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European Journal of Medicinal Chemistry Dec 2019A novel series of phenothiazine derivatives containing diethanolamine, methoxyethylamine, flavonoids, and a nitric oxide (NO) donor was designed and synthesized for the... (Review)
Review
A novel series of phenothiazine derivatives containing diethanolamine, methoxyethylamine, flavonoids, and a nitric oxide (NO) donor was designed and synthesized for the treatment of breast cancer. Phenothiazine derivatives (l) did not noticeably inhibit the growth of SUM159, MDA-MB-231, MCF-7, and SKBR-3 cells, whereas phenothiazine derivatives (ll) containing the NO donor were more potent or had comparable inhibitory activity to trifluoperazine (TFP) and thioridazine against SUM159, MDA-MB-231, MCF-7, and SKBR-3 cells. Compounds 20a-c and 21a-c showed the strongest activity in SUM159, MDA-MB-231, MCF-7, and SKBR-3 cells, and more potent inhibitory activity than TFP against KG1a cells (IC = 1.63, 2.93, 1.14, 1.78, 2.20, and 1.20 vs. 4.58 μM). Compounds 20a and 21a had lower toxicity than compounds 20b-c and 21b-c, and inhibited colony formation in MCF-7 cells, decreased the formation of mammospheres in SUM159 cells, and inhibited the migration of MDA-MB-231 cells. Compounds 20a and 21a could inhibited pNF-κB-p65 as shown by dual-luciferase reporter assays and western blotting in MDA-MB-231 cells.
Topics: Antineoplastic Agents; Cell Proliferation; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Phenothiazines; Structure-Activity Relationship
PubMed: 31541872
DOI: 10.1016/j.ejmech.2019.111692 -
Archives of Virology Nov 2022Dengue virus (DENV), a member of the genus Flavivirus, family Flaviviridae, is the most widespread viral pathogen transmitted to humans by mosquitoes. Despite the...
Dengue virus (DENV), a member of the genus Flavivirus, family Flaviviridae, is the most widespread viral pathogen transmitted to humans by mosquitoes. Despite the increased incidence of DENV infection, there are no antiviral drugs available for treatment or prevention. Phenothiazines are heterocyclic compounds with various pharmacological properties that are very adaptable for drug repurposing. In the present report, we analyzed the antiviral activity against DENV and the related Zika virus (ZIKV) of trifluoperazine (TFP), a phenothiazine derivative in clinical use as an antipsychotic and antiemetic agent. TFP exhibited dose-dependent inhibitory activity against the four DENV serotypes and ZIKV in monkey Vero cells at non-cytotoxic concentrations with 50% effective concentration values in the range 1.6-6.4 µM. A similar level of antiviral efficacy was exhibited by TFP against flavivirus infection in the human cell lines A549 and HepG2. Mechanistic studies, performed using time-dependent infectivity assays, real-time RT-PCR, Western blot, and immunofluorescence techniques, indicated that uncoating of the virus during penetration into the cell was the main target for TFP in infected cells, but the compound also exerted a minor effect on a late stage of the virus multiplication cycle. This study demonstrates that TFP, a pharmacologically active phenothiazine, is a selective inhibitor of DENV multiplication in cell culture. Our findings open perspectives for the repositioning of phenothiazines like TFP with a wide spectrum of antiviral efficacy as potential agents for the control of pathogenic flaviviruses.
Topics: Animals; Antiemetics; Antipsychotic Agents; Antiviral Agents; Chlorocebus aethiops; Dengue; Dengue Virus; Humans; Phenothiazines; Trifluoperazine; Vero Cells; Virus Replication; Zika Virus; Zika Virus Infection
PubMed: 35920983
DOI: 10.1007/s00705-022-05555-y -
Veterinary Anaesthesia and Analgesia Mar 2021To evaluate the effects of incremental doses of acepromazine on hemodynamics in isoflurane-anesthetized dogs.
OBJECTIVE
To evaluate the effects of incremental doses of acepromazine on hemodynamics in isoflurane-anesthetized dogs.
STUDY DESIGN
Prospective, experimental study.
ANIMALS
Healthy, adult, mixed-breed dogs (two male and four female) weighing 16.8 ± 5.1 kg (mean ± standard deviation).
METHODS
Dogs were anesthetized with propofol (7 mg kg) intravenously (IV) and isoflurane. Thermodilution and arterial catheters were placed for hemodynamic monitoring and arterial blood sampling for blood gas analysis. Baseline measurements were performed with stable expired concentration of isoflurane (Fe'Iso) at 1.8%. Each dog was then administered four incremental acepromazine injections (10, 15, 25 and 50 μg kg) IV, and measurements were repeated 20 minutes after each acepromazine injection with Fe'Iso decreased to 1.2%. The four acepromazine injections resulted in cumulative doses of 10, 25, 50 and 100 μg kg (time points ACP, ACP, ACP and ACP, respectively).
