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Objective: Cervical epidural steroid injections (ESIs) can provide effective pain management for patients suffering from chronic neck pain due to various pathological changes of the cervical spine. There are several rare adverse effects reported from interventional pain procedures, including persistent hiccups ("singultus"). Based on a limited number of cases, we propose a modified treatment algorithm for this adverse outcome (Fig. 3). Case report: Singultus has been documented as an adverse effect of interventional pain procedures, including epidural steroid, facet joint, and sacroiliac joint injections. We describe the case of a general contractor who presented to our clinic with chronic neck pain and central canal stenosis. The patient received an uncomplicated lumbar ESI in the past and was recommended for a cervical interlaminar ESI. After an uneventful C6-C7 interlaminar ESI with dexamethasone, 1% lidocaine, and normal saline the patient developed singultus. Baclofen was sent to his pharmacy, but this was unsuccessful at alleviating his hiccups. The patient was subsequently started on chlorpromazine and found relief from his symptomatology. Conclusion: Persistent hiccups after ESI or interventional pain procedures can be treated with conservative measures and non-pharmacologic methods, with escalation to therapy with baclofen, gabapentin, pregabalin, metoclopramide, chlorpromazine, other antipsychotic or antidopaminergic agents, and possible dual or triple therapy if further indicated. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusion Women may experience unique mental disorders due to hormone shifts. Rates of schizophrenia and bipolar disorder are similar between genders, but onset and symptoms may differ. Women tend to use more psychotropic drugs due to limited therapeutic options. This study was aimed to estimate the prevalence of psychotropic polypharmacy among females of childbearing potential and factors impacting prescribing patterns.This was a quantitative retrospective chart review for patients admitted to inpatient units at the Mental Health Hospital in Qatar. SPSS® Statistics was used for data analysis. In addition to descriptive statistics applied, linear regression and binary logistic regression models were used to examine the clinical and sociodemographic factors associated with polypharmacy and full therapeutic response upon discharge, respectively. An alpha value of 0.05 was used.Of the 347 patients, 52.7% of the patients received a prescription of at least two psychotropic drugs upon discharge. Around two‐thirds (63.1%) were prescribed at least one antipsychotic. Potential predictors of polypharmacy were age (p = 0.027), longer hospital stay (p = 0.003), family history (p < 0.001), absence of suicidal history (p = 0.005), and a diagnosis of a mood disorder (p = 0.009), or a diagnosis of a psychotic disorder (p = 0.015). A full response upon discharge was less likely to occur in patients with a longer stay (OR = 0.940; p = 0.029) and in those with a substance use disorder (OR = 0.166; p = 0.035).There is a notably high prevalence of total polypharmacy upon discharge. Some identified factors are modifiable. Evidence‐based prescription practices through hospital guidelines and education should be emphasized to avoid unreasonable polypharmacy. [ABSTRACT FROM AUTHOR]

Introduction: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is gaining attention in pharmacovigilance, but its association with antipsychotics, other than clozapine, is still unclear. Methods: We conducted a case/non-case study with disproportionality analysis based on the World Health Organization (WHO) global spontaneous reporting database, VigiBase®. We analyzed individual case safety reports of DRESS syndrome related to antipsychotics compared to (1) all other medications in VigiBase®, (2) carbamazepine (a known positive control), and (3) within classes (typical/atypical) of antipsychotics. We calculated reporting odds ratio (ROR) and Bayesian information component (IC), with 95% confidence intervals (CIs). Disproportionate reporting was prioritized based on clinical importance, according to predefined criteria. Additionally, we compared characteristics of patients reporting with serious/non-serious reactions. Results: A total of 1534 reports describing DRESS syndrome for 19 antipsychotics were identified. The ROR for antipsychotics as a class as compared to all other medications was 1.0 (95% CI 0.9–1.1). We found disproportionate reporting for clozapine (ROR 2.3, 95% CI 2.1–2.5; IC 1.2, 95% CI 1.1–1.3), cyamemazine (ROR 2.3, 95% CI 1.5–3.5; IC 1.2, 95% CI 0.5–1.7), and chlorpromazine (ROR 1.5, 95% CI 1.1–2.1; IC 0.6, 95% CI 0.1–1.0). We found 35.7% of cases with co-reported anticonvulsants, and 25% with multiple concurrent antipsychotics in serious compared to 8.6% in non-serious cases (p = 0.03). Fatal cases were 164 (10.7%). Conclusions: Apart from the expected association with clozapine, chlorpromazine and cyamemazine (sharing an aromatic heteropolycyclic molecular structure) emerged with a higher-than-expected reporting of DRESS. Better knowledge of the antipsychotic-related DRESS syndrome should increase clinicians' awareness leading to safer prescribing of antipsychotics. [ABSTRACT FROM AUTHOR]

Near-infrared spectroscopy (NIRS) is a noninvasive functional neuroimaging modality that can detect changes in blood oxygenation levels by tracking cortical neural activity. We recorded the resting-state brain activity of 24 individuals with schizophrenia and 90 healthy controls for 8 min using a whole-head NIRS arrangement and then used partial correlation analysis to estimate the resting-state functional connectivity (RSFC) between 17 cortical regions. We found that the RSFC between the bilateral orbitofrontal cortices (OFCs) and between the right temporal and parietal lobes was significantly higher in patients with schizophrenia than in healthy controls. The RSFC between the bilateral OFCs was positively correlated with negative symptom severity, whereas the RSFC between the right temporal and parietal lobes was positively correlated with the chlorpromazine equivalent for antipsychotics prescribed to patients with schizophrenia. This finding was consistent with that for the RSFC calculated using the anterior 52-channel signals. Our results suggest that NIRS-based RSFC measurements have potential clinical applications. [ABSTRACT FROM AUTHOR]

Goats respond to pain and often require chemical restraints for veterinary procedures. Information regarding the cardiopulmonary, haematological and biochemical effects of chlorpromazine (CPZ) or chlorpromazine-pentazocine (CPZ-PTZ) in West African Dwarf (WAD) goats has not been fully established. The study aimed to evaluate the cardiopulmonary, haematological and biochemical responses of WAD goats following sedation with either CPZ alone or a combination of CPZ-PTZ. Six healthy adult WAD bucks were randomly selected for two separate experiments using CPZ or CPZ-PTZ in a prospective crossover trial. Anaesthetic indices were taken. Blood samples were collected before the experiment (0 minutes), 45 minutes, 90 minutes and 24 hours for haematology and serum biochemistry assay. Heart rate (HR), respiratory rate (RR) and rectal temperature (°C) were measured at intervals of 10 minutes for 90 minutes. In between clinical trials, the bucks were given a 14-day break. The duration of recumbency for CPZ (43.00 ± 12.95 minutes) was significantly lower compared to the CPZ-PTZ protocol (46.50 ± 27.32 minutes). Analgesia was recorded in only the CPZ-PTZ group for 41.67 ± 1.75 minutes. The HR was significantly higher (p<0.05) in the CPZ-PTZ group than in the CPZ group from 0 to 70 minutes. The CPZ-PTZ protocol was a better one as it did not exert a negative effect on the red blood cells or serum protein compared with CPZ alone in the goats. Haematological, biochemical and cardiopulmonary changes were also evident in the goats. Further research may determine the risk-benefit profile of this anaesthetic regimen. [ABSTRACT FROM AUTHOR]

