No evidence of clinical efficacy of oxomemazine in cough, according to a systematic review.

PURPOSE: Cough is a prevalent symptom driving patients to seek medical attention in general practice. Despite its widespread use, the clinical efficacy of oxomemazine, the second most reimbursed molecule in France for symptomatic cough treatment, remains uncertain. This study aims to systematically evaluate the clinical efficacy of oxomemazine in cough. METHODS: A systematic literature review with meta-analysis of randomized controlled trials (RCTs) was conducted according to the Rebuild the Evidence Base (REB) protocol. Clinical trials comparing the efficacy of oxomemazine versus placebo or active comparator in cough were searched for. Trials with insufficient data were excluded. Searches were conducted across major databases (Medline, Cochrane Central Register of Controlled Trials, and Embase) and trial registries (World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov). RCTs comparing oxomemazine versus placebo or active comparators in cough were sought. Risk of bias was assessed using the Cochrane Collaboration's RoB2 tool. The protocol was preregistered on PROSPERO under the number CRD42022345496 (15). This study received no funding. RESULTS: No RCTs were at low risk of bias. Therefore, no meta-analysis was conducted, in accordance to the pre-specified protocol. CONCLUSIONS: This systematic review highlights the lack of evidence regarding the efficacy of oxomemazine in cough treatment and underscores the need for further well-designed clinical trials to inform its clinical utility in primary care settings.

Design and synthesis of sulfonamide phenothiazine derivatives as novel ferroptosis inhibitors and their therapeutic effects in spinal cord injury.

Ferroptosis is a novel style of cell death, and studies have shown that ferroptosis is strongly associated with spinal cord injury (SCI). A large number of ferroptosis inhibitors have been reported, but so far no ferroptosis inhibitor has been used clinically. Therefore there is an urgent need to discover a better inhibitor of ferroptosis. In this study, 24 novel sulfonamide phenothiazine ferroptosis inhibitors were designed and synthesized, followed by structure-activity relationship studies on these compounds. Among them, compound 23b exhibited the best activity in Erastin-induced PC12 cells (EC50 = 0.001 µM) and demonstrated a low hERG inhibition activity (IC50 > 30 µM). Additionally, compound 23b was identified as a ROS scavenger and showed promising therapeutic effects in an SD rat model of SCI. Importantly, 23b did not display significant toxicity in both in vivo and in vitro experiments and show good pharmacokinetic properties. These findings suggest that compound 23b, a novel ferroptosis inhibitor, holds potential as a therapeutic agent for spinal cord injury and warrants further investigation.

A novel approach to investigate the combinatorial effects of TLK1 (Tousled-Like Kinase1) inhibitors with Temozolomide for glioblastoma therapy.

Glioblastoma multiforme (GBM) is an aggressive, incurable brain tumor with poor prognosis and limited treatment options. Temozolomide (TMZ) is the standard chemotherapeutic treatment for GBM, but its efficacy has drawn strong criticism from clinicians due to short survival gains and frequent relapses. One critical limitation of TMZ therapy is the hyperactivation of DNA repair pathways, which over time neutralizes the cytotoxic effects of TMZ, thus highlighting the urgent need for new treatment approaches. Addressing this, our study explores the therapeutic potential of in-house-designed phenothiazine-based Tousled-like kinase-1 (TLK1) inhibitors for GBM treatment. TLK1, overexpressed in GBM, plays a role in DNA repair. Phenothiazines are known to cross the blood-brain barrier (BBB). Among all molecules, J54 was identified as a potential lead molecule with improved cytotoxicity. In the context of O6-methylguanine-DNA methyltransferase (MGMT)-deficient GBM cells, the combined administration of phenothiazines and TMZ exhibited a collective reduction in clonogenic growth, coupled with anti-migratory and anti-invasion effects. Conversely, in MGMT-proficient cells, phenothiazine monotherapy alone showed reduced clonogenic growth, along with anti-migratory and anti-invasion effects. Notably, a synergistic increase in γH2AX levels and concurrent attenuation of DNA repair upon combinatorial exposure to TMZ and J54 were observed, implying increased cytotoxicity due to sustained DNA strand breaks. Overall, this study provides new insights into TLK1 inhibition for GBM therapy. Collectively, these findings indicate that TLK1 is one of the upregulated kinases in GBM and phenothiazine-based TLK1 inhibitors could be a promising treatment option for GBM patients.

