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Canadian Medical Association Journal Sep 1964Thioridazine, chlorpromazine and trifluoperazine were administered to six psychiatric patients. Each was used in four dosage levels (thioridazine and chlorpromazine:...
Thioridazine, chlorpromazine and trifluoperazine were administered to six psychiatric patients. Each was used in four dosage levels (thioridazine and chlorpromazine: 200, 400, 800 and 1200 mg. daily; trifluoperazine: 8, 16, 32, 64 mg. daily); and each increase in dosage was effected after four days of drug administration.Before the trial, twice during each drug period and before commencement of the next dose regimen, an electrocardiogram (ECG) was recorded. The findings indicated that thioridazine modifies the terminal portion (S-T segment, T and U waves) of the human ECG. A similar change occurred in three of six subjects while taking chlorpromazine and in one of six while taking trifluoperazine. Thioridazine induced changes in all six subjects studied, viz., blunting and notching of T waves with or without prolongation of QT interval. In some the notching produced a doublehump appearance in which a T wave of reduced voltage formed the proximal hump and a positive U wave of increased voltage formed the distal hump.Thioridazine-induced alterations in the ECG have been described as resembling those caused by quinidine; they also resemble changes associated with hypokalemia.
Topics: Antipsychotic Agents; Biomedical Research; Chlorpromazine; Electrocardiography; Pharmacology; Phenothiazines; Research; Schizophrenia; Thioridazine; Toxicology; Trifluoperazine
PubMed: 14176059
DOI: No ID Found -
Medical Science Monitor : International... Jul 2017BACKGROUND It has been reported that trifluoperazine (TFP) inhibits proliferation of cancer cells, however, the effects of TFP in renal proliferation diseases are still...
BACKGROUND It has been reported that trifluoperazine (TFP) inhibits proliferation of cancer cells, however, the effects of TFP in renal proliferation diseases are still unclear. This study examined the effects of TFP on proliferation of human renal mesangial cells and analyzed the underlying mechanisms. MATERIAL AND METHODS Cell proliferation in vivo was determined by HE staining, immunohistochemistry of proliferating cell nuclear antigen (PCNA), and Western blot analysis (Ki-67 and PCNA). Effects of different TFP concentrations and treatment duration on cell proliferation and cell cycle were analyzed using the MTT assay and flow cytometry. Expression of G0/G1 phase cell cycle-related proteins and TFP-induced MAPK and PI3K/AKT signaling pathways was estimated with Western blot analysis. RESULTS Our findings suggest that TFP inhibits cell proliferation in a dose- and time-dependent manner and decreased PCNA and Ki-67 levels in lupus MRL/lpr mice. TFP arrested the cell cycle in the G0/G1 phase, down-regulating cyclin D1, CDK2, and CDK4, and up-regulating p21 expression in a dose-dependent manner. In addition, TFP inhibited p-AKT and p-JNK, possibly by suppressing the activation of PI3K/AKT and JNK/MAPK signaling pathways. TFP treatment remarkably reduced the levels of serum creatinine (Cr) in lupus mice. CONCLUSIONS TFP exhibits inhibitory activity against mesangial cells in vivo and in vitro, which is associated with G1 cell cycle arrest by inactivation of PI3K/AKT and JNK/MAPK signaling pathways. These results suggest the potential of TFP in treatment of mesangial proliferative diseases.
Topics: Animals; Apoptosis; Cell Cycle; Cell Line; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Female; G1 Phase Cell Cycle Checkpoints; Humans; Kidney Glomerulus; Mesangial Cells; Mice; Mice, Inbred C57BL; Mice, Inbred MRL lpr; Phosphatidylinositol 3-Kinases; Phosphorylation; Proliferating Cell Nuclear Antigen; Signal Transduction; Trifluoperazine
PubMed: 28713151
DOI: 10.12659/msm.902522 -
The Journal of the Royal College of... Jun 1969
Clinical Trial Comparative Study
Topics: Adolescent; Adult; Anxiety; Clinical Trials as Topic; Humans; Middle Aged; Opipramol; Stress, Psychological; Trifluoperazine
PubMed: 4891824
DOI: No ID Found -
Journal of Neuropathology and... Nov 2014Chemotherapeutic agents effective against malignant peripheral nerve sheath tumors (MPNSTs) are urgently needed. We recently found that tamoxifen potently impedes...
Combinatorial therapy with tamoxifen and trifluoperazine effectively inhibits malignant peripheral nerve sheath tumor growth by targeting complementary signaling cascades.