Background: In the fight against GBM, drug repurposing emerges as a viable and time-saving approach to explore new treatment options. Chlorpromazine, an old antipsychotic medication, has recently arisen as a promising candidate for repositioning in GBM therapy in addition to temozolomide, the first-line standard of care. We previously demonstrated the antitumor efficacy of chlorpromazine and its synergistic effects with temozolomide in suppressing GBM cell malignant features in vitro. This prompted us to accomplish a Phase II clinical trial to evaluate the efficacy and safety of adding chlorpromazine to temozolomide in GBM patients with unmethylated MGMT gene promoter. In this in vitro study, we investigate the potential role of chlorpromazine in overcoming temozolomide resistance. Methods: In our experimental set, we analyzed Connexin-43 expression at both the transcriptional and protein levels in control- and chlorpromazine-treated GBM cells. DNA damage and subsequent repair were assessed by immunofluorescence of γ-H2AX and Reverse-Phase Protein microArrays in chlorpromazine treated GBM cell lines. To elucidate the relationship between DNA repair systems and chemoresistance, we analyzed a signature of DNA repair genes in GBM cells after treatment with chlorpromazine, temozolomide and Connexin-43 downregulation. Results: Chlorpromazine treatment significantly downregulated connexin-43 expression in GBM cells, consequently compromising connexin-dependent cellular resilience, and ultimately contributing to cell death. In line with this, we observed concordant post-translational modifications of molecular determinants involved in DNA damage and repair pathways. Our evaluation of DNA repair genes revealed that temozolomide elicited an increase, while chlorpromazine, as well as connexin-43 silencing, a decrease in DNA repair gene expression in GBM cells. Conclusions: Chlorpromazine potentiates the cytotoxic effects of the alkylating agent temozolomide through a mechanism involving downregulation of Cx43 expression and disruption of the cell cycle arrest essential for DNA repair processes. This finding suggests that chlorpromazine may be a potential therapeutic strategy to overcome TMZ resistance in GBM cells by inhibiting their DNA repair mechanisms. [ABSTRACT FROM AUTHOR]

A nanosodalite (SOD) was synthesized utilizing Cameroonian kaolin and then used to prepare a nanocomposite (SOD‐GF) with graphene foam (GF). The as‐synthesized materials were characterized using X‐ray diffractometry (XRD), Fourier transform‐infrared (FT‐IR) spectroscopy, N2 adsorption‐desorption and scanning electron microscopy coupled with emission dispersive X‐ray (SEM/EDX). The results show a pure sodalite with high degree of crystallinity with crystallite size and BET surface area of 38.3 nm and 22 m2/g, respectively. The composite's characterization revealed a well‐integrated material in which the structural integrity of each material is maintained, its surface area being 4‐fold that of pristine SOD. Stable SOD and SOD‐GF modified glassy carbon electrode (GCE) were prepared by drop coating without a binder and utilized to study the electrochemistry of chlorpromazine (CPZ) in acidic, neutral and basic pHs. It appeared that (i) CPZ's electrochemical oxidation was a two‐step one‐electron process at SOD/GCE and a one‐step two‐electron process at SOD‐GF/GCE and (ii) the electrochemical reaction mechanism was an EEC mechanism at SOD/GCE while at SOD‐GF/GCE the mechanism was EEC at pH<4 and EC for greater pH. SOD/GCE and SOD‐GF/GCE were used to sense CPZ within CPZ's concentration ranging from 0.5‐30 μM with low detection limits. [ABSTRACT FROM AUTHOR]

The article reviews examples where additional focus or training is needed to optimize pharmacological treatments of schizophrenia. These include the use of hierarchical approach to treatment planning, making the therapeutic relationship with patients a priority, and embracing expertise in pharmacological management.

The tractable preparation of Phase I drug metabolites is a critical step to understand the firstpass behaviour of novel chemical entities (NCEs) in drug discovery. In this study, we have developed a structure–electroactivity relationship (SeAR)-informed electrochemical reaction of the parent 2-chlorophenothiazine and the antipsychotic medication, chlorpromazine. With the ability to dial-in under current controlled conditions, the formation of S-oxide and novel S,S-dioxide metabolites has been achieved for the first time on a multi-milligram scale using a direct batch electrode platform. A potential rationale for the electrochemical formation of these metabolites in situ is proposed using molecular docking to a cytochrome P450 enzyme. [ABSTRACT FROM AUTHOR]

Key Points: Question: Does the increase in risk of transition to psychosis associated with baseline antipsychotic dose in individuals at clinical high risk of psychosis (CHR-P) follow a dose-effect pattern? Findings: In this systematic review and meta-analysis of 290 individuals at CHR-P from 8 studies, those who were exposed to higher antipsychotic doses at baseline had an increased likelihood of transitioning to psychosis compared to those exposed to lower doses. Meaning: The findings suggest that evaluating baseline antipsychotic dosage could enhance current CHR-P criteria-based risk stratification and improve the precision of outcome prediction models, leading to a more personalized approach to treatment management. This systematic review and meta-analysis evaluates the association of baseline antipsychotic dose and transition to psychosis among individuals at high risk for psychosis. Importance: Emerging meta-analytical evidence indicates that baseline exposure to antipsychotics is associated with an increased risk of transitioning to psychosis in individuals at clinical high-risk for psychosis (CHR-P) and that such effect is not a result of pretest risk enrichment. However, to maximize its translational utility for prognostic stratification in clinical practice, testing for the potential presence of a dose-response association is crucial. Objective: To test whether the negative prognostic effect of baseline antipsychotic exposure in individuals at CHR-P follows a dose-effect pattern, as indicated by mean chlorpromazine equivalent doses (CPZ-ED). Data Sources: MEDLINE and Cochrane Library, performed up to August 31, 2023, searching for English-language studies on individuals at CHR-P reporting data on exposure to antipsychotics at baseline and detailed information on dosage by transition status. Study Selection: Studies that provided information on antipsychotic exposure at baseline and included detailed dosage data categorized by transition status. Data Extraction and Synthesis: Eligible studies were identified following PRISMA guidelines and evaluated independently by 2 reviewers with the Newcastle-Ottawa Scale for assessing the quality of nonrandomized studies in meta-analyses. Main Outcomes and Measures: The primary outcome was transition to psychosis in individuals at CHR-P who were receiving antipsychotic treatment at baseline, measured by baseline mean CPZ-ED in individuals at CHR-P who transitioned to psychosis compared to those who did not. Results: Eight studies were included in the systematic review and meta-analysis. Among 290 individuals at CHR-P (mean [SD] age, 19.4 [2.6] years) who were exposed to antipsychotics at baseline and remained in contact up to the completion of the study, 66 converted to psychosis and 224 did not. The mean CPZ-ED ranged 60 to 395 mg/d in those who converted and 13 to 224 mg/d in those who did not. Those who converted to psychosis had higher CPZ-ED than those who did not in both the common-effects model (Hedges g, 0.41; 95% CI, 0.12-0.70; z, 2.78; P =.005) and in the random-effects model (Hedges g, 0.41; 95% CI, 0.15-0.67; z, 3.69; P =.008; τ2, 0.0). There was no relevant heterogeneity (Cochran Q, 3.99; df, 7; P =.78; I2, 0.0%; 95% CI, 0.0-68.0). The radial plot indicated a good fit of the model. Conclusions and Relevance: In individuals at CHR-P who were exposed to antipsychotics at baseline, those receiving higher antipsychotic doses demonstrated an increased likelihood of transitioning to psychosis. This meta-analytic evidence of putative dose-effect association confirms that baseline antipsychotic exposure and the corresponding dosage carry salient prognostic information that could improve current CHR-P criteria-based risk stratification at inception. [ABSTRACT FROM AUTHOR]