Discovery of 2-vinyl-10H-phenothiazine derivatives as a class of ferroptosis inhibitors with minimal human Ether-a-go-go related gene (hERG) activity for the treatment of DOX-induced cardiomyopathy.

Ferroptosis was an iron-dependent, nonapoptotic form of regulated cell death. In our previous study, we discovered a potent ferroptosis inhibitor with phenothiazine scaffold (1), but subsequent investigation showed that this compound had potent hERG binding affinity. Herein, we report the discovery of a series of 2-vinyl-10H-phenothiazine derivatives as new class of ferroptosis inhibitors. Structure-activity relationship (SAR) analyses led to the identification of compound 7j, which exhibited significantly reduced hERG inhibition (IC50 > 30 µM) while maintaining high ferroptosis inhibitory activity (EC50 = 0.001 µM on the erastin-induced HT1080 cell ferroptosis model). Further studies confirmed 7j acted as a ROS scavenger and could relieve DOX-induced cardiomyopathy. 7j also displayed favorable pharmacokinetic properties and exhibited no obvious toxicity in vivo and vitro. Overall, this study provides a promising lead compound for drug discovery targeting ferroptosis.

Inhibition of dengue virus infection by trifluoperazine.

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.

Development of Phenothiazine Hybrids with Potential Medicinal Interest: A Review.

The molecular hybridization approach has been used to develop compounds with improved efficacy by combining two or more pharmacophores of bioactive scaffolds. In this context, hybridization of various relevant pharmacophores with phenothiazine derivatives has resulted in pertinent compounds with diverse biological activities, interacting with specific or multiple targets. In fact, the development of new drugs or drug candidates based on phenothiazine system has been a promising approach due to the diverse activities associated with this tricyclic system, traditionally present in compounds with antipsychotic, antihistaminic and antimuscarinic effects. Actually, the pharmacological actions of phenothiazine hybrids include promising antibacterial, antifungal, anticancer, anti-inflammatory, antimalarial, analgesic and multi-drug resistance reversal properties. The present review summarizes the progress in the development of phenothiazine hybrids and their biological activity.

NADPH oxidase 1 is a novel pharmacological target for the development of an antiplatelet drug without bleeding side effects.

Growing evidence supports a central role of NADPH oxidases (NOXs) in the regulation of platelets, which are circulating cells involved in both hemostasis and thrombosis. Here, the use of Nox1-/- and Nox1+/+ mice as experimental models of human responses demonstrated a critical role of NOX1 in collagen-dependent platelet activation and pathological arterial thrombosis, as tested in vivo by carotid occlusion assays. In contrast, NOX1 does not affect platelet responses to thrombin and normal hemostasis, as assayed in tail bleeding experiments. Therefore, as NOX1 inhibitors are likely to have antiplatelet effects without associated bleeding risks, the NOX1-selective inhibitor 2-acetylphenothiazine (2APT) and a series of its derivatives generated to increase inhibitory potency and drug bioavailability were tested. Among the 2APT derivatives, 1-(10H-phenothiazin-2-yl)vinyl tert-butyl carbonate (2APT-D6) was selected for its high potency. Both 2APT and 2APT-D6 inhibited collagen-dependent platelet aggregation, adhesion, thrombus formation, superoxide anion generation, and surface activation marker expression, while responses to thrombin or adhesion to fibrinogen were not affected. In vivo administration of 2APT or 2APT-D6 led to the inhibition of mouse platelet aggregation, oxygen radical output, and thrombus formation, and carotid occlusion, while tail hemostasis was unaffected. Differently to in vitro experiments, 2APT-D6 and 2APT displayed similar potency in vivo. In summary, NOX1 inhibition with 2APT or its derivative 2APT-D6 is a viable strategy to control collagen-induced platelet activation and reduce thrombosis without deleterious effects on hemostasis. These compounds should, therefore, be considered for the development of novel antiplatelet drugs to fight cardiovascular diseases in humans.