Chemotherapeutic agents effective against malignant peripheral nerve sheath tumors (MPNSTs) are urgently needed. We recently found that tamoxifen potently impedes xenograft growth. In vitro, tamoxifen inhibits MPNST proliferation and survival in an estrogen receptor-independent manner; these effects are phenocopied by the calmodulin inhibitor trifluoperazine. The present study was performed to establish the mechanism of action of tamoxifen in vivo and optimize its therapeutic effectiveness. To determine if tamoxifen has estrogen receptor-dependent effects in vivo, we grafted MPNST cells in castrated and ovariectomized mice; xenograft growth was unaffected by reductions in sex hormones. To establish whether tamoxifen and trifluoperazine additively or synergistically impede MPNST growth, mice xenografted with neurofibromatosis type 1-associated or sporadic MPNST cells were treated with tamoxifen, trifluoperazine, or both drugs for 30 days. Both monotherapies inhibited graft growth by 50%, whereas combinatorial treatment maximally reduced graft mass by 90% and enhanced decreases in proliferation and survival. Kinomic analyses showed that tamoxifen and trifluoperazine have both shared and distinct targets in MPNSTs. In addition, trifluoperazine prevented tamoxifen-induced increases in serum/glucocorticoid regulated kinase 1, a protein linked to tamoxifen resistance. These findings suggest that combinatorial therapy with tamoxifen and trifluoperazine is effective against MPNSTs because these agents target complementary pathways that are essential for MPNST pathogenesis.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Proliferation; Drug Delivery Systems; Female; Male; Mice; Neurilemmoma; Signal Transduction; Tamoxifen; Treatment Outcome; Trifluoperazine; Xenograft Model Antitumor Assays
PubMed: 25289889
DOI: 10.1097/NEN.0000000000000126 -
The Cochrane Database of Systematic... Jan 2015Haloperidol is worldwide one of the most frequently used antipsychotic drugs with a very high market share. Previous narrative, unsystematic reviews found no differences... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Haloperidol is worldwide one of the most frequently used antipsychotic drugs with a very high market share. Previous narrative, unsystematic reviews found no differences in terms of efficacy between the various first-generation ("conventional", "typical") antipsychotic agents. This established the unproven psychopharmacological assumption of a comparable efficacy between the first-generation antipsychotic compounds codified in textbooks and treatment guidelines. Because this assumption contrasts with the clinical impression, a high-quality systematic review appeared highly necessary.
OBJECTIVES
To compare the efficacy, acceptability, and tolerability of haloperidol with other first-generation antipsychotics in schizophrenia and schizophrenia-like psychosis.
SEARCH METHODS
In October 2011 and July 2012, we searched the Cochrane Schizophrenia Group's Trials Register, which is based on regular searches of CINAHL, BIOSIS, AMED, EMBASE, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. To identify further relevant publications, we screened the references of all included studies and contacted the manufacturers of haloperidol for further relevant trials and missing information on identified studies. Furthermore, we contacted the corresponding authors of all included trials for missing data.
SELECTION CRITERIA
We included all randomised controlled trials (RCTs) that compared oral haloperidol with another oral first-generation antipsychotic drug (with the exception of the low-potency antipsychotics chlorpromazine, chlorprothixene, levopromazine, mesoridazine, perazine, prochlorpromazine, and thioridazine) in schizophrenia and schizophrenia-like psychosis. Clinically important response to treatment was defined as the primary outcome. Secondary outcomes were global state, mental state, behaviour, overall acceptability (measured by the number of participants leaving the study early due to any reason), overall efficacy (attrition due to inefficacy of treatment), overall tolerability (attrition due to adverse events), and specific adverse effects.
DATA COLLECTION AND ANALYSIS
At least two review authors independently extracted data from the included trials. The methodological quality of the included studies was assessed using The Cochrane Collaboration`s 'Risk of bias' tool.We analysed dichotomous outcomes with risk ratios (RR) and continuous outcomes with mean differences (MD), both with the associated 95% confidence intervals (CI). All analyses were based on a random-effects model and we preferably used data on an intention-to-treat basis where possible.