Background and Hypothesis The brain-predicted age difference (brain-PAD) may serve as a biomarker for neurodegeneration. We investigated the brain-PAD in patients with schizophrenia (SCZ), first-episode schizophrenia spectrum disorders (FE-SSDs), and treatment-resistant schizophrenia (TRS) using structural magnetic resonance imaging (sMRI). Study Design We employed a convolutional network-based regression (SFCNR), and compared its performance with models based on three machine learning (ML) algorithms. We pretrained the SFCNR with sMRI data of 7590 healthy controls (HCs) selected from the UK Biobank. The parameters of the pretrained model were transferred to the next training phase with a new set of HCs (n  = 541). The brain-PAD was analyzed in independent HCs (n  = 209) and patients (n  = 233). Correlations between the brain-PAD and clinical measures were investigated. Study Results The SFCNR model outperformed three commonly used ML models. Advanced brain aging was observed in patients with SCZ, FE-SSDs, and TRS compared to HCs. A significant difference in brain-PAD was observed between FE-SSDs and TRS with ridge regression but not with the SFCNR model. Chlorpromazine equivalent dose and cognitive function were correlated with the brain-PAD in SCZ and FE-SSDs. Conclusions Our findings indicate that there is advanced brain aging in patients with SCZ and higher brain-PAD in SCZ can be used as a surrogate marker for cognitive dysfunction. These findings warrant further investigations on the causes of advanced brain age in SCZ. In addition, possible psychosocial and pharmacological interventions targeting brain health should be considered in early-stage SCZ patients with advanced brain age. [ABSTRACT FROM AUTHOR]

Introduction There is no consensus on the optimal antipsychotic for acute agitation. Whereas haloperidol is frequently used and has proven efficacy, second generation antipsychotics show similar efficacy and improved safety and tolerability. This study aimed to determine the effectiveness of short-acting intramuscular (IM) haloperidol versus other IM antipsychotics for acute agitation in adults admitted to an inpatient psychiatry unit. Methods This was a retrospective medical record review of patients who received 1 or more doses of a short-acting IM antipsychotic, including chlorpromazine, haloperidol, olanzapine, or ziprasidone. The primary endpoint was the need for subsequent IM antipsychotic(s) or physical restraint within 2 hours of the initial IM antipsychotic. Secondary endpoints assessed outcomes at 24 hours and adverse events. Results One hundred six patients were included. Four patients in the haloperidol group and 0 patients in the other antipsychotic group received an additional IM antipsychotic or required physical restraints within 2 hours (5.3% versus 0%, p = .319). More patients in the other antipsychotic group required an additional dose of IM antipsychotic within 24 hours compared with the haloperidol group (p = .0096). More adverse events were seen in patients who received haloperidol. Discussion Haloperidol was used more frequently than other short-acting IM antipsychotics. Whereas the effectiveness at 2 hours was not significantly different between groups, patients who received haloperidol were more likely to experience adverse events and were more often subjected to polypharmacy with benzodiazepines and/or diphenhydramine. This study further supports the use of olanzapine and ziprasidone for acute agitation in patients hospitalized in inpatient psychiatry.

Abstract Background In the fight against GBM, drug repurposing emerges as a viable and time-saving approach to explore new treatment options. Chlorpromazine, an old antipsychotic medication, has recently arisen as a promising candidate for repositioning in GBM therapy in addition to temozolomide, the first-line standard of care. We previously demonstrated the antitumor efficacy of chlorpromazine and its synergistic effects with temozolomide in suppressing GBM cell malignant features in vitro. This prompted us to accomplish a Phase II clinical trial to evaluate the efficacy and safety of adding chlorpromazine to temozolomide in GBM patients with unmethylated MGMT gene promoter. In this in vitro study, we investigate the potential role of chlorpromazine in overcoming temozolomide resistance. Methods In our experimental set, we analyzed Connexin-43 expression at both the transcriptional and protein levels in control- and chlorpromazine-treated GBM cells. DNA damage and subsequent repair were assessed by immunofluorescence of γ-H2AX and Reverse-Phase Protein microArrays in chlorpromazine treated GBM cell lines. To elucidate the relationship between DNA repair systems and chemoresistance, we analyzed a signature of DNA repair genes in GBM cells after treatment with chlorpromazine, temozolomide and Connexin-43 downregulation. Results Chlorpromazine treatment significantly downregulated connexin-43 expression in GBM cells, consequently compromising connexin-dependent cellular resilience, and ultimately contributing to cell death. In line with this, we observed concordant post-translational modifications of molecular determinants involved in DNA damage and repair pathways. Our evaluation of DNA repair genes revealed that temozolomide elicited an increase, while chlorpromazine, as well as connexin-43 silencing, a decrease in DNA repair gene expression in GBM cells. Conclusions Chlorpromazine potentiates the cytotoxic effects of the alkylating agent temozolomide through a mechanism involving downregulation of Cx43 expression and disruption of the cell cycle arrest essential for DNA repair processes. This finding suggests that chlorpromazine may be a potential therapeutic strategy to overcome TMZ resistance in GBM cells by inhibiting their DNA repair mechanisms.

Purpose: to study sex differences in self-reported symptoms measured with the Scale of Patient-Reported Impact of Symptoms in Schizophrenia (PRISS), to investigated sex differences in the degree of agreements between self-reported symptoms and clinical symptoms assessed by professionals, and to identify which clinical and sociodemographic variables predicted a greater presence of self-reported symptoms split by sex. Methods: 161 patients (37 females; 124 males), aged between 18 and 65 years, with a diagnosis of schizophrenia assisted in non-acute mental health services at four mental health catchment areas in Andalucia and Catalonia were included. The PRISS scale was administered to asses self-reported symptoms. Results: males reported higher presence of excitement, grandiosity, motor retardation and poor attention) than women. There was less agreement in the presence of psychotic symptoms in men than in women when comparing self-reported symptoms and clinical symptoms assessed by professionals. Finally, in men the predictors variables for the greater presence of self-perceived symptoms were greater psychotic symptomatology and more disability, while in women were greater presence of alogia and higher doses of chlorpromazine. Conclusions: Assessing and being aware of the self-perceived symptoms of patients with schizophrenia should be considered in the clinic, especially in men, as there appears to be a lack of agreement on certain items. This would allow treatments to be more focused on patients' need by sex, and would make them feel part of the therapeutic process, improving their therapeutic adherence, evolution and quality of life. [ABSTRACT FROM AUTHOR]

This study examined the possibility of using an alcoholic extract of S. costus root as a protective agent against chlorpromazine, which causes male infertility. The study divided white male rats into five groups, each containing six rats, for 30 days. The results revealed that the rats that received doses of chlorpromazine had significant changes in the hormones LH, FSH, and testosterone, in addition to a decrease in sperm motility, distortion of some sperm, and death of others. When injecting the rats with different doses of the alcoholic extract of the S. costus plant (at concentrations of 1.25 mg/kg, 2.4 mg/kg, and 4 mg/kg), in conjunction with doses of chlorpromazine at 2 mg/kg, there was no decrease in the aforementioned attributes. The histological test of the testicles showed significant changes in the histological structure of the testis in the group that received chlorpromazine. Both the amount of Leydig and Sertoli cells were reduced, as well as the average diameter of the seminiferous tubules, as a result of taking the drug. This led to a lower number of sperm-forming cells, the presence of gaps or spaces between the seminiferous tubules, and few or no mature sperm. Compared to the control group, the interstitial tissue was similarly dense, the spacing between the seminiferous tubules was reduced, and spermatogenic cells with mature spermatogonia appeared within the lumen of the tubules. There was a slight increase in the diameter of the seminiferous tubules and the number of Sertoli and Leydig cells compared to the control group. Seminiferous tubules and the average Leydig and Sertoli cell diameters increased significantly in the two groups at doses of 2.4 mg/kg and 4 mg/kg.