Unimolecular Photodynamic O2-Economizer To Overcome Hypoxia Resistance in Phototherapeutics.

Tumor hypoxia has proven to be the major bottleneck of photodynamic therapy (PDT) to clinical transformation. Different from traditional O2 delivery approaches, here we describe an innovative binary photodynamic O2-economizer (PDOE) tactic to reverse hypoxia-driven resistance by designing a superoxide radical (O2•-) generator targeting mitochondria respiration, termed SORgenTAM. This PDOE system is able to block intracellular O2 consumption and down-regulate HIF-1α expression, which successfully rescues cancer cells from becoming hypoxic and relieves the intrinsic hypoxia burden of tumors in vivo, thereby sparing sufficient endogenous O2 for the PDT process. Photosensitization mechanism studies demonstrate that SORgenTAM has an ideal intersystem crossing rate and triplet excited state lifetime for generating O2•- through type-I photochemistry, and the generated O2•- can further trigger a biocascade to reduce the PDT's demand for O2 in an O2-recycble manner. Furthermore, SORgenTAM also serves to activate the AMPK metabolism signaling pathway to inhibit cell repair and promote cell death. Consequently, using this two-step O2-economical strategy, under relatively low light dose irradiation, excellent therapeutic responses toward hypoxic tumors are achieved. This study offers a conceptual while practical paradigm for overcoming the pitfalls of phototherapeutics.

Exploitation of a novel phenothiazine derivative for its anti-cancer activities in malignant glioblastoma.

Glioblastoma remains the most malignant of all primary adult brain tumours with poor patient survival and limited treatment options. This study adopts a drug repurposing approach by investigating the anti-cancer activity of a derivative of the antipsychotic drug phenothiazine (DS00329) in malignant U251 and U87 glioblastoma cells. Results from MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and clonogenic assays showed that DS00329 inhibited short-term glioblastoma cell viability and long-term survival while sparing non-cancerous cells. Western blot analysis with an antibody to γH2AX showed that DS00329 induced DNA damage and flow cytometry and western blotting confirmed that it triggered a G1 cell cycle arrest which correlated with decreased levels in Cyclin A, Cyclin B, Cyclin D1 and cyclin dependent kinase 2 and an increase in levels of the cyclin dependent kinase inhibitor p21. DS00329 treated glioblastoma cells exhibited morphological and molecular markers typical of apoptotic cells such as membrane blebbing and cell shrinkage and an increase in levels of cleaved PARP. Flow cytometry with annexin V-FITC/propidium iodide staining confirmed that DS00329 induced apoptotic cell death in glioblastoma cells. We also show that DS00329 treatment of glioblastoma cells led to an increase in the autophagosome marker LC3-II and autophagy inhibition studies using bafilomycin A1 and wortmannin, showed that DS00329-induced-autophagy was a pro-death mechanism. Furthermore, DS00329 treatment of glioblastoma cells inhibited the phosphatidylinositol 3'-kinase/Akt cell survival pathway. Our findings suggest that DS00329 may be an effective treatment for glioblastoma and provide a rationale for further exploration and validation of the use of phenothiazines and their derivatives in the treatment of glioblastoma.

Anti-Trypanosoma cruzi effect of the photodynamic antiparasitic chemotherapy using phenothiazine derivatives as photosensitizers.

Chagas disease is endemic in Latin America and increasingly found in non-endemic countries. Its treatment is limited due to the variable efficacy and several side effects of benznidazole. Photodynamic antimicrobial chemotherapy (PACT) may be an attractive approach for treating Chagas disease. Here, the trypanocidal activity of PACT was investigated in vitro using phenothiazine derivatives. The cytotoxicity of both, methylene blue (MB) and toluidine blue (TBO), was determined on macrophages cultures using AlamarBlue method. The trypanocidal activity of the two photosensitizers was initially evaluated by determining their IC50 values against trypomastigote forms. After this, the trypanocidal effect was evaluated in cultures of infected macrophages using an automatized image analysis protocol. All experiments were performed in the dark and in the clear phase (after a photodynamic exposure). The compounds showed no cytotoxicity in both phases at the tested concentrations. The IC50 values for the sole use of MB and TBO were 2.6 and 1.2 µM, respectively. The photoactivation of the compounds using a fixed energy density (J/cm2) caused a reduction of the IC50 values to 1.0 and 0.9 µM, respectively. It was found that, on infected macrophage, the use of TBO significantly reduced the number of infected cells and parasitic load, and this effect was increased in the presence of light. The results of the present study are indicative that PACT may be considered as both selective and effective therapeutic intervention for treating Chagas disease.

