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Journal of Applied Toxicology : JAT Apr 2023In this review, we summarized the current literature on the impact of phenothiazine derivatives on autophagy in vitro. Phenothiazines are antipsychotic drugs used in the... (Review)
Review
In this review, we summarized the current literature on the impact of phenothiazine derivatives on autophagy in vitro. Phenothiazines are antipsychotic drugs used in the treatment of schizophrenia, which is related to altered neurotransmission and dysregulation of neuronal autophagy. Thus, phenothiazine derivatives can impact autophagy. We identified 35 papers, where the use of the phenothiazines in the in vitro autophagy assays on normal and cancer cell lines, Caenorhabditis elegans, and zebrafish were discussed. Chlorpromazine, fluphenazine, mepazine, methotrimeprazine, perphenazine, prochlorperazine, promethazine, thioridazine, trifluoperazine, and novel derivatives can modulate autophagy. Stimulation of autophagy by phenothiazines may be either mammalian target of rapamycin (mTOR)-dependent or mTOR-independent. The final effect depends on the used concentration as well as the cell line. A further investigation of the mechanisms of autophagy regulation by phenothiazine derivatives is required to understand the biological actions and to increase the therapeutic potential of this class of drugs.
Topics: Animals; Antipsychotic Agents; Zebrafish; Promazine; Phenothiazines; Chlorpromazine; Mammals
PubMed: 36165981
DOI: 10.1002/jat.4397 -
Current Opinion in Supportive and... Sep 2015To provide an overview of recent evidence relating to nonopioid medication for the treatment of refractory breathlessness. (Review)
Review
PURPOSE OF REVIEW
To provide an overview of recent evidence relating to nonopioid medication for the treatment of refractory breathlessness.
RECENT FINDINGS
A search of publications since 2013 found systematic reviews on phenothiazines and nebulized medications, together with one study examining the use of benzodiazepines and another nebulized furosemide. However, all provided limited data and concluded that further clinical trials are required.
SUMMARY
Based on this review, there is insufficient evidence to support the routine use of nonopioid medication in the treatment of refractory breathlessness.
Topics: Anti-Anxiety Agents; Antidepressive Agents; Cannabinoids; Clinical Trials as Topic; Dyspnea; Furosemide; Humans; Palliative Care; Phenothiazines
PubMed: 26125307
DOI: 10.1097/SPC.0000000000000149 -
European Journal of Medicinal Chemistry Jun 2023Cancer is a leading cause of death worldwide and there are still limited options for cure. Chemotherapy is the most significant treatment for cancer which increased... (Review)
Review
Cancer is a leading cause of death worldwide and there are still limited options for cure. Chemotherapy is the most significant treatment for cancer which increased survival rates, despite this, it is associated with numerous side effects, as well as cancer relapsing due to drug resistance insurgence; consequently, it is still a challenging task to develop new potent and less toxic anti-cancer agents for patients' care. Phenothiazine moiety, which leads a class of well-known antipsychotic drugs, possesses a wide range of biological activities and has been also introduced in cancer chemotherapy. This review aims in disclosing the use of phenothiazines during the last five years for the development of different anti-cancer drug candidates. The design and the synthetic strategies adopted, the SAR investigations and the role of reviewed phenothiazine derivatives as anti-cancer agents and multi-drug resistance (MDR) reversals are here fully described and discussed.
Topics: Humans; Phenothiazines; Antineoplastic Agents; Antipsychotic Agents; Drug Resistance, Multiple
PubMed: 37060756
DOI: 10.1016/j.ejmech.2023.115337 -
Journal of Applied Toxicology : JAT Jan 2021Drug repositioning is an approach that could accelerate the clinical use of compounds in different diseases. The goal is to take advantage of the fact that approved... (Review)
Review
Drug repositioning is an approach that could accelerate the clinical use of compounds in different diseases. The goal is to take advantage of the fact that approved drugs have been tested on humans and detailed information is available on their pharmacology, toxicity and formulation. It can significantly reduce the costs and time needed to implement necessary therapies on the market. In recent years, phenothiazines are being tested for cancer, viral, bacterial, fungal and other diseases. Most research focuses on chlorpromazine as a model drug in this class, but other drugs such as fluphenazine, perphenazine and prochlorperazine have been proven to inhibit the viability of different cancer cell lines. In this study, we performed an extensive literature search to find and summarize all papers on the chosen phenothiazines and their potential in treating different types of cancerin vitro for further animal/clinical trials. Fluphenazine, perphenazine and prochlorperazine possess anticancer activity towards different types of human cancer. The antitumor activity is mainly mediated by an effect of the drugs on the cell cycle, proliferation or apoptosis. Possible molecular targets of phenothiazine derivatives are the drug's efflux pumps (ABCB1 and P-glycoprotein) and two parallel pathways (AKT and Wnt) regulated by the D receptor antagonists. The drugs have the potential to reduce the viability of human cancer cell lines, fragment the DNA, stimulate apoptosis, inhibit cell migration and invasiveness as well as impair the production of reactive oxygen species. In addition, due to the sedative and antiemetic properties antipsychotics can be used as an adjuvant for the treatment of chemotherapy side effects.