Abstract Introduction Hiccups are among the rare complications of COVID-19 infections. There are several published reports of persistent hiccups presenting during the acute COVID-19 period. However, there are very few published reports of persistent hiccups occurring in the post-acute COVID-19 period. Consequently, most clinicians may not be aware of this rare presentation. This case highlights an atypical presentation of persistent hiccups that manifested during the post-acute COVID -19 period that clinicians need to be aware of. The caseadds to the ever increasing body of knowledge about symptoms and signs associated with Severe Acute Respiratory Syndrome Corona Virus type 2 (SARS CoV-2) infection. Case presentation A 27 year old male black Zambian patient presented to the emergency department of our hospital with persistent hiccup, 35 days after the initial acute episode of COVID-19. This was associated with breathlessness. There were no other symptoms. He had no history of pulmonary, gastrointestinal, neurological disease or malignancy. He did not take any alcohol or smoke. He had never used any recreational drugs. He was employed as a monitoring and evaluation officer at one of the main COVID centres in the capital. On examination, the patient was anxious. Blood pressure was 141/82, pulse rate was 95 beats per minute, respiratory rate was 26 breaths per minute, temperature was 36.8C and oxygen saturation was 97% on room air. Systemic examination was normal. Chest X-ray and abdominal ultrasonography were normal. A rapid COVID-19 antigen test, and COVID-19 Polymerase Chain Reaction (PCR) test that were done the following day were negative. All other haematological and biochemical tests, including D-dimer and C-reactive protein (CRP), were also normal. A diagnosis of post-acute COVID-19 associated hiccups was made. The patient responded well to treatment with chlorpromazine 25 mg 8 hourly. The hiccups disappeared completely after the fourth dose of chlorpromazine. Conclusion This is one of the few published cases of COVID-19 associated persistent hiccups, occurring more than a month after the initial presentation. Most of the published cases report hiccups occurring in the acute COVID-19 period. Consequently, hiccups occurring in the post-acute COVID-19 period may not be attributable to COVID-19. This case has highlighted the need to consider post-acute COVID-19 in the differential diagnosis of persistent hiccup.

Chlorpromazine (CPZ) is one of the most effective antipsychotic drugs used for managing psychotic related disorders owing to its dopamine receptor blocking action. However, pharmacological investigations against CPZ’s cytotoxic effect have remained scarce. Hence, this study investigated the preventive and reversal effects of taurine and coenzyme-Q10 (COQ-10), which are compounds with proven natural antioxidant properties, against CPZ-induced hematological impairments in male rats. In the preventive study, rats received oral saline (10 ml/kg), taurine (150 mg/kg/day), COQ-10 (10 mg/kg/day) or in combination for 56 days, alongside CPZ (30 mg/kg, p.o.) between days 29–56. In the reversal protocol, rats had CPZ repeatedly for 56 days before taurine and COQ-10 treatments or their combination from days 29–56. Rats were also given taurine (150 mg/kg/day), and COQ-10 (10 mg/kg/day) alone for 56 days. Serums were extracted and assayed for hematological, with oxidative and inflammatory markers. CPZ induced decreased red/white blood cells, erythropoietin, platelet count, packed cell volume and hemoglobin, neutrophil, and lymphocyte, which were prevented and reversed by taurine and COQ-10, or their combination. Taurine and COQ-10 improved mean corpuscular volume, hemoglobin concentration, with increased erythropoietin levels relative to CPZ groups. CPZ-induced increased malondialdehyde, tumor necrosis factor-alpha and interleukin-6 levels with decreased interleukin-10, glutathione, and superoxide-dismutase were prevented and reversed by taurine and COQ-10 in comparison with CPZ groups. Taurine and COQ-10 alone notably improved the antioxidant/anti-inflammatory status relative to controls. Among other mechanisms, taurine and COQ-10 abated CPZ-induced hematological deficiencies, via decreased serum levels of oxidative stress, and pro-inflammatory cytokines release, with increased antioxidants and anti-inflammation function.

Introduction: Hiccups are among the rare complications of COVID-19 infections. There are several published reports of persistent hiccups presenting during the acute COVID-19 period. However, there are very few published reports of persistent hiccups occurring in the post-acute COVID-19 period. Consequently, most clinicians may not be aware of this rare presentation. This case highlights an atypical presentation of persistent hiccups that manifested during the post-acute COVID -19 period that clinicians need to be aware of. The caseadds to the ever increasing body of knowledge about symptoms and signs associated with Severe Acute Respiratory Syndrome Corona Virus type 2 (SARS CoV-2) infection. Case presentation: A 27 year old male black Zambian patient presented to the emergency department of our hospital with persistent hiccup, 35 days after the initial acute episode of COVID-19. This was associated with breathlessness. There were no other symptoms. He had no history of pulmonary, gastrointestinal, neurological disease or malignancy. He did not take any alcohol or smoke. He had never used any recreational drugs. He was employed as a monitoring and evaluation officer at one of the main COVID centres in the capital. On examination, the patient was anxious. Blood pressure was 141/82, pulse rate was 95 beats per minute, respiratory rate was 26 breaths per minute, temperature was 36.8C and oxygen saturation was 97% on room air. Systemic examination was normal. Chest X-ray and abdominal ultrasonography were normal. A rapid COVID-19 antigen test, and COVID-19 Polymerase Chain Reaction (PCR) test that were done the following day were negative. All other haematological and biochemical tests, including D-dimer and C-reactive protein (CRP), were also normal. A diagnosis of post-acute COVID-19 associated hiccups was made. The patient responded well to treatment with chlorpromazine 25 mg 8 hourly. The hiccups disappeared completely after the fourth dose of chlorpromazine. Conclusion: This is one of the few published cases of COVID-19 associated persistent hiccups, occurring more than a month after the initial presentation. Most of the published cases report hiccups occurring in the acute COVID-19 period. Consequently, hiccups occurring in the post-acute COVID-19 period may not be attributable to COVID-19. This case has highlighted the need to consider post-acute COVID-19 in the differential diagnosis of persistent hiccup. [ABSTRACT FROM AUTHOR]

Understanding the transport mechanism is crucial for developing inhibitors that block allergen absorption and transport and prevent allergic reactions. However, the process of how beta-conglycinin, the primary allergen in soybeans, crosses the intestinal mucosal barrier remains unclear. The present study indicated that the transport of beta-conglycinin hydrolysates by IPEC-J2 monolayers occurred in a time- and quantity-dependent manner. The beta-conglycinin hydrolysates were absorbed into the cytoplasm of IPEC-J2 monolayers, while none were detected in the intercellular spaces. Furthermore, inhibitors such as methyl-beta-cyclodextrin (MβCD) and chlorpromazine (CPZ) significantly suppressed the absorption and transport of beta-conglycinin hydrolysates. Of particular interest, sodium cromoglycate (SCG) exhibited a quantity-dependent nonlinear suppression model on the absorption and transport of beta-conglycinin hydrolysates. In conclusion, beta-conglycinin crossed the IPEC-J2 monolayers through a transcellular pathway, involving both clathrin-mediated and caveolae-dependent endocytosis mechanisms. SCG suppressed the absorption and transport of beta-conglycinin hydrolysates by the IPEC-J2 monolayers by a quantity-dependent nonlinear model via clathrin-mediated and caveolae-dependent endocytosis. These findings provide promising targets for both the prevention and treatment of soybean allergies. [ABSTRACT FROM AUTHOR]

