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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 -
Journal of Molecular Modeling Aug 2015Ommochromes are colored substances that apparently function as biological signals among arthropods and insects. These substances may prevent oxidative stress by...
Ommochromes are colored substances that apparently function as biological signals among arthropods and insects. These substances may prevent oxidative stress by scavenging free radicals. Two principal mechanisms exist for scavenging free radicals: the electron transfer and hydrogen atom transfer. In this investigation, a theoretical study of the antiradical capacity of five ommochromes was performed within the density functional theory framework. Vertical ionization energy and vertical electron affinity were used to study the electron transfer mechanism between ommochromes and four free radicals: CH3O•, NO2•, HO•, and HOO•. For the hydrogen transfer mechanism, dissociation energy (D0) and Gibbs free energy were calculated, taking into account hydrogen atoms at different positions in the ommochromes. Both mechanisms are thermodynamically possible. The best antiradical is ommatin D. The UV/VIS spectra for ommochromes were obtained with ommatin D registering as the ommochrome with the greatest λmax value. In summary, ommatin D is the best antiradical and also the redder molecule. These results are important and may help to elucidate the function of these molecules in the animal kingdom. Graphical abstract Ommochromes are red and yellow substances present in arthropods and insects. According with computational chemistry, these substances present the capacity of prevent oxidative stress since they scavenge free radicals. These results may help to elucidate the function of these molecules in the animal Kingdom.
Topics: Animals; Arthropods; Free Radical Scavengers; Free Radicals; Phenothiazines; Thermodynamics
PubMed: 26238086
DOI: 10.1007/s00894-015-2773-3 -
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 -
Journal of Insect Physiology Aug 2017Ommochromes are major pigments involved in coloration of eggs, eyes, wings, and epidermis of insects. Bombyx mori (silkworm) eggs contain a mixture of ommochrome...
Ommochromes are major pigments involved in coloration of eggs, eyes, wings, and epidermis of insects. Bombyx mori (silkworm) eggs contain a mixture of ommochrome pigments and their precursors. Here, we analyzed the pigment composition of every egg color strain using egg color mutants (w-2, pe, and re) and wild-type strains (dazao and C108) by using full wavelength scanning and high-performance liquid chromatography. We identified ommochrome pigments and their precursors in pigment extracts from non-diapause eggs and diapause eggs, and found that the quantities of ommochrome precursor 3-hydroxy-kynurenine were much higher in the diapause eggs. Ommochrome pigments were absent in the non-diapause eggs. We analyzed the pigment composition of every egg color strain and found an accumulation of 3-hydroxy-kynurenine and absence of ommochromes in the yellow eggs (w-2 and pe), suggesting that the essential factors for ommochrome biosynthesis are high levels of 3-hydroxy-kynurenine, enzymes for ommochrome synthesis and transferase, and spermatiation. Moreover, we confirmed that both decarboxylated xanthommatin and xanthommatin are major ommochrome pigments, and the quantity of decarboxylated xanthommatin is much higher than that of xanthommatin in silkworm eggs. Since ommochrome pigments can change color under oxidative/reductive conditions and the egg color mutant re turns crimson when preserved at a low temperature for a few weeks, we used an oxidation-reduction reaction in vitro to explore mechanisms behind the pigment-based color change. Specifically, during diapause, the contents of decarboxylated xanthommatin and xanthommatin are increased, and the ommochrome pigments convert into their reduced forms.
Topics: Animals; Bombyx; Chromatography, High Pressure Liquid; Diapause, Insect; Ovum; Phenothiazines; Pigmentation; Pigments, Biological
PubMed: 28750999
DOI: 10.1016/j.jinsphys.2017.07.013 -
Current Pharmaceutical Design 2023
Topics: Humans; Antipsychotic Agents; Phenothiazines; Drug Repositioning; Nanotechnology; Tumor Cells, Cultured; Neoplasms
PubMed: 37605391
DOI: 10.2174/1381612829666230821092254 -
Molecular Neurobiology Dec 2021A depressive or hibernation-like effect of chlorpromazine and promethazine (C + P) on brain activity was reported to induce neuroprotection, with or without...