Chlorpromazine versus piperacetazine for schizophrenia.

BACKGROUND: Schizophrenia is a severe mental disorder with a prevalence of about 1% among the general population. It is listed among the top 10 causes of disability-adjusted life years (DALYs) worldwide. Antipsychotics are the mainstay treatment. Piperacetazine has been reported to be as clinically effective as chlorpromazine, a well established 'benchmark' antipsychotic, for people with schizophrenia. However, the side effect profiles of these antipsychotics differ and it is important that an evidence base is available comparing the benefits, and potential harms of these two antipsychotics. OBJECTIVES: To assess the clinical and side effects of chlorpromazine for people with schizophrenia and schizophrenia-like psychoses in comparison with piperacetazine. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Trials Register (6 June 2015 and 8 October 2018) which is based on regular searches of CINAHL, CENTRAL, BIOSIS, AMED, Embase, PubMed, MEDLINE, PsycINFO and registries of clinical trials. There are no language, date, document type, or publication status limitations for inclusion of records in the register. SELECTION CRITERIA: We included randomised controlled trials (RCTs) focusing on chlorpromazine versus piperacetazine for people with schizophrenia, reporting useable data. DATA COLLECTION AND ANALYSIS: We extracted data independently. For binary outcomes, we calculated risk ratio (RR) and its 95% confidence interval (CI), on an intention-to-treat basis. For continuous data, we estimated the mean difference (MD) between groups and its 95% CI. We employed a fixed-effect model for analyses. We assessed risk of bias for included studies and created 'Summary of findings' tables using GRADE. MAIN RESULTS: We found 12 records referring to six trials. We included five trials, all from the 1970s, randomising 343 participants. We excluded one trial. The overall methodology and data reporting by the trials was poor. Only short-term data were available.Results from the included trials found that, in terms of global state improvement, when rated by a psychiatrist, there was no clear difference between chlorpromazine and piperacetazine (RR 0.90, 95% CI 0.80 to 1.02; participants = 208; studies = 2; very low-quality evidence). One trial reported change scores on the mental state scale Brief Psychiatric Rating Scale (BPRS); no clear difference was observed (MD -0.40, 95% CI -1.41 to 0.61; participants = 182; studies = 1; very low-quality evidence). Chlorpromazine appears no worse or better than piperacetazine regarding adverse effects. In both treatment groups, around 60% of participants experienced some sort of adverse effect (RR 1.00, 95% CI 0.75 to 1.33; participants = 74; studies = 3; very low-quality evidence), with approximately 40% of these participants experiencing some parkinsonism-type movement disorder (RR 0.95, CI 0.61 to 1.49; participants = 106; studies = 3; very low-quality evidence). No clear difference in numbers of participants leaving the study early for any reason was observed (RR 0.50, 95% CI 0.10 to 2.56; participants = 256; studies = 4; very low-quality evidence). No trial reported data for change in negative symptoms or economic costs. AUTHORS' CONCLUSIONS: The results of this review show chlorpromazine and piperacetazine may have similar clinical efficacy, but data are based on very small numbers of participants and the evidence is very low quality. We can not make firm conclusions based on such data. Currently, should clinicians and people with schizophrenia need to choose between chlorpromazine and piperacetazine they should be aware there is no good quality evidence to base decisions. More high quality research is needed.

Molecular binding of toxic phenothiazinium derivatives, azures to bovine serum albumin: A comparative spectroscopic, calorimetric, and in silico study.