Chlorpromazine, one of the oldest antipsychotic medications, remains widely available and is still taken in overdose. We aimed to investigate the clinical effects of chlorpromazine overdose and determine if there is a relationship between the reported dose ingested and intensive care unit admission or endotracheal intubation. We performed a retrospective analysis of patients admitted to our toxicology tertiary referral hospital with chlorpromazine overdose (reported dose ingested greater than 300 mg) between 1987 and 2023. We extracted demographic information, details of ingestion, clinical effects and complications (Glasgow Coma Scale, hypotension [systolic blood pressure less than 90 mmHg], delirium, dysrhythmias), length of stay, intensive care unit admission, and endotracheal intubation. There were 218 chlorpromazine overdose cases, with presentations decreasing in frequency over the 36 years. The median age at presentation was 32 years (interquartile range: 25–40 years) and 143 (61 per cent) were female. The median reported dose ingested was 1,250 mg (interquartile range; 700–2,500 mg). The majority of presentations (135; 62 per cent) involved reported co-ingestion of other medications, typically benzodiazepines, paracetamol or antipsychotics. There were 76 (35 per cent) chlorpromazine alone ingestions in which there was a slightly higher median reported dose ingested of 1,650 mg (interquartile range: 763–3,000 mg) compared to the reported co-ingestion group, median reported dose ingested of 1,200 mg (interquartile range: 700–2,100 mg). Of all presentations, 36 (27 per cent) had a Glasgow Coma Scale less than 9, 50 (23 per cent) were admitted to the intensive care unit, and 32 (15 per cent) were endotracheally intubated. There was a significant difference in the median reported dose ingested between patients intubated (2,000 mg; interquartile range: 1,388–3,375 mg) and those not intubated (1,200 mg; interquartile range: 644–2,050mg; P < 0.001), and between those admitted to the intensive care unit and not admitted to the intensive care unit (P < 0.0001). The median reported dose ingested in seven chlorpromazine alone presentations who were intubated was 2,500 mg (interquartile range: 2,000–8,000 mg, range: 1,800–20,000 mg). Eighteen (8 per cent) patients developed delirium, eight (4 per cent) had hypotension, three had seizures, and there was one death. Almost one quarter of cases were admitted to the intensive care unit and over half of these were intubated. Whist the decision to admit to an intensive care unit or intubate a patient is based on clinical need, there was a significant association between reported dose ingested and requirement for endotracheal intubation. Both the frequency of presentation and reported dose ingested declined after 2013. The major limitations of the study were a retrospective design and no analytical confirmation of ingestion. We found that the most common effect of chlorpromazine overdose was central nervous system depression and that endotracheal intubation was associated with larger reported doses ingested, particularly in single chlorpromazine ingestions. [ABSTRACT FROM AUTHOR]

Copyright of Anbar Journal of Agricultural Sciences is the property of Republic of Iraq Ministry of Higher Education & Scientific Research (MOHESR) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Indonesian Journal of Veterinary Science / Jurnal Kedokteran Hewan is the property of Universitas Syiah Kuala, Faculty of Veterinary Medicine and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Catatonia is characterized by psychomotor alterations and reduced contact with the environment. Initially linked to schizophrenia, it also occurs in mood disorders or organic conditions. In children, catatonia remains poorly delineated, despite dramatically increasing the risk of premature death. As data on pediatric drug-induced catatonia bears many uncertainties, we aimed to characterize its age-dependent patterns, using real-world data from the WHO safety database (VigiBase®).VigiBase® was queried for all reports of catatonia registered up to December 8th 2022. Reports involving patients <18 years were classified into 3 groups: ≤23 months, 2–11 years, and 12–17 years. Disproportionality analyses relied on the Reporting Odds Ratio (ROR), and the positivity of the lower end of the 95% confidence interval of the Information Component (IC) was required to suspect a signal. Catatonia was evoked in 421 pediatric reports. In infants, vaccines were leading. In children, the main signals involved haloperidol (ROR 104.3; 95% CI 45.6–238.5), ondansetron (ROR 40.5; 95% CI 16.5–99.5), and ciclosporin (ROR 27.4; 95% CI 13.8–54.1). In adolescents, chlorpromazine (ROR 199.1; 95% CI 134.8–294.1), benzatropine (ROR 193; 95% CI 104.1–361.6), and olanzapine (ROR 135.7; 95% CI 104.6–175.9) reached the highest RORs. In infants, catatonia was related to vaccines, it was ascribed to multiple drugs in children, and mainly to psychotropic drugs in adolescents. Less suspected drugs, such as ondansetron, were highlighted. Despite limitations inherent in spontaneous reporting systems, this study supports that a careful anamnesis is warranted to separate catatonia associated with medical conditions from drug-induced catatonia in pediatric patients. [ABSTRACT FROM AUTHOR]

Phenothiazine derivatives are widely studied in various fields such as biology, chemistry, and medicine research because of their pharmaceutical effects. The first compound used successfully in the treatment of psychosis was a phenthiazine derivative, chlorpromazine. Apart from its activity in neurons, chlorpromazine has also been reported to display anticancer and antibacterial properties. In this study, we present the synthesis and research on the activity of A549, MDA, MiaPaCa, PC3, and HCT116 cancer cell lines and of S. aureus, S. epidermidis, E. coli, and P. aeruginosa bacterial strains against a series of new tetracyclic chlorpromazine analogues containing a quinoline scaffold in their structure instead of the benzene ring and various substituents at the thiazine nitrogen. The structure of these novel molecules has been determined by 1H NMR, 13C NMR, and HRMS spectral techniques. The seven most active of the twenty-four new chlorpromazine analogues tested were selected to study the mechanism of cytotoxic action. Their ability to induce apoptosis or necrosis in cancer cells was assessed by flow cytometry analysis. The results obtained confirmed the proapoptotic activity of selected compounds, especially in terms of inducing late apoptosis or necrosis in cancer cell lines A549, MiaPaCa-2, and HCT-116. Furthermore, studies on the induction of cell cycle arrest suggest that the new chlorpromazine analogues exert antiproliferative effects by inducing cell cycle arrest in the S phase and, consequently, apoptosis. [ABSTRACT FROM AUTHOR]

Tumors often overexpress glucose‐regulated proteins, and agents that interfere with the production or activity of these proteins may represent novel cancer treatments. The chlorpromazine derivative JX57 exhibits promising effects against endometrial cancer with minimal extrapyramidal side effects; however, its mechanisms of action are currently unknown. Here, glucose‐regulated protein 75 kD (GRP75) is identified as a direct target of JX57 using activity‐based protein profiling and loss‐of‐function experiments. The findings show that GRP75 is necessary for the biological activity of JX57, as JX57 exhibits moderate anticancer properties in GRP75‐deficient cancer cells, both in vitro and in vivo. High GRP75 expression is correlated with poor differentiation and poor survival in patients with endometrial cancer, whereas the knockdown of GRP75 can significantly suppress tumor growth. Mechanistically, the direct binding of JX57 to GRP75 impairs the structure of the mitochondria‐associated endoplasmic reticulum membrane and disrupts the endoplasmic reticulum–mitochondrial calcium homeostasis, resulting in a mitochondrial energy crisis and AMP‐activated protein kinase activation. Taken together, these findings highlight GRP75 as a potential prognostic biomarker and direct therapeutic target in endometrial cancer and suggest that the chlorpromazine derivative JX57 can potentially be a new therapeutic option for endometrial cancer. [ABSTRACT FROM AUTHOR]