A depressive or hibernation-like effect of chlorpromazine and promethazine (C + P) on brain activity was reported to induce neuroprotection, with or without induced-hypothermia. However, the underlying mechanisms remain unclear. The current study evaluated the pharmacological function of C + P on the inhibition of neuroinflammatory response and inflammasome activation after ischemia/reperfusion. A total of 72 adult male Sprague-Dawley rats were subjected to 2 h middle cerebral artery occlusion (MCAO) followed by 6 or 24 h reperfusion. At the onset of reperfusion, rats received C + P (8 mg/kg) with temperature control. Brain cell death was detected by measuring CD68 and myeloperoxidase (MPO) levels. Inflammasome activation was measured by mRNA levels of NLRP3, IL-1β, and TXNIP, and protein quantities of NLRP3, IL-1β, TXNIP, cleaved-Caspase-1, and IL-18. Activation of JAK2/STAT3 pathway was detected by the phosphorylation of STAT3 (p-STAT3) and JAK2 (p-JAK2), and the co-localization of p-STAT3 and NLRP3. Activation of the p38 pathway was assessed with the protein levels of p-p38/p38. The mRNA and protein levels of HIF-1α, FoxO1, and p-FoxO1, and the co-localization of p-STAT3 with HIF-1α or FoxO1 were quantitated. As expected, C + P significantly reduced cell death and attenuated the neuroinflammatory response as determined by reduced CD68 and MPO. C + P decreased ischemia-induced inflammasome activation, shown by reduced mRNA and protein expressions of NLRP3, IL-1β, TXNIP, cleaved-Caspase-1, and IL-18. Phosphorylation of JAK2/STAT3 and p38 pathways and the co-localization of p-STAT3 with NLRP3 were also inhibited by C + P. Furthermore, mRNA levels of HIF-1α and FoxO1 were decreased in the C + P group. While C + P inhibited HIF-1α protein expression, it increased FoxO1 phosphorylation, which promoted the exclusion of FoxO1 from the nucleus and inhibited FoxO1 activity. At the same time, C + P reduced the co-localization of p-STAT3 with HIF-1α or FoxO1. In conclusion, C + P treatment conferred neuroprotection in stroke by suppressing neuroinflammation and NLRP3 inflammasome activation. The present study suggests that JAK2/STAT3/p38/HIF-1α/FoxO1 are vital regulators and potential targets for efficacious therapy following ischemic stroke.
Topics: Animals; Cell Death; Cytokines; Disease Models, Animal; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammasomes; Ischemic Stroke; Male; NLR Family, Pyrin Domain-Containing 3 Protein; Neuroinflammatory Diseases; Phenothiazines; Phosphorylation; Rats; Rats, Sprague-Dawley; Signal Transduction
PubMed: 34455546
DOI: 10.1007/s12035-021-02542-3 -
Potential of phenothiazines to synergistically block calmodulin and reactivate PP2A in cancer cells.PloS One 2022Phenothiazines (PTZ) were developed as inhibitors of monoamine neurotransmitter receptors, notably dopamine receptors. Because of this activity they have been used for...
Phenothiazines (PTZ) were developed as inhibitors of monoamine neurotransmitter receptors, notably dopamine receptors. Because of this activity they have been used for decades as antipsychotic drugs. In addition, they possess significant anti-cancer properties and several attempts for their repurposing were made. However, their incompletely understood polypharmacology is challenging. Here we examined the potential of the PTZ fluphenazine (Flu) and its mustard derivative (Flu-M) to synergistically act on two cancer associated targets, calmodulin (CaM) and the tumor suppressor protein phosphatase 2A (PP2A). Both proteins are known to modulate the Ras- and MAPK-pathway, cell viability and features of cancer cell stemness. Consistently, we show that the combination of a CaM inhibitor and the PP2A activator DT-061 synergistically inhibited the 3D-spheroid formation of MDA-MB-231 (K-Ras-G13D), NCI-H358 (K-Ras-G12C) and A375 (B-raf-V600E) cancer cells, and increased apoptosis in MDA-MB-231. We reasoned that these activities remain combined in PTZ, which were the starting point for PP2A activator development, while several PTZ are known CaM inhibitors. We show that both Flu and Flu-M retained CaM inhibitory activity in vitro and in cells, with a higher potency of the mustard derivative in cells. In line with the CaM dependence of Ras plasma membrane organization, the mustard derivative potently reduced the functional membrane organization of oncogenic Ras, while DT-061 had a negligible effect. Like DT-061, both PTZ potently decreased c-MYC levels, a hallmark of PP2A activation. Benchmarking against the KRAS-G12C specific inhibitor AMG-510 in MIA PaCa-2 cells revealed a higher potency of Flu-M than combinations of DT-061 and a CaM inhibitor on MAPK-output and a strong effect on cell proliferation. While our study is limited, our results suggest that improved PTZ derivatives that retain both, their CaM inhibitory and PP2A activating properties, but have lost their neurological side-effects, may be interesting to pursue further as anti-cancer agents.