RESULTS
Compared with baseline, cardiac index (CI) increased significantly by 34%, whereas systemic vascular resistance index (SVRI) decreased by 25% at ACP and ACP. Arterial oxygen content (CaO) was significantly lower than baseline after all acepromazine injections (maximum decreases of 11%) and was lower at ACP and ACP than at ACP. No significant change was found in heart rate, stroke index, oxygen delivery index and systolic, mean and diastolic blood pressures. Hypotension (mean arterial pressure < 60 mmHg) was observed in one dog at baseline, ACP, ACP and ACP, and in two dogs at ACP.
CONCLUSIONS AND CLINICAL RELEVANCE
Compared with isoflurane alone, anesthesia with acepromazine-isoflurane resulted in increased CI and decreased SVRI and CaO values. These effects were dose-related, being more pronounced at ACP and ACP. Under the conditions of this study, acepromazine administration did not change blood pressure.
Topics: Acepromazine; Animals; Blood Pressure; Cross-Over Studies; Dogs; Female; Heart Rate; Hemodynamics; Isoflurane; Male; Prospective Studies
PubMed: 33388251
DOI: 10.1016/j.vaa.2020.11.003 -
Cell Death & Disease Dec 2023Glioblastoma (GBM) is the most frequent and lethal brain tumor, whose therapeutic outcome - only partially effective with current schemes - places this disease among the...
Glioblastoma (GBM) is the most frequent and lethal brain tumor, whose therapeutic outcome - only partially effective with current schemes - places this disease among the unmet medical needs, and effective therapeutic approaches are urgently required. In our attempts to identify repositionable drugs in glioblastoma therapy, we identified the neuroleptic drug chlorpromazine (CPZ) as a very promising compound. Here we aimed to further unveil the mode of action of this drug. We performed a supervised recognition of the signal transduction pathways potentially influenced by CPZ via Reverse-Phase Protein microArrays (RPPA) and carried out an Activity-Based Protein Profiling (ABPP) followed by Mass Spectrometry (MS) analysis to possibly identify cellular factors targeted by the drug. Indeed, the glycolytic enzyme PKM2 was identified as one of the major targets of CPZ. Furthermore, using the Seahorse platform, we analyzed the bioenergetics changes induced by the drug. Consistent with the ability of CPZ to target PKM2, we detected relevant changes in GBM energy metabolism, possibly attributable to the drug's ability to inhibit the oncogenic properties of PKM2. RPE-1 non-cancer neuroepithelial cells appeared less responsive to the drug. PKM2 silencing reduced the effects of CPZ. 3D modeling showed that CPZ interacts with PKM2 tetramer in the same region involved in binding other known activators. The effect of CPZ can be epitomized as an inhibition of the Warburg effect and thus malignancy in GBM cells, while sparing RPE-1 cells. These preclinical data enforce the rationale that allowed us to investigate the role of CPZ in GBM treatment in a recent multicenter Phase II clinical trial.
Topics: Humans; Glioblastoma; Chlorpromazine; Pyruvate Kinase; Cell Line, Tumor; Energy Metabolism
PubMed: 38092755
DOI: 10.1038/s41419-023-06353-3 -
Academic Emergency Medicine : Official... Sep 2022This review was designated to evaluate the efficacy of parenteral ketorolac in treating acute migraine headache. (Meta-Analysis)
Meta-Analysis
OBJECTIVES
This review was designated to evaluate the efficacy of parenteral ketorolac in treating acute migraine headache.
METHODS
We searched databases Cochrane Central Register of Controlled Trials (CENTRAL), Medline, and Google Scholar up to January 2021 and identified randomized controlled trials comparing ketorolac to any other medications in treating patients presenting with migraine headache.
RESULTS
Thirteen trials were included in our review, comprising 944 participants. We derived seven comparisons: ketorolac versus phenothiazines, metoclopramide, sumatriptan, dexamethasone, sodium valproate, caffeine, and diclofenac. There were no significant differences in the reduction of pain intensity at 1 h under the comparisons between ketorolac and phenothiazines (standard mean difference [SMD] = 0.09, p = 0.74) or metoclopramide (SMD = 0.02, p = 0.95). We also found no difference in the outcome recurrence of headache (ketorolac vs. phenothiazines (risk ratio [RR] =0.98, p = 0.97)], ability to return to work or usual activity (ketorolac vs. metoclopramide [RR = 0.64, p = 0.13]), need for rescue medication (ketorolac vs. phenothiazines [RR = 1.72, p = 0.27], ketorolac vs. metoclopramide [RR 2.20, p = 0.18]), and frequency of adverse effects (ketorolac vs. metoclopramide [RR = 1.07, p = 0.82]). Limited trials suggested that ketorolac offered better pain relief at 1 h compared to sumatriptan and dexamethasone; had lesser frequency of adverse effects than phenothiazines; and was superior to sodium valproate in terms of reduction of pain intensity at 1 h, need for rescue medication, and sustained headache freedom within 24 h.