The rapid fabrication is described of binary electrocatalyst based on a highly porous metal–organic framework with zirconium metal core (Zr-MOF) decorated over the graphitic carbon nitride (g-C3N4) nanosheets via facile ultrasonication method. It is used for the robust determination of antipsychotic drug chlorpromazine (CLP) from environmental samples. The electrochemical behaviour of 2D Zr-MOF@g-C3N4 was characterized by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) studies. The crystalline and porous nature of the composite was characterized by XRD and SEM analysis. The functional groups and surface characteristics were investigated by FT-IR, Raman and XPS. The major electrochemical properties of the Zr-MOF@g-C3N4 composite towards CLP detection were analyzed by CV, chronocoulometric (CC), chronoamperometric (CA) and differential pulse voltammetry (DPV) techniques. The composite exhibits a low detection limit (LOD) of 2.45 nM with a linear range of 0.02 to 2.99 µM and attractive sensitivity for CLP. The sensor system shows higher selectivity towards the possible interferences of CLP drug and exhibits better repeatability and stability. Finally, the fabricated sensor system shows a high recovery range varying from 96.2 to 98.9% towards the real samples. The proposed electrochemical probe might be a promising alternative to the prevailing diagnostic tools for the detection of CLP. [ABSTRACT FROM AUTHOR]

Liver cancer annually accounts for over 800,000 cases and 700,000 deaths worldwide. Hepatocellular carcinoma is responsible for over 80% of liver cancer cases. Due to ineffective treatment options and limited surgical interventions, hepatocellular carcinoma is notoriously difficult to treat. Nonetheless, drugs utilized for other medical conditions, such as the antihypertensive medication prazosin, the neuroleptic medication chlorpromazine, and the neuroleptic medication haloperidol, have gained attention for their potential anti-cancer effects. Therefore, this study used these medications for investigating toxicity to hepatocellular carcinoma while testing the adverse effects on a noncancerous liver cell line model THLE-2. After treatment, an XTT cell viability assay, cell apoptosis assay, reactive oxygen species (ROS) assay, apoptotic proteome profile, and western blot were performed. We calculated IC50 values for chlorpromazine and prazosin to have a molar range of 35–65 µM. Our main findings suggest the capability of both of these treatments to reduce cell viability and generate oxidative stress in HepG2 and THLE-2 cells (p value < 0.05). Haloperidol, however, failed to demonstrate any reduction in cell viability revealing no antitumor effect up to 100 µM. Based on our findings, a mechanism of cell death was not able to be established due to lack of cleaved caspase-3 expression. Capable of bypassing many aspects of the lengthy, costly, and difficult cancer drug approval process, chlorpromazine and prazosin deserve further investigation for use in conjunction with traditional chemotherapeutics. [ABSTRACT FROM AUTHOR]

Abstract A nanosodalite (SOD) was synthesized utilizing Cameroonian kaolin and then used to prepare a nanocomposite (SOD‐GF) with graphene foam (GF). The as‐synthesized materials were characterized using X‐ray diffractometry (XRD), Fourier transform‐infrared (FT‐IR) spectroscopy, N2 adsorption‐desorption and scanning electron microscopy coupled with emission dispersive X‐ray (SEM/EDX). The results show a pure sodalite with high degree of crystallinity with crystallite size and BET surface area of 38.3 nm and 22 m2/g, respectively. The composite's characterization revealed a well‐integrated material in which the structural integrity of each material is maintained, its surface area being 4‐fold that of pristine SOD. Stable SOD and SOD‐GF modified glassy carbon electrode (GCE) were prepared by drop coating without a binder and utilized to study the electrochemistry of chlorpromazine (CPZ) in acidic, neutral and basic pHs. It appeared that (i) CPZ's electrochemical oxidation was a two‐step one‐electron process at SOD/GCE and a one‐step two‐electron process at SOD‐GF/GCE and (ii) the electrochemical reaction mechanism was an EEC mechanism at SOD/GCE while at SOD‐GF/GCE the mechanism was EEC at pH

Abstract Background Drug induced bile duct injury is a frequently observed clinical problem leading to a wide range of pathological features. During the past decades, several agents have been identified with various postulated mechanisms of bile duct damage, however, mostly still poorly understood. Methods Here, we investigated the mechanisms of chlorpromazine (CPZ) induced bile duct injury using advanced in vitro cholangiocyte cultures. Intrahepatic cholangiocyte organoids (ICOs) were driven into mature cholangiocyte like cells (CLCs), which were exposed to CPZ under cholestatic or non-cholestatic conditions through the addition of a bile acid cocktail. Results CPZ caused loss of monolayer integrity by reducing expression levels of tight junction protein 1 (TJP1), E-cadherin 1 (CDH1) and lysyl oxidase homolog 2 (LOXL2). Loss of zonula occuludens-1 (ZO-1) and E-cadherin was confirmed by immunostaining after exposure to CPZ and rhodamine-123 leakage further confirmed disruption of the cholangiocyte barrier function. Furthermore, oxidative stress seemed to play a major role in the early damage response by CPZ. The drug also decreased expression of three main basolateral bile acid transporters, ABCC3 (ATP binding cassette subfamily C member 3), SLC51A/B (solute carrier family 51 subunit alpha/beta) and multidrug resistance transporter ABCB1 (ATP binding cassette subfamily B member 1), thereby contributing to bile acid accumulation. CPZ did not induce an inflammatory response by itself, but addition of TNFα revealed a synergistic effect. Conclusion These results show that ICOs present a model to identify toxic drugs affecting the bile ducts while providing mechanistic insights into hepatotoxicity.

Background: Drug induced bile duct injury is a frequently observed clinical problem leading to a wide range of pathological features. During the past decades, several agents have been identified with various postulated mechanisms of bile duct damage, however, mostly still poorly understood. Methods: Here, we investigated the mechanisms of chlorpromazine (CPZ) induced bile duct injury using advanced in vitro cholangiocyte cultures. Intrahepatic cholangiocyte organoids (ICOs) were driven into mature cholangiocyte like cells (CLCs), which were exposed to CPZ under cholestatic or non-cholestatic conditions through the addition of a bile acid cocktail. Results: CPZ caused loss of monolayer integrity by reducing expression levels of tight junction protein 1 (TJP1), E-cadherin 1 (CDH1) and lysyl oxidase homolog 2 (LOXL2). Loss of zonula occuludens-1 (ZO-1) and E-cadherin was confirmed by immunostaining after exposure to CPZ and rhodamine-123 leakage further confirmed disruption of the cholangiocyte barrier function. Furthermore, oxidative stress seemed to play a major role in the early damage response by CPZ. The drug also decreased expression of three main basolateral bile acid transporters, ABCC3 (ATP binding cassette subfamily C member 3), SLC51A/B (solute carrier family 51 subunit alpha/beta) and multidrug resistance transporter ABCB1 (ATP binding cassette subfamily B member 1), thereby contributing to bile acid accumulation. CPZ did not induce an inflammatory response by itself, but addition of TNFα revealed a synergistic effect. Conclusion: These results show that ICOs present a model to identify toxic drugs affecting the bile ducts while providing mechanistic insights into hepatotoxicity. [ABSTRACT FROM AUTHOR]