Topics: Calmodulin; Cell Line, Tumor; Cell Survival; Neoplasms; Phenothiazines; Protein Phosphatase 2
PubMed: 35617282
DOI: 10.1371/journal.pone.0268635 -
Antiviral Research Jan 2023Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters cells using angiotensin-converting enzyme 2 (ACE2) and neuropilin-1 (NRP-1) as the primary receptor...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters cells using angiotensin-converting enzyme 2 (ACE2) and neuropilin-1 (NRP-1) as the primary receptor and entry co-factor, respectively. Cell entry is the first and major step in initiation of the viral life cycle, representing an ideal target for antiviral interventions. In this study, we used a recombinant replication-deficient vesicular stomatitis virus-based pseudovirus bearing the spike protein of SARS-CoV-2 (SARS2-S) to screen a US Food and Drug Administration-approved drug library and identify inhibitors of SARS-CoV-2 cell entry. The screen identified 24 compounds as primary hits, and the largest therapeutic target group formed by these primary hits was composed of seven dopamine receptor D2 (DRD2) antagonists. Cell-based and biochemical assays revealed that the DRD2 antagonists inhibited both fusion activity and the binding of SARS2-S to NRP-1, but not its binding to ACE2. On the basis of structural similarity to the seven identified DRD2 antagonists, which included six phenothiazines, we examined the anti-SARS-CoV-2 activity of an additional 15 phenothiazines and found that all the tested phenothiazines shared an ability to inhibit SARS2-S-mediated cell entry. One of the phenothiazines, alimemazine, which had the lowest 50% effective concentration of the tested phenothiazines, exhibited a clear inhibitory effect on SARS2-S-NRP-1 binding and SARS-CoV-2 multiplication in cultured cells but not in a mouse infection model. Our findings provide a basis for the development of novel anti-SARS-CoV-2 therapeutics that interfere with SARS2-S binding to NRP-1.
Topics: Animals; Mice; Angiotensin-Converting Enzyme 2; COVID-19; Neuropilin-1; Phenothiazines; Protein Binding; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Virus Internalization; Humans
PubMed: 36481388
DOI: 10.1016/j.antiviral.2022.105481 -
Journal of Biological Inorganic... Jul 2018In recent years, the search for effective anticancer compounds based on transition metal complexes has been the focus of medical investigations. The synergy between the...
In recent years, the search for effective anticancer compounds based on transition metal complexes has been the focus of medical investigations. The synergy between the ruthenium(II) and N-alkylphenothiazine counter-ions (chlorpromazine hydrochloride, thioridazine hydrochloride and trifluoperazine dihydrochloride, respectively) through the formation of three different complexes (1-3) was investigated. We explored whether the selected counter-ions and complexes might affect redox homeostasis and genome integrity of normal human blood cells, and induce an inhibition of Na/K-ATPase and AChE at pharmacologically relevant doses. Our results have shown that counter-ions and complexes did not affect the activity of Na/K-ATPase, while AChE activity was inhibited in a dose-dependent manner. All investigated compounds disturbed the viability and redox homeostasis of lymphocytes. Complexes 1 and 2 displayed potent cytotoxic and prooxidant action while complex 3 behaved as a weaker genotoxic inducer. Still, the tested complexes appeared to be less genotoxic and more cytostatic than the corresponding counter-ions. The effects of selected complexes were also tested in PC12 and U2OS cancer cells with special attention being given to the ability of phenothiazines to affect dopamine D2 receptors. Using the confocal laser scanning microscopy, we observed that all the complexes reduced cell viability. Although all investigated complexes have been bound to the dopamine receptor D-eGFP, only complex 3 reduced its surface density and increased its lateral mobility in investigated cell lines. Albeit the role of alternative targets for complex 3 cannot be ruled out, its effects should be further examined as potential treatment strategy against cancer cells that overexpress D2.
Topics: Acetylcholinesterase; Adult; Animals; Antineoplastic Agents; Catalase; Cell Line, Tumor; Cell Survival; Coordination Complexes; Homeostasis; Humans; Malondialdehyde; Microscopy, Confocal; Mutagenicity Tests; Oxidation-Reduction; Phenothiazines; Rats; Receptors, Dopamine D2; Ruthenium; Sodium-Potassium-Exchanging ATPase; Spectrometry, Fluorescence; Spectrophotometry, Ultraviolet
PubMed: 29644470
DOI: 10.1007/s00775-018-1560-x