperazine, methdilazine and thioridazine were found to have distinct antitubercular action. Thioridazine took the lead as researchers repeatedly claimed its potentiality. Although thioridazine is known for its central nervous system and cardiotoxic side-effects, extensive and repeated in vitro and in vivo studies by several research groups revealed that a very small dose of thioridazine is required to kill tubercle bacilli inside macrophages in the lungs, where the bacteria try to remain and multiply silently. Such a small dose is devoid of its adverse side-effects. Recent studies have shown that the (-) thioridazine is a more active antimicrobial agent and devoid of the toxic side effects normally encountered. This review describes the possibilities of bringing down thioridazine and its (-) form to be combined with other antitubercular drugs to treat infections by drug-resistant strains of Mycobacterium tuberculosis and try to eradicate this deadly disease.
Topics: Antipsychotic Agents; Antitubercular Agents; Chlorpromazine; Humans; Mycobacterium tuberculosis; Phenothiazines; Thioridazine; Trifluoperazine; Tuberculosis, Multidrug-Resistant
PubMed: 26415662
DOI: 10.2436/20.1501.01.229 -
Biomolecular Concepts May 2018Treatment with analogues of the SERCA-inhibitor Thapsigargin is a promising new approach for a wide variety of cancer entities. However, our previous studies on various...
Treatment with analogues of the SERCA-inhibitor Thapsigargin is a promising new approach for a wide variety of cancer entities. However, our previous studies on various tumor cells suggested resistance of SEC62 over-expressing tumors to this treatment. Therefore, we proposed the novel concept that e.g. lung-, prostate-, and thyroid-cancer patients should be tested for SEC62 over-expression, and developed a novel therapeutic strategy for a combinatorial treatment of SEC62 over-expressing tumors. The latter was based on the observations that treatment of SEC62 over-expressing tumor cells with SEC62-targeting siRNAs showed less resistance to Thapsigargin as well as a reduction in migratory potential and that the siRNA effects can be mimicked by the Calmodulin antagonist Trifluoperazine. Therefore, the combinatorial treatment of SEC62 over-expressing tumors was proposed to involve Thapsigargin and Trifluoperazine. Here, we addressed the impact of Thapsigargin and Trifluoperazine in separate and combined treatments of heterotopic tumors, induced by inoculation of human hypopharyngeal squamous cell carcinoma (FaDu)-cells into the mouse flank. Seeding of the tumor cells and/or their growth rate were significantly reduced by all three treatments, suggesting Trifluoperazine is a small molecule to be considered for future therapeutic strategies for patients, suffering from Sec62-overproducing tumors.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Calmodulin; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Enzyme Inhibitors; Head and Neck Neoplasms; Humans; Hypopharyngeal Neoplasms; Membrane Transport Proteins; Mice; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Squamous Cell Carcinoma of Head and Neck; Thapsigargin; Trifluoperazine
PubMed: 29779013
DOI: 10.1515/bmc-2018-0006 -
British Medical Journal Oct 1959
Topics: Antipsychotic Agents; Heterocyclic Compounds; Phenothiazines; Trifluoperazine
PubMed: 13856813
DOI: No ID Found