Introduction: Loss of proteasome function, proteinopathy, and proteotoxicity may cause neurodegeneration across the human lifespan in several forms of brain injury and disease. Drugs that activate brain proteasomes in vivo could thus have a broad therapeutic impact in neurology. Methods: Using pigs, a clinically relevant large animal with a functionally compartmental gyrencephalic cerebral cortex, we evaluated the localization and biochemical activity of brain proteasomes and tested the ability of small molecules to activate brain proteasomes. Results: By Western blotting, proteasome protein subunit PSMB5 and PSMA3 levels were similar in different pig brain regions. Immunohistochemistry for PSMB5 showed localization in the cytoplasm (diffuse and particulate) and nucleus (cytoplasm < nucleus). Some PSMB5 immunoreactivity was colocalized with mitochondrial (voltage-gated anion channel and cyclophilin D) and cell death (Aven) proteins in the neuronal soma and neuropil in the neocortex of pig and human brains. In the nucleus, PSMB5 immunoreactivity was diffuse, particulate, and clustered, including perinucleolar decorations. By fluorogenic assay, proteasome chymotrypsin-like activities (CTL) in crude tissue soluble fractions were generally similar within eight different pig brain regions. Proteasome CTL activity in the hippocampus was correlated with activity in nasal mucosa biopsies. In pilot analyses of subcellular fractions of pig cerebral cortex, proteasome CTL activity was highest in the cytosol and then ~50% lower in nuclear fractions; ~15-20% of total CTL activity was in pure mitochondrial fractions. With in-gel activity assay, 26S-singly and -doubly capped proteasomes were the dominant forms in the pig cerebral cortex. With a novel in situ histochemical activity assay, MG132-inhibitable proteasome CTL activity was localized to the neuropil, as a mosaic, and to cell bodies, nuclei, and centrosome-like perinuclear satellites. In piglets treated intravenously with pyrazolone derivative and chlorpromazine over 24 h, brain proteasome CTL activity was modestly increased. Discussion: This study shows that the proteasome in the pig brain has relative regional uniformity, prominent nuclear and perinuclear presence with catalytic activity, a mitochondrial association with activity, 26S-single cap dominance, and indications from small molecule systemic administration of pyrazolone derivative and chlorpromazine that brain proteasome function appears safely activable. [ABSTRACT FROM AUTHOR]

Leukocyte elastase is a marker of inflammation. Previously, a relationship was found between the severity of mental disorders in patients and elastase-like activity of blood plasma. The effect of various neurotropic drugs on leukocyte elastase activity was analyzed in an in vitro experiment. We revealed an inhibitory effect of the benzodiazepine tranquilizers diazepam and bromodihydrochlorophenylbenzodiazepine and immunomodulators aminodihydrophthalazinedione and diclofenac on the plasma elastase-like activity of healthy donors and pure human neutrophil elastase. The antipsychotics chlorpromazine and alimemazine, as well as the nootropic vinpocetine increased elastase-like activity in a dose-dependent manner. The activating effect of chlorpromazine and vinpocetine, but not alimemazine, was reproduced in neutrophil elastase. We hypothesized that these drugs can affect the development of inflammatory reactions in the complex therapy of mental disorders. [ABSTRACT FROM AUTHOR]

Tardive Dyskinesia (TD) is a medication induced movement disorder characterised by involuntary athetoid or choreiform movements generally of the tongue, lower face and jaw, and extremities developing in association with the use of a neuroleptic medication for at least a few months that persists despite discontinuation or change of the medications. This study was done to help in the early recognition and management of tardive dyskinesia and to obtain useful data to help prevent the same. The study aimed to estimate the prevalence of tardive dyskinesia in patients with psychiatric illness having more than 3 months cumulative exposure to neuroleptics, and to determine the clinical correlates of tardive dyskinesia in them. Methodology: This cross sectional observational study was carried out after obtaining clearance from the Institution's Ethics Committee (YEC2/658) between January 1st, 2021 and April 2022. A total of 207 participants were enrolled who were patients with psychiatric illness having more than 3 months of cumulative exposure to neuroleptics. Participants were then evaluated using the Schooler Kane criteria, Abnormal Involuntary Movement Scale and various sociodemographic and clinical variables were assessed. Results: Patients with schizophrenia are most at risk of developing tardive dyskinesia (67.1%). It was also discovered that chlorpromazine comparable dosages were significantly higher among participants with tardive dyskinesia. Orofacial tardive dyskinesia had the highest overall prevalence (23.2%). Conclusion: Many patients with psychotic diseases experienced movement difficulties brought on by conventional antipsychotics, which are viewed as burdensome and stigmatizing events. Designing treatment guidelines, expanding the availability of medications with minimum adverse effects, and providing psychoeducation on related aspects are crucial. [ABSTRACT FROM AUTHOR]

Abstract Tumors often overexpress glucose‐regulated proteins, and agents that interfere with the production or activity of these proteins may represent novel cancer treatments. The chlorpromazine derivative JX57 exhibits promising effects against endometrial cancer with minimal extrapyramidal side effects; however, its mechanisms of action are currently unknown. Here, glucose‐regulated protein 75 kD (GRP75) is identified as a direct target of JX57 using activity‐based protein profiling and loss‐of‐function experiments. The findings show that GRP75 is necessary for the biological activity of JX57, as JX57 exhibits moderate anticancer properties in GRP75‐deficient cancer cells, both in vitro and in vivo. High GRP75 expression is correlated with poor differentiation and poor survival in patients with endometrial cancer, whereas the knockdown of GRP75 can significantly suppress tumor growth. Mechanistically, the direct binding of JX57 to GRP75 impairs the structure of the mitochondria‐associated endoplasmic reticulum membrane and disrupts the endoplasmic reticulum–mitochondrial calcium homeostasis, resulting in a mitochondrial energy crisis and AMP‐activated protein kinase activation. Taken together, these findings highlight GRP75 as a potential prognostic biomarker and direct therapeutic target in endometrial cancer and suggest that the chlorpromazine derivative JX57 can potentially be a new therapeutic option for endometrial cancer.

Magnetic dispersive micro solid-phase extraction as a proper and selective sample preparation was developed to extract and clean up three drugs, including Caffeine (CAF), Lidocaine (LID), and Chlorpromazine (CPZ), before determining by HPLC-DAD. Nickel-doped BiFeO3 was synthesised using the sol–gel method as a magnetic sorbent core and coated with tetraethyl orthosilicate (TEOS) to enhance the sorbent stability and the sorbent selectivity. In the extraction procedure, the sorbent was dispersed into acetonitrile as disperser solvent and sodium dodecyl sulphate (SDS) as a disperser agent before injecting into the sample solution to extract the analytes. Several influential factors in the method were evaluated using an experimental design strategy. Under the optimum conditions, the method displayed wide linearity in the concentration ranges of 20.8–365, 1.4–389, and 2.7–355 ng mL−1 to determine CAF, LID, and CPZ with a suitable R2 between 0.9963 and 0.9971, respectively. Intra-day and inter-day relative standard deviations were in the ranges of 3.5–3.8 and 3.9–4.3%. LODs and LOQs for the determination of CAF, LID, and CPZ were lower than 6.3 and 20.8 ng mL−1. The method is convenient for determining the analytes in real water and biological samples with RSD (n = 3) and recovery in the ranges of 3.0–4.3% and 87.5–96.9%, respectively. [ABSTRACT FROM AUTHOR]

Background Efflux pump inhibitors (EPIs) offer an attractive therapeutic option when combined with existing classes. However, their optimal dosing strategies are unknown. Methods MICs of ciprofloxacin (CIP)+/−chlorpromazine, phenylalanine-arginine β naphthylamide (PAβN) and a developmental molecule MBX-4191 were determined and the pharmacodynamics (PD) was studied in an in vitro model employing Escherichia coli MG1655 and its isogenic MarR mutant (I1147). Exposure ranging experiments were performed initially then fractionation. Changes in bacterial load and population profiles were assessed. Strains recovered after EPI simulations were studied by WGS. Results The CIPMICs for E. coli MG1655 and I1147 were 0.08 and 0.03 mg/L. Chlorpromazine at a concentration of 60 mg/L, PAβN concentrations of 30 mg/L and MBX-4191 concentrations of 0.5–1.0 mg/L reduced CIP MICs for I1147 and enhanced bacterial killing. Using CIP at an AUC of 1.2 mg·h/L, chlorpromazine AUC was best related to reduction in bacterial load at 24 h, however, when the time drug concentration was greater than 25 mg/L (T > 25 mg/L) chlorpromazine was also strongly related to the effect. For PaβN with CIP AUC, 0.6 mg·h/L PaβN AUC was best related to a reduction in bacterial load. MBX-4191T > 0.5–0.75 mg·h/L was best related to reduction in bacterial load. Changes in population profiles were not seen in experiments of ciprofloxacin + EPIs. WGS of recovered strains from simulations with all three EPIs showed mutations in gyrA , gyrB or marR. Conclusions AUC was the pharmacodynamic driver for chlorpromazine and PAβN while T > threshold was the driver for MBX-4191 and important in the activity of chlorpromazine and PAβN. Changes in population profiles did not occur with combinations of ciprofloxacin + EPIs, however, mutations in gyrA , gyrB and marR were detected. [ABSTRACT FROM AUTHOR]