Topics: Antineoplastic Agents; Antipsychotic Agents; Dopamine Antagonists; Drug Repositioning; Fluphenazine; Humans; In Vitro Techniques; Neoplasms; Perphenazine; Prochlorperazine
PubMed: 32852120
DOI: 10.1002/jat.4046 -
The Journal of the Association of... Apr 2022Many novel drugs were used in COVID19 pandemic to improve outcome. One such molecule is Methylene blue which is a, tricyclic phenothiazine compound approved for the... (Observational Study)
Observational Study
UNLABELLED
Many novel drugs were used in COVID19 pandemic to improve outcome. One such molecule is Methylene blue which is a, tricyclic phenothiazine compound approved for the treatment of acquired methemoglobinemia and some other uses US FDA. This molecule was found to inhibit the interaction of COVID19 virus and target cells in dose dependent manner. It was also found to inhibit interaction of viron with host cells, by inhibiting interaction of SARS CoV2 spike protein and ACE inhibitor receptor interactions.
MATERIAL AND METHODS
A) Aim & Objectives: To evaluate the effect of Nebulised Methylene blue on the clinical course and outcomes of patients with COVID-19 infections. B) Study design Observational Study C) Participants 63 COVID19 RT-PCR positive cases divided in 3 groups. Group 1 consists of patients who were prescribed Methylene blue nebulization in form of Methylene blue 0.5 mg via nebulization along with bronchodilator Levosalbutamol (1.25 mg) + Ipratropium (500 mcg) three times a day . Group 2 consists of patients with Methylene blue nebulization in form of Methylene blue 0.5 mg via nebulization along with inhalational steroid Budesonide (1 mg). Group 3 acted were those patients who had no Methylene blue nebulisation in their treatment.
OBSERVATION
1) Analysis 63 cases were divided in 3 groups of 21 each, descriptive and frequency analysis of cases in groups are shown.
CONCLUSION
No statistically significant difference in outcome measures like Spo2, duration of hospital stay or inflammatory markers. A general trend of fall in inflammatory markers and O2 requirements in group receiving methylene blue but this difference was not consistantly statistically significant.
Topics: Humans; Methemoglobinemia; Methylene Blue; Pandemics; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35443513
DOI: No ID Found -
Colloids and Surfaces. B, Biointerfaces May 2018Phase separation in amphiphilic systems is an important phenomenon. The temperature at which an amphiphilic solution phase separates is known as Cloud Point (CP). This... (Review)
Review
Phase separation in amphiphilic systems is an important phenomenon. The temperature at which an amphiphilic solution phase separates is known as Cloud Point (CP). This article reviews in detail the process of phase separation in various amphiphiles (surfactants, polymers and drugs) and effect of different classes of additives on the CP of these amphiphilic systems. Ions affect the CP of drugs in a different way: kosmotropes and hard bases decrease while chaotropes and soft bases increase the CP of nonionic and cationic surfactants. Anionic surfactants show CP in presence of quaternary salts only. Thus, depending upon the nature and concentration of additive, the CP of an amphiphilic system gets increased or decreased and, hence, properties of the system may be tuned as per the need and use. A system with CP at high concentration can be made to phase separate at lower concentration by simply introducing an appropriate additive in it. This makes the system cost effective. On the other hand, if not required, a low CP can be enhanced with the help of another type of a suitable additive.
Topics: Antidepressive Agents, Tricyclic; Chemistry, Pharmaceutical; Humans; Phenothiazines; Polymers; Quaternary Ammonium Compounds; Salts; Solubility; Surface-Active Agents; Temperature; Thermodynamics
PubMed: 29547842
DOI: 10.1016/j.colsurfb.2018.01.060 -
Current Opinion in Genetics &... Aug 2021The order Odonata (dragonflies and damselflies) comprises diurnal insects with well-developed vision, showing diverse colors in adult wings and bodies. It is one of the... (Review)
Review
The order Odonata (dragonflies and damselflies) comprises diurnal insects with well-developed vision, showing diverse colors in adult wings and bodies. It is one of the most ancestral winged insect groups. Because Odonata species use visual cues to recognize each other, color patterns have been investigated from ecological and evolutionary viewpoints. Here we review the recent progress on molecular mechanisms of pigmentation, especially focused on light-blue coloration. Results from histology and pigment analysis showed that ommochrome pigments on the proximal layer and pteridine pigments on the distal layer of the epidermis are essential for light-blue coloration. We also summarize genes involved in the biosynthesis of three major insect pigments conserved across insects and discuss that gene-functional analysis deserves future studies.
Topics: Animals; Color; Odonata; Phenothiazines; Phenotype; Pigmentation; Wings, Animal
PubMed: 33482606
DOI: 10.1016/j.gde.2020.12.014 -
Cell Apr 2020Protein phosphatase 2A (PP2A) enzymes can suppress tumors, but they are often inactivated in human cancers overexpressing inhibitory proteins. Here, we identify a class...