In this paper, the comparative binding behavior of antimalarial drug azure A, azure B and azure C with bovine serum albumin (BSA) has been studied. The interaction has been confirmed by multispectroscopic (UV, fluorescence, Fourier transform infrared (FT-IR), and circular dichroism) and molecular docking techniques. The experimental results show that azure B has the highest BSA binding affinity followed by azure A and azure C. The experimental evidence of binding showed a static quenching mechanism in the interaction azures with BSA. The isothermal titration calorimetry result reveals that the binding was exothermic with positive entropy contribution in each case. The thermodynamic parameters ΔH, ΔG, and ΔS at 25°C were calculated, which indicates that the weak van der Waals forces and hydrogen bonding rather than the hydrophobic effect played an important role in the interaction. According to the theory of Förster nonradiative energy transfer, the distance (r) between the donor (BSA) and acceptor azures found to be <7 nm in all the case. The circular dichroism and FT-IR studies show that the content of α-helix structure has increased for the azures-BSA system. Overall, experimental studies characterize the interaction dynamics and energetics of the binding of three toxic analogs towards the physiologically relevant serum albumins. We hope, the outcome of this work will be most helpful for synthesizing a new type of phenothiazinium derivatives of the better therapeutic application.

Antimicrobial photodynamic therapy minimizes the deleterious effect of nicotine in female rats with induced periodontitis.

The aim of this study was to compare the use of antimicrobial photodynamic therapy (aPDT) as an adjunct to scaling and root planing (SRP) in the treatment of experimentally induced periodontitis in female rats that were systemically treated with or without nicotine. Female rats (n = 180) were divided into two groups: vehicle administration (Veh) and nicotine administration (Nic). Mini-pumps containing either vehicle or nicotine were implanted in the rats 30 days before the induction of experimental periodontitis (EP). EP was induced by placing a cotton ligature around the left mandibular first molar. After 7 days, the ligature was removed, and the rats were randomly divided into three treatment subgroups: SRP (only SRP), DL (SRP plus diode laser), and aPDT (SRP plus aPDT). The aPDT consisted of phenothiazine photosensitizer deposition followed by diode laser irradiation. Ten rats from each subgroup were euthanized at 7, 15, and 30 days after treatment. Alveolar bone loss (ABL) in the furcation region was evaluated using histological, histometric, and immunohistochemical analyses. The rats that were treated with nicotine showed more ABL compared to those treated with vehicle. In both the Veh and Nic groups, SRP plus aPDT treatment resulted in reduced ABL, smaller numbers of both TRAP- and RANKL-positive cells, and higher numbers of PCNA-positive cells compared to SRP treatment alone. aPDT was an effective adjunctive therapy for the treatment of periodontitis in female rats regardless of whether they received nicotine.

[ETACISIN-INDUCED BRUGADA SYNDROME IN A PATIENT WITH LONG-STANDING SUPRAVENTRICULAR EXTRASYSTOLE].

Brugada syndrome is a commonest cause of malignant disorders of cardiac rhythm associated with sudden death. It is diagnosed based on characteristic ECG signs and ventricular arrhythmia. This paper reports a 49 year-old patient with long-standing latent BS manifest as supraventricular and transient blockade of the right branch of the His bundle. The ECG pattern of BS became apparent in association with a 7 day treatment with class IC antiarrhythmic agent etacisin. Diagnostic difficulties account for the fact that the disease was initially described as myocardial infarction. Diagnosis of BS was confirmed by an electrophysiological study in which stable ventricular tachycardia and fibrillation were induced by etacisin. A cardioverter defibrillator was implanted to the patient.

Potential antimicrobial agents for the treatment of multidrug-resistant tuberculosis.