Pharmacoencephalography (pharmaco-EEG) is a prominent instrument for the pharmacological screening of new psychoactive molecules. This experimental approach has not remained a vestige of neurobiological studies, and can be used successfully to complete today's research objectives. The development and rise to universal use of machine learning techniques opens up novel prospects for the use of pharmaco-EEG data to solve the problems of classification and prognosis. We have previously shown that naïve Bayes classifier (NBC) combined with principal component analysis (PCA) can be used to differentiate between antipsychotic and sedative drug effects as well as to distinguish among the antipsychotics' effects. In the present study, we evaluated the possibility to employ this method to assess the dose-dependency of antipsychotic effects. The experiments were carried out in white outbred male rats with chronically implanted electrocorticographic electrodes. As the agents of interest, we chose two drugs with antipsychotic activity, chlorpromazine and promethazine, in three doses each (0.1, 1, 10 mg/kg and 0.5, 5 and 20 mg/kg, respectively). The training set, used as a reference to determine the pharmacological effects of the agents of interest, included the D2-dopamine receptor blocker haloperidol, M-cholinergic receptor blocker tropicamide, H1-histamine receptor blocker chloropyramine, the sedative dexmedetomidine, and the anxiolytic phenazepam. We have shown that the lowest chlorpromazine dose (0.1 mg/kg) can be characterized as antipsychotic with a marked histaminolytic effect, while the highest one (10 mg/kg) exhibits predominantly antipsychotic activity with a cataleptogenic effect. All three doses demonstrated anticholinergic activity, which increased with the dose. For promethazine, we observed a clear dose-dependent shift from antipsychotic action to cataleptogenic, alongside a notable antimuscarinic effect of all doses. None of promethazine doses showed any resemblance to chloropyramine, which probably indicates its anti-dopaminergic and antimuscarinic effects being able to mask its H1-antihistamine effect in the used dose range. In summary, our results demonstrate that NBC combined with PCA can be used to determine the dose-dependency of antipsychotic agents' effects based on their impact on electrocorticogram parameters. Further development of this method as well as expansion of psychotropic agent electropharmacogram library would allow for more precise prediction of pharmacological activity of the agents of interest. [ABSTRACT FROM AUTHOR]

Introductions: Alcohol effects are not limited to one's physical state but also mental processes, including psychosis such as hallucinations or paranoia. Psychotic manifestations can also occur in general medical conditions or other neurological disorders associated with alcohol dependence. Cases: A 29-year-old man presented with a major depressive episode with psychotic symptoms. Since junior high school, the patient admitted to having a history of consuming crystal methamphetamine, heroin, and alcoholic drinks and often saw and heard the voices of 2 men. The patient was treated with Chlorpromazine for anxiety and Olanzapine for maintenance. The patient was allowed to go home with Olanzapine and scheduled for follow-up one week later. Discussions: Previous history indicates a possibility of alcohol-induced psychosis. However, specific diagnosis and management for such a condition is not possible due to no alcohol blood level tests available. Conclusions: The risk of psychotic disorders exists in all alcohol users, especially those with a history of psychosis and use of other addictive substances. A detailed history and appropriate investigations are helpful in monitoring the etiology and course of patients with alcohol-related psychosis. [ABSTRACT FROM AUTHOR]

Aim: We investigated our previous finding of increased retention of poly(lactic-co-glycolic) acid nanoparticles (PLGA-NPs) with metabolic inhibitors (MI) and studied the effect of some small molecule inhibitors on PLGA-NP assimilation. Materials & methods: Intracellular PLGA-NP colocalization in the presence of MI was investigated by confocal microscopy. Intracellular retention of PLGA-NPs by some small molecules was estimated by fluorescence microscopy and flow cytometry after Pulse/Chase experiments. Results: MI caused PLGA-NP colocalization in intracellular membranous structures, mainly endosomes and lysosomes. Some small molecule inhibitors demonstrated increased intracellular PLGA-NP accumulation. Conclusion: This study elucidates the movement of PLGA-NP in cells and suggests that clinically used small molecules can reduce their extrusion by enhancing their stay within intracellular vesicles, with possible clinically beneficial consequences. Nanoparticles are increasingly being used to carry drugs for treatment of cancer. We wish to decrease their movement out of the cells. This may give time for them to unload their drugs. Cells were treated with nanoparticles for 30 min and observed. Then the nanoparticles were washed off. Cells were again observed after 30 min. Various intracellular trafficking inhibitors were also added. Nanoparticle retention and subcellular localization were measured. We found that nanoparticles are trapped in some membranous compartments within the cells after energy depletion. We also discovered some commonly used clinical molecules that can decrease the excretion of nanoparticles from the cells. These inhibitors can be utilized for increasing the intracellular stay of the drug-loaded nanoparticles. [ABSTRACT FROM AUTHOR]

IntroductionLoss of proteasome function, proteinopathy, and proteotoxicity may cause neurodegeneration across the human lifespan in several forms of brain injury and disease. Drugs that activate brain proteasomes in vivo could thus have a broad therapeutic impact in neurology.MethodsUsing pigs, a clinically relevant large animal with a functionally compartmental gyrencephalic cerebral cortex, we evaluated the localization and biochemical activity of brain proteasomes and tested the ability of small molecules to activate brain proteasomes.ResultsBy Western blotting, proteasome protein subunit PSMB5 and PSMA3 levels were similar in different pig brain regions. Immunohistochemistry for PSMB5 showed localization in the cytoplasm (diffuse and particulate) and nucleus (cytoplasm

Background: According to COVID-19 mutation and no defined treatment, it is necessary to find effective treatment. Chlorpromazine, a phenothiazine antipsychotic drug, has been shown in animal studies to have antiviral effects by inhibiting clathrin-mediated endocytosis. The aim of this study was to evaluate the effectiveness of adding chlorpromazine to the atazanavir/ritonavir regimen in the treatment of moderate COVID-19 patients. Methods: In this randomized double-blind clinical trial, sixty hospitalized patients with moderate COVID-19 confirmed by CT findings or polymerase chain reaction (PCR) were enrolled. All patients received atazanavir/ritonavir 300mg/100mg once daily. In two parallel groups, chlorpromazine 25 mg three times a day or a placebo was administered for up to 14 days. Complete blood count with differential, C-reactive protein (CRP), liver enzymes, and erythrocyte sedimentation rate was measured on days 1, 3, 5, 7, and 10. The primary outcome was the improvement of oxygen saturation and the secondary outcome was the duration of hospitalization and conversion of PCR test results. Results: Oxygen saturation during the hospitalization was not different among the two groups. The mean duration of hospitalization in the chlorpromazine group was 7.4±2.7 days and in the placebo was 8.2±3 days (P=0.2). Compared to baseline, both groups showed an increase in white blood cell count (P=0.04) and polymorphonuclear cells (P=0.04) but lymphocyte count decreased. At the end of the study, the PCR test was negative in 100% of patients in the chlorpromazine group and 95% of patients in the placebo group. Conclusion: In adult hospitalized patients with moderate symptomatic COVID-19, adding chlorpromazine to the atazanavir/ritonavir regimen did not improve outcomes.