MAIN RESULTS
The systematic review currently includes 63 randomised trials with 3675 participants. Bromperidol (n = 9), loxapine (n = 7), and trifluoperazine (n = 6) were the most frequently administered antipsychotics comparator to haloperidol. The included studies were published between 1962 and 1993, were characterised by small sample sizes (mean: 58 participants, range from 18 to 206) and the predefined outcomes were often incompletely reported. All results for the main outcomes were based on very low or low quality data. In many trials the mechanism of randomisation, allocation, and blinding was frequently not reported. In short-term studies (up to 12 weeks), there was no clear evidence of a difference between haloperidol and the pooled group of the other first-generation antipsychotic agents in terms of the primary outcome "clinically important response to treatment" (40 RCTs, n = 2132, RR 0.93 CI 0.87 to 1.00). In the medium-term trials, haloperidol may be less effective than the other first-generation antipsychotic group but this evidence is based on only one trial (1 RCT, n = 80, RR 0.51 CI 0.37 to 0.69).Based on limited evidence, haloperidol alleviated more positive symptoms of schizophrenia than the other antipsychotic drugs. There were no statistically significant between-group differences in global state, other mental state outcomes, behaviour, leaving the study early due to any reason, due to inefficacy, as well as due to adverse effects. The only statistically significant difference in specific side effects was that haloperidol produced less akathisia in the medium term.
AUTHORS' CONCLUSIONS
The findings of the meta-analytic calculations support the statements of previous narrative, unsystematic reviews suggesting comparable efficacy of first-generation antipsychotics. In efficacy-related outcomes, there was no clear evidence of a difference between the prototypal drug haloperidol and other, mainly high-potency first-generation antipsychotics. Additionally, we demonstrated that haloperidol is characterised by a similar risk profile compared to the other first-generation antipsychotic compounds. The only statistically significant difference in specific side effects was that haloperidol produced less akathisia in the medium term. The results were limited by the low methodological quality in many of the included original studies. Data for the main results were low or very low quality. Therefore, future clinical trials with high methodological quality are required.
Topics: Administration, Oral; Antipsychotic Agents; Haloperidol; Humans; Loxapine; Psychotic Disorders; Randomized Controlled Trials as Topic; Schizophrenia; Trifluoperazine
PubMed: 25592299
DOI: 10.1002/14651858.CD009831.pub2 -
The Ulster Medical Journal Oct 1990
Topics: Adult; Diagnostic Errors; Dystonia; Humans; Male; Trifluoperazine
PubMed: 2278124
DOI: No ID Found -
Proceedings of the National Academy of... May 2020Glioblastoma (GBM) is the deadliest adult brain cancer, and all patients ultimately succumb to the disease. Radiation therapy (RT) provides survival benefit of 6 mo over...
Glioblastoma (GBM) is the deadliest adult brain cancer, and all patients ultimately succumb to the disease. Radiation therapy (RT) provides survival benefit of 6 mo over surgery alone, but these results have not improved in decades. We report that radiation induces a glioma-initiating cell phenotype, and we have identified trifluoperazine (TFP) as a compound that interferes with this phenotype conversion. TFP causes loss of radiation-induced Nanog mRNA expression, and activation of GSK3 with consecutive posttranslational reduction in p-Akt, Sox2, and β-catenin protein levels. TFP did not alter the intrinsic radiation sensitivity of glioma-initiating cells (GICs). Continuous treatment with TFP and a single dose of radiation reduced the number of GICs in vivo and prolonged survival in syngeneic and patient-derived orthotopic xenograft (PDOX) mouse models of GBM. Our findings suggest that the combination of a dopamine receptor antagonist with radiation enhances the efficacy of RT in GBM by preventing radiation-induced phenotype conversion of radiosensitive non-GICs into treatment-resistant, induced GICs (iGICs).
Topics: Animals; Brain Neoplasms; Disease Models, Animal; Dopamine Antagonists; Gene Expression Regulation, Neoplastic; Glioblastoma; Glioma; Glycogen Synthase Kinase 3; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Phenotype; RNA, Messenger; Radiation Tolerance; Receptors, Dopamine; SOXB1 Transcription Factors; Trifluoperazine; Xenograft Model Antitumor Assays; beta Catenin
PubMed: 32358191
DOI: 10.1073/pnas.1920154117 -
Antimicrobial Agents and Chemotherapy Jan 2018Earlier, we reported that three Food and Drug Administration-approved drugs, trifluoperazine (TFP; an antipsychotic), amoxapine (AXPN; an antidepressant), and doxapram...