Treatment of multidrug-resistant (MDR) tuberculosis (TB) is challenging because of the high toxicity of second-line drugs and the longer treatment duration than for drug-susceptible TB patients. In order to speed up novel treatment for MDR-TB, we suggest considering expanding the indications of already available drugs. Six drugs with antimicrobial activity (phenothiazine, metronidazole, doxycycline, disulfiram, tigecycline and co-trimoxazole) are not listed in the World Health Organization guidelines on MDR-TB treatment but could be potential candidates for evaluation against Mycobacterium tuberculosis. A systematic review was conducted to evaluate antituberculous activity of these drugs against M. tuberculosis. We searched PubMed, Google Scholar and Embase for English articles published up to December 31, 2012. We reviewed in vitro, in vivo and clinical antituberculous activity of these drugs in addition to pharmacokinetics and side-effects. Of the drugs effective against actively replicating M. tuberculosis, co-trimoxazole seems to be the most promising, because of its consistent pharmacokinetic profile, easy penetration into tissue and safety profile. For the dormant state of TB, thioridazine may play a potential role as an adjuvant for treatment of MDR-TB. A strategy consisting of pharmacokinetic/pharmacodynamic studies, dose finding and phase III studies is needed to explore the role of these drugs in MDR-TB treatment.

Pharmacological inhibition of MALT1 protease activity protects mice in a mouse model of multiple sclerosis.

BACKGROUND: The paracaspase mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is crucial for lymphocyte activation through signaling to the transcription factor NF-κB. Besides functioning as a scaffold signaling protein, MALT1 also acts as a cysteine protease that specifically cleaves a number of substrates and contributes to specific T cell receptor-induced gene expression. Recently, small molecule inhibitors of MALT1 proteolytic activity were identified and shown to have promising anticancer properties in subtypes of B cell lymphoma. However, information on the therapeutic potential of small compound inhibitors that target MALT1 protease activity in autoimmunity is still lacking. METHODS: The present study aimed to elucidate whether MALT1 protease inhibitors are also useful in the treatment of lymphocyte-mediated autoimmune pathologies such as multiple sclerosis (MS). For this, we studied the therapeutic potential of a recently identified inhibitor of MALT1 protease activity, the phenothiazine derivative mepazine, in the context of experimental autoimmune encephalomyelitis (EAE), the main animal model for MS. RESULTS: We demonstrate that administration of mepazine prophylactically or after disease onset, can attenuate EAE. Importantly, while complete absence of MALT1 affects the differentiation of regulatory T (Treg) cells in vivo, the MALT1 protease inhibitor mepazine did not affect Treg development. CONCLUSIONS: Altogether, these data indicate that small molecule inhibitors of MALT1 not only hold great promise for the treatment of B cell lymphomas but also for autoimmune disorders such as MS.

Pericyazine for schizophrenia.

BACKGROUND: Pericyazine is a 3-cyano-10 (3-4'-hydroxypiperidinopropyl) phenothiazine. It is overall pharmacologically similar with chlorpromazine, though particularly sedating. Dopamine receptor subtype analysis has not been performed for pericyazine, but the drug appears to induce greater noradrenergic than dopaminergic blockade. Compared to chlorpromazine, pericyazine reportedly has more potent antiemetic, antiserotonin, and anticholinergic activity. OBJECTIVES: To evaluate the clinical effects and safety of pericyazine in comparison with placebo, typical and atypical antipsychotic agents and standard care for people with schizophrenia. SEARCH METHODS: We searched the Cochrane Schizophrenia Group Trials Register (February 2013) which is based on regular searches of CINAHL, EMBASE, MEDLINE and PsycINFO. We inspected references of all identified studies for further trials. SELECTION CRITERIA: All relevant randomised controlled trials focusing on pericyazine for schizophrenia and other types of schizophrenia-like psychoses (schizophreniform and schizoaffective disorders). We excluded quasi-randomised trials. DATA COLLECTION AND ANALYSIS: Data were extracted independently from included papers by at least two review authors. Risk ratios (RR) and 95% confidence intervals (CI) of homogeneous dichotomous data were calculated. We assessed risk of bias for included studies and used GRADE to judge quality of evidence. MAIN RESULTS: We could only include five studies conducted between 1965 and 1980. Most of the included studies did not report details of randomisation, allocation concealment, details of blinding and we could not assess the impact of attrition due to poor reporting.For the primary outcome of Global state - not improved, the confidence interval was compatible with a small benefit and increased risk of not improving with pericyazine compared with typical antipsychotics (2 RCTs, n = 122, RR 1.24 CI 0.93 to 1.66, very low quality of evidence) or atypical antipsychotics (1 RCT, n = 93, RR 0.97 CI 0.67 to 1.42, very low quality of evidence).When compared with typical antipsychotics relapse was only experienced by one person taking pericyazine (1 RCT, n = 80, RR 2.59 CI 0.11 to 61.75, very low quality of evidence).Pericyazine was associated with more extrapyramidal side effects than typical antipsychotics (3 RCTs, n = 163, RR 0.52 CI 0.34 to 0.80, very low quality of evidence) and atypical antipsychotics (1 RCT, n = 93, RR 2.69 CI 1.35 to 5.36, very low quality of evidence).The estimated risk of leaving the study early for specific reasons was imprecise for the comparisons of pericyazine with typical antipsychotics (2 RCTs, n = 71, RR 0.46 CI 0.11 to 1.90, very low quality of evidence), and with atypical antipsychotics (1 RCT, n = 93, RR 0.13 CI 0.01 to 2.42, very low quality of evidence). AUTHORS' CONCLUSIONS: On the basis of very low quality evidence we are unable to determine the effects of pericyazine in comparison with typical or atypical antipsychotics for the treatment of schizophrenia. However, there is some evidence that pericyazine may be associated with a higher incidence of extrapyramidal side effects than other antipsychotics, and again this was judged to be very low quality evidence. Large, robust studies are still needed before any firm conclusions can be drawn.