Protein phosphatase 2A (PP2A) enzymes can suppress tumors, but they are often inactivated in human cancers overexpressing inhibitory proteins. Here, we identify a class of small-molecule iHAPs (improved heterocyclic activators of PP2A) that kill leukemia cells by allosterically assembling a specific heterotrimeric PP2A holoenzyme consisting of PPP2R1A (scaffold), PPP2R5E (B56ε, regulatory), and PPP2CA (catalytic) subunits. One compound, iHAP1, activates this complex but does not inhibit dopamine receptor D2, a mediator of neurologic toxicity induced by perphenazine and related neuroleptics. The PP2A complex activated by iHAP1 dephosphorylates the MYBL2 transcription factor on Ser241, causing irreversible arrest of leukemia and other cancer cells in prometaphase. In contrast, SMAPs, a separate class of compounds, activate PP2A holoenzymes containing a different regulatory subunit, do not dephosphorylate MYBL2, and arrest tumor cells in G1 phase. Our findings demonstrate that small molecules can serve as allosteric switches to activate distinct PP2A complexes with unique substrates.
Topics: Apoptosis; Cell Cycle Proteins; Cell Line, Tumor; Enzyme Activators; G1 Phase; Humans; Multiprotein Complexes; Phenothiazines; Phosphorylation; Protein Phosphatase 2; Protein Subunits; Trans-Activators; Transcription Factors
PubMed: 32315619
DOI: 10.1016/j.cell.2020.03.051 -
Prion Sep 2017Sporadic fatal insomnia (sFI) is a rapid progressive neurodegenerative disease characterised by gradual to perpetual insomnia, followed by dysautonomia, coma and death.... (Review)
Review
BACKGROUND
Sporadic fatal insomnia (sFI) is a rapid progressive neurodegenerative disease characterised by gradual to perpetual insomnia, followed by dysautonomia, coma and death. The cause of sFI was recently mapped to a mutation in a protein, the prion, found in the human brain. It is the unfolding of the prion that leads to the generation of toxic oligomers that destroy brain tissue and function. Recent studies have confirmed that a methionine mutation at codon 129 of the human Prion is characteristic of sFI. Current treatment slows down the progression of the disease, but no cure has been found, yet.
METHODS
We used Molecular Docking and Molecular Dynamics simulation methods, to study the toxic Fatal-Insomnia-prion conformations at local unfolding. The idea was to determine these sites and to stabilise these regions against unfolding and miss-folding, using a small ligand, based on a phenothiazine "moiety".
CONCLUSION
As a result we here discuss current fatal insomnia therapy and present seven novel possible compounds for in vitro and in vivo screening.
Topics: Antipsychotic Agents; Brain; Chlorpromazine; Drug Design; Humans; Insomnia, Fatal Familial; Molecular Docking Simulation; Molecular Dynamics Simulation; Mutation; Phenothiazines; Prion Proteins; Protein Unfolding
PubMed: 28976233
DOI: 10.1080/19336896.2017.1368937 -
Current Medicinal Chemistry 2021Molecules with a phenothiazine scaffold have been considered versatile organic structures with a wide variety of biological activities, such as antipsychotic,... (Review)
Review
BACKGROUND
Molecules with a phenothiazine scaffold have been considered versatile organic structures with a wide variety of biological activities, such as antipsychotic, anticancer, antibacterial, antifungal, antiviral, anti-inflammatory, antimalarial, and trypanocidal, etc. It was first discovered in the 19th century as a histochemical dye, phenothiazine methylene blue. Since then, its derivatives have been studied, showing new activities; moreover, they have also been repurposed.
OBJECTIVE
This review aims to describe the main synthetic routes of phenothiazines and, particularly, the anticancer and antiprotozoal activities reported during the second decade of the 2000s (2010 - 2020).
RESULTS
Several studies on phenothiazines against cancer and protozoa have revealed that these compounds show IC50 values in the micromolar and near nanomolar range. The structural analyses have revealed that compounds bearing halogens or electron-withdrawing groups at 2-position have favorable anticancer activity. Phenothiazine dyes have shown a photosensitizing activity against trypanosomatids at a micromolar range. Tetra and pentacyclic azaphenothiazines are structures with a high broad-spectrum anticancer activity.
CONCLUSION
The phenothiazine scaffold is favorable for developing anticancer agents, especially those bearing halogens and electron-withdrawing groups bound at 2-position with enhanced biological activities through a variety of aromatic, aliphatic and heterocyclic substituents in the thiazine nitrogen. Further studies are warranted along these investigation lines to attain more active anticancer and antiprotozoal compounds with minimal to negligible cytotoxicity.
Topics: Antineoplastic Agents; Antiprotozoal Agents; Antipsychotic Agents; Chemistry, Pharmaceutical; Humans; Phenothiazines; Structure-Activity Relationship
PubMed: 33820509
DOI: 10.2174/0929867328666210405120330