Earlier, we reported that three Food and Drug Administration-approved drugs, trifluoperazine (TFP; an antipsychotic), amoxapine (AXPN; an antidepressant), and doxapram (DXP; a breathing stimulant), identified from an murine macrophage cytotoxicity screen, provided mice with 40 to 60% protection against pneumonic plague when administered at the time of infection for 1 to 3 days. In the present study, the therapeutic potential of these drugs against pneumonic plague in mice was further evaluated when they were administered at up to 48 h postinfection. While the efficacy of TFP was somewhat diminished as treatment was delayed to 24 h, the protection of mice with AXPN and DXP increased as treatment was progressively delayed to 24 h. At 48 h postinfection, these drugs provided the animals with significant protection (up to 100%) against challenge with the agent of pneumonic or bubonic plague when they were administered in combination with levofloxacin. Likewise, when they were used in combination with vancomycin, all three drugs provided mice with 80 to 100% protection from fatal oral infection when they were administered at 24 h postinfection. Furthermore, AXPN provided 40 to 60% protection against respiratory infection with when it was administered at the time of infection or at 24 h postinfection. Using the same cytotoxicity assay, we identified an additional 76/780 nonantibiotic drugs effective against For , 121 nonantibiotic drugs were identified to inhibit bacterium-induced cytotoxicity in murine macrophages. Of these 121 drugs, 13 inhibited the macrophage cytotoxicity induced by two additional multiple-antibiotic-resistant strains. Six of these drugs decreased the intracellular survival of all three strains in macrophages. These results provided further evidence of the broad applicability and utilization of drug repurposing screening to identify new therapeutics to combat multidrug-resistant pathogens of public health concern.
Topics: Acinetobacter baumannii; Amoxapine; Animals; Anti-Bacterial Agents; Cell Line; Disease Models, Animal; Doxapram; Drug Repositioning; Drug Resistance, Multiple, Bacterial; Female; Klebsiella pneumoniae; Levofloxacin; Macrophages; Mice; Mice, Inbred C57BL; Plague; RAW 264.7 Cells; Trifluoperazine
PubMed: 29109161
DOI: 10.1128/AAC.01943-17 -
Journal of Biochemistry Jun 1985Crystals suitable for X-ray structure analysis were obtained for CaM complexed with both calcium ions and a phenothiazine drug, trifluoperazine (TFP). The TFP/CaM...
Crystals suitable for X-ray structure analysis were obtained for CaM complexed with both calcium ions and a phenothiazine drug, trifluoperazine (TFP). The TFP/CaM binding ratio in crystals was experimentally determined to be nearly 1. An attempt at crystallizing calcium-free calmodulin (CaM) resulted in rigid but non-birefringent solids which exhibited no X-ray reflections.
Topics: Animals; Binding Sites; Binding, Competitive; Calcium; Calmodulin; Cattle; Chromatography, High Pressure Liquid; Crystallization; Trifluoperazine; X-Ray Diffraction
PubMed: 4030751
DOI: 10.1093/oxfordjournals.jbchem.a135242 -
Brain Research Bulletin Jan 2016The roles of calmodulin (CaM), a multifunctional intracellular calcium receptor protein, as concerns selected morphological and functional characteristics of pure...
The roles of calmodulin (CaM), a multifunctional intracellular calcium receptor protein, as concerns selected morphological and functional characteristics of pure microglial cells derived from mixed primary cultures from embryonal forebrains of rats, were investigated through use of the CaM antagonists calmidazolium (CALMID) and trifluoperazine (TFP). The intracellular localization of the CaM protein relative to phalloidin, a bicyclic heptapeptide that binds only to filamentous actin, and the ionized calcium-binding adaptor molecule 1 (Iba1), a microglia-specific actin-binding protein, was determined by immunocytochemistry, with quantitative analysis by immunoblotting. In unchallenged and untreated (control) microglia, high concentrations of CaM protein were found mainly perinuclearly in ameboid microglia, while the cell cortex had a smaller CaM content that diminished progressively deeper into the branches in the ramified microglia. The amounts and intracellular distributions of both Iba1 and CaM proteins were altered after lipopolysaccharide (LPS) challenge in activated microglia. CALMID and TFP exerted different, sometimes opposing, effects on many morphological, cytoskeletal and functional characteristics of the microglial cells. They affected the CaM and Iba1 protein expressions and their intracellular localizations differently, inhibited cell proliferation, viability and fluid-phase phagocytosis to different degrees both in unchallenged and in LPS-treated (immunologically challenged) cells, and differentially affected the reorganization of the actin cytoskeleton in the microglial cell cortex, influencing lamellipodia, filopodia and podosome formation. In summary, these CaM antagonists altered different aspects of filamentous actin-based cell morphology and related functions with variable efficacy, which could be important in deciphering the roles of CaM in regulating microglial functions in health and disease.
Topics: Actin Cytoskeleton; Animals; Blotting, Western; Calcium-Binding Proteins; Calmodulin; Cell Proliferation; Cell Survival; Cells, Cultured; Central Nervous System Agents; Frontal Lobe; Imidazoles; Immunohistochemistry; Intracellular Space; Ki-67 Antigen; Lipopolysaccharides; Microfilament Proteins; Microglia; Phagocytosis; Rats, Sprague-Dawley; Trifluoperazine
PubMed: 26551061
DOI: 10.1016/j.brainresbull.2015.11.003