CONCLUSIONS
Ketorolac may have similar efficacy to phenothiazines and metoclopramide in treating acute migraine headache. Ketorolac may also offer better pain control than sumatriptan, dexamethasone, and sodium valproate. However, given the lack of evidence due to inadequate number of trials available, future studies are warranted.
Topics: Caffeine; Dexamethasone; Diclofenac; Humans; Ketorolac; Metoclopramide; Migraine Disorders; Pain; Phenothiazines; Sumatriptan; Valproic Acid
PubMed: 35138658
DOI: 10.1111/acem.14457 -
Regulatory Toxicology and Pharmacology... Dec 2019The phenothiazine-derived antipsychotic drugs, such as chlorpromazine and thioridazine, are bactericidal against drug-sensitive and drug-resistant strains of...
The phenothiazine-derived antipsychotic drugs, such as chlorpromazine and thioridazine, are bactericidal against drug-sensitive and drug-resistant strains of Mycobacterium tuberculosis, but produce undesirable side effects at clinically relevant doses. We have previously modified four novel phenothiazines and maintained their antimycobacterial activity. This study evaluated the pharmacological and toxicity profiles of these novel non-neuroleptic phenothiazines, PTZ3, PTZ4, PTZ31 and PTZ32, for their metabolic stability, kinetic solubility and potential cytotoxic effects in vitro. To further support the safet use of these drug candidates, the in vivo pharmacological and toxicity profiles were assessed in C57BL/6 mice via single or repeated oral gavage. In acute toxicity studies, all four modified phenothiazines showed favourable safety in mice. When treated daily with 100 mg/kg of PTZ3 and PTZ4 for 2 weeks, mice displayed no signs of toxicity. Alternatively, treatment with PTZ31 resulted in 20% mortality with no toxicity evident in biochemical or histological analysis, while exposure to PTZ32 resulted in a 45% survival with increased serum concentrations of uric acid and alkaline phosphatase. The combined non-neuroleptic and antimycobacterial effects of the novel phenothiazines PTZ3, PTZ4, PTZ31 and PTZ32 demonstrated favourable pharmacological and toxicity profiles in this study, highlight the potential of these compounds as suitable anti-tuberculosis drug candidates.
Topics: Animals; Antitubercular Agents; Cells, Cultured; Female; Macrophages; Mice; Phenothiazines; Primary Cell Culture; Thioridazine; Toxicity Tests, Acute; Toxicity Tests, Subacute
PubMed: 31672509
DOI: 10.1016/j.yrtph.2019.104508 -
Neuroscience and Biobehavioral Reviews Oct 2022Over a century ago, the phenothiazine dye, methylene blue, was discovered to have both antipsychotic and anti-cancer effects. In the 20th-century, the first... (Review)
Review
Over a century ago, the phenothiazine dye, methylene blue, was discovered to have both antipsychotic and anti-cancer effects. In the 20th-century, the first phenothiazine antipsychotic, chlorpromazine, was found to inhibit cancer. During the years of elucidating the pharmacology of the phenothiazines, reserpine, an antipsychotic with a long historical background, was likewise discovered to have anti-cancer properties. Research on the effects of antipsychotics on cancer continued slowly until the 21st century when efforts to repurpose antipsychotics for cancer treatment accelerated. This review examines the history of these developments, and identifies which antipsychotics might treat cancer, and which cancers might be treated by antipsychotics. The review also describes the molecular mechanisms through which antipsychotics may inhibit cancer. Although the overlap of molecular pathways between schizophrenia and cancer have been known or suspected for many years, no comprehensive review of the subject has appeared in the psychiatric literature to assess the significance of these similarities. This review fills that gap and discusses what, if any, significance the similarities have regarding the etiology of schizophrenia.
Topics: Antipsychotic Agents; Chlorpromazine; Humans; Methylene Blue; Neoplasms; Phenothiazines; Reserpine; Schizophrenia
PubMed: 35970416
DOI: 10.1016/j.neubiorev.2022.104809 -
Current Pharmaceutical Design 2023
Topics: Humans; Antipsychotic Agents; Phenothiazines; Drug Repositioning; Nanotechnology; Tumor Cells, Cultured; Neoplasms
PubMed: 37605391
DOI: 10.2174/1381612829666230821092254 -
Redox Biology Jul 2024Inflammation and subsequent mitochondrial dysfunction and cell death worsen outcomes after revascularization in ischemic stroke. Receptor-interacting protein kinase 1...