Targeting autophagy by antipsychotic phenothiazines: potential drug repurposing for cancer therapy.

Cancer is recognized as the major cause of death worldwide and the most challenging public health issues. Tumor cells exhibit molecular adaptations and metabolic reprograming to sustain their high proliferative rate and autophagy plays a pivotal role to supply the high demand for metabolic substrates and for recycling cellular components, which has attracted the attention of the researchers. The modulation of the autophagic process sensitizes tumor cells to chemotherapy-induced cell death and reverts drug resistance. In this regard, many in vitro and in vivo studies having shown the anticancer activity of phenothiazine (PTZ) derivatives due to their potent cytotoxicity in tumor cells. Interestingly, PTZ have been used as antiemetics in antitumor chemotherapy-induced vomiting, maybe exerting a combined antitumor effect. Among the mechanisms of cytotoxicity, the modulation of autophagy by these drugs has been highlighted. Therefore, the use of PTZ derivatives can be considered as a repurposing strategy in antitumor chemotherapy. Here, we provided an overview of the effects of antipsychotic PTZ on autophagy in tumor cells, evidencing the molecular targets and discussing the underlying mechanisms. The modulation of autophagy by PTZ in tumor cells have been consistently related to their cytotoxic action. These effects depend on the derivative, their concentration, and also the type of cancer. Most data have shown the impairment of autophagic flux by PTZ, probably due to the blockade of lysosome-autophagosome fusion, but some studies have also suggested the induction of autophagy. These data highlight the therapeutic potential of targeting autophagy by PTZ in cancer chemotherapy.

Discovery of Novel Azaphenothiazine Derivatives to Suppress Endometrial Cancer by Targeting GRP75 to Impair Its Interaction with IP3R and Mitochondrial Ca2+ Homeostasis.

Endometrial cancer (EC) is the most common cancer of the female reproductive tract, and there is an urgent need to develop new candidate drugs with good efficacy and safety to improve the survival rate and life quality of EC patients. Herein, a series of new azaphenothiazine derivatives were designed and synthesized and their anti-EC activities were evaluated. Among them, compound 33 showed excellent antiproliferative activities against both progesterone-sensitive ISK cells and progesterone-resistant KLE cells. Moreover, 33 could significantly inhibit colony formation and migration of EC cells and induce cell apoptosis. Remarkably, 33 significantly suppressed KLE xenograft tumor growth without influencing body weights or key organs. In addition, 33 exhibited good pharmacokinetic properties and low extrapyramidal side effects. Mechanism research indicated that 33 reduced Ca2+ levels in mitochondria by targeting GRP75 and disrupting its interaction with IP3R. Overall, 33 showed promising potential as an anti-EC candidate agent.