Modulation of NLRP3 inflammasome-related-inflammation via RIPK1/RIPK3-DRP1 or HIF-1α signaling by phenothiazine in hypothermic and normothermic neuroprotection after acute ischemic stroke.
BACKGROUND
Inflammation and subsequent mitochondrial dysfunction and cell death worsen outcomes after revascularization in ischemic stroke. Receptor-interacting protein kinase 1 (RIPK1) activated dynamin-related protein 1 (DRP1) in a NLRPyrin domain containing 3 (NLRP3) inflammasome-dependent fashion and Hypoxia-Inducible Factor (HIF)-1α play key roles in the process. This study determined how phenothiazine drugs (chlorpromazine and promethazine (C + P)) with the hypothermic and normothermic modality impacts the RIPK1/RIPK3-DRP1 and HIF-1α pathways in providing neuroprotection.
METHODS
A total of 150 adult male Sprague-Dawley rats were subjected to 2 h middle cerebral artery occlusion (MCAO) followed by 24 h reperfusion. 8 mg/kg of C + P was administered at onset of reperfusion. Infarct volumes, mRNA and protein expressions of HIF-1α, RIPK1, RIPK3, DRP-1, NLRP3-inflammation and cytochrome c-apoptosis were assessed. Apoptotic cell death, infiltration of neutrophils and macrophages, and mitochondrial function were evaluated. Interaction between RIPK1/RIPK3 and HIF-1α/NLRP3 were determined. In SH-SY5Y cells subjected to oxygen/glucose deprivation (OGD), the normothermic effect of C + P on inflammation and apoptosis were examined.
RESULTS
C + P significantly reduced infarct volumes, mitochondrial dysfunction (ATP and ROS concentration, citrate synthase and ATPase activity), inflammation and apoptosis with and without induced hypothermia. Overexpression of RIPK1, RIPK3, DRP-1, NLRP3-inflammasome and cytochrome c-apoptosis were all significantly reduced by C + P at 33 °C and the RIPK1 inhibitor (Nec1s), suggesting hypothermic effect of C + P via RIPK1/RIPK3-DRP1pathway. When body temperature was maintained at 37 °C, C + P and HIF-1α inhibitor (YC-1) reduced HIF-1α expression, leading to reduction in mitochondrial dysfunction, NLRP3 inflammasome and cytochrome c-apoptosis, as well as the interaction of HIF-1α and NLRP3. These were also evidenced in vitro, indicating a normothermic effect of C + P via HIF-1α.
CONCLUSION
Hypothermic and normothermic neuroprotection of C + P involve different pathways. The normothermic effect was mediated by HIF-1α, while hypothermic effect was via RIPK1/RIPK3-DRP1 signaling. This provides a theoretical basis for future precise exploration of hypothermic and normothermic neuroprotection.
Topics: Animals; Receptor-Interacting Protein Serine-Threonine Kinases; NLR Family, Pyrin Domain-Containing 3 Protein; Rats; Ischemic Stroke; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Signal Transduction; Inflammasomes; Dynamins; Rats, Sprague-Dawley; Phenothiazines; Inflammation; Neuroprotection; Humans; Disease Models, Animal; Hypothermia, Induced
PubMed: 38692093
DOI: 10.1016/j.redox.2024.103169 -
Chemosphere Jan 2022Methylene blue (MB) is categorized as an organic dye (OD) released as effluents after various industrial activities and is one of the most abundant pollutants in the... (Review)
Review
Methylene blue (MB) is categorized as an organic dye (OD) released as effluents after various industrial activities and is one of the most abundant pollutants in the aquatic environment. Significantly, because of its potential toxicity, removing MB from wastewater has been a matter of necessity in recent times. Numerous analytical techniques have been applied, among which polysaccharide-based composite hydrogels appear as the most favorable for MB removal because of their large surface area, excellent mechanical properties, swelling capability, and large-scale production. In this review, the first section gives adequate information about the ODs' adverse effects on the environment and the contribution of polysaccharide-based hydrogels for OD removal, especially MB. Next, various mechanisms such as electrostatic interactions, π-π interactions, hydrogen bonding, hydrophobic interaction, van der Waals force, and coordination interaction involved in the adsorption technique are investigated. The third section extensively describes the MB removal by incorporation of various materials such as monomers, metal oxides, magnetic nanoparticles, and clay into the polysaccharide matrix to produce composite hydrogels. Finally, the current limitations and future perspectives of the polysaccharide-based composite hydrogel techniques are addressed. Overall, this review acknowledged the vital role of polysaccharide-based composite hydrogels for MB adsorption by surveying 110 research articles published in the past five years (2015-2021).
Topics: Adsorption; Environmental Pollutants; Hydrogels; Methylene Blue; Polysaccharides; Water Pollutants, Chemical
PubMed: 34426282
DOI: 10.1016/j.chemosphere.2021.131890