Photopolymerization of Chlorpromazine-Loaded Gelatin Methacryloyl Hydrogels: Characterization and Antimicrobial Applications.

This study investigates the synthesis, characterization, and antimicrobial properties of hydrogels synthesized through the UV-pulsed laser photopolymerization of a polymer-photoinitiator-chlorpromazine mixture. Chlorpromazine was used for its known enhanced antimicrobial properties when exposed to UV laser radiation. The hydrogel was formed from a mixture containing 0.05% Irgacure 2959, 10% gelatin methacryloyl, and various concentrations of chlorpromazine (1, 2, and 4 mg/mL). Laser-induced fluorescence spectroscopy was employed to monitor the photoinduced changes of chlorpromazine and Irgacure 2959 during hydrogel formation, providing insight into the photodegradation dynamics. FTIR spectroscopy confirmed the incorporation of irradiated chlorpromazine within the hydrogel matrix, while the release profiles of chlorpromazine showed sustained release only in hydrogels containing 1 mg/mL of CPZ. The hydrogel showed significant antimicrobial activity against MRSA bacteria when compared to that of penicillin. These findings highlight the potential of CPZ loaded during the photopolymerization process into hydrogels as effective antimicrobial agents with sustained release properties, making them suitable for combating resistant bacterial strains.

Conductive Polypropylene Additive Manufacturing Feedstock: Application to Aqueous Electroanalysis and Unlocking Nonaqueous Electrochemistry and Electrosynthesis.

Additive manufacturing electrochemistry is an ever-expanding field; however, it is limited to aqueous environments due to the conductive filaments currently available. Herein, the production of a conductive poly(propylene) filament, which unlocks the door to organic electrochemistry and electrosynthesis, is reported. A filament with 40 wt % carbon black possessed enhanced thermal stability, excellent low-temperature flexibility, and high conductivity. The filament produced highly reproducible additive manufactured electrodes that were electrochemically characterized, showing a k0 of 2.00 ± 0.04 × 10-3 cm s-1. This material was then applied to three separate electrochemical applications. First, the electroanalytical sensing of colchicine within environmental waters, where a limit of detection of 10 nM was achieved before being applied to tap, bottled, and river water. Second, the electrodes were stable in organic solvents for 100 cyclic voltammograms and 15 days. Finally, these were applied toward an electrosynthetic reaction of chlorpromazine, where the electrodes were stable for 24-h experiments, outperforming a glassy carbon electrode, and were able to be reused while maintaining a good electrochemical performance. This material can revolutionize the field of additive manufacturing electrochemistry and expand research into a variety of new fields.

FOXP3 inhibits proliferation and migration by competitively inhibiting YAP1 in nasopharyngeal carcinoma.

Hippo signalling is involved in the coordination of extracellular signals that control tissue homeostasis and organ size. Yes-associated protein 1 (YAP1) is regulated primarily by Hippo signalling through coactivation of transcription factors with GATA domains called TEADs. However, small-molecule orthosteric inhibitors of YAP1 are difficult to develop due to its tight binding to TEAD4 via a flat interface. Previous studies have shown that chlorpromazine (CPZ) can inhibit YAP1 expression. MTT, colony formation, wound healing, Transwell migration and Western blot assays were performed to explore how CPZ affects nasopharyngeal carcinoma (NPC) cells through FOXP3. In addition, immunofluorescence and live-cell imaging were used to detect YAP1 intracellular localization after CPZ administration. Through the HDOCK website, we predicted protein binding regions between FOXP3 and TEAD4. Western blot and co-IP experiments were used to verify the relationship between FOXP3 and YAP1. The UCSC Xena database, LinkedOmics database and KM plotter website were used to assess the prognostic value of FOXP3 in head and neck squamous cell carcinoma (HNSCC). Age, sex, pathological tumour-node-metastasis (pTMN) stage, grade, smoking status and FOXP3 expression were included in an overall survival nomogram model. Our findings revealed that FOXP3 has the ability to competitively interacts competitively with TEAD4 to inhibit YAP1 expression. By increasing FOXP3 expression, CPZ induces YAP1 nuclear export and phosphorylation, consequently suppressing NPC cell proliferation and migration. Collectively, our findings indicate that FOXP3 competitively binds TEAD4 to regulate YAP1 localization in the nucleus and cytoplasm to suppress NPC progression. Consequently, FOXP3 may be a prognostic indicator for HNSCC.

Lymphatic targeting of cilnidipine by designing and developing a nanostructured lipid carrier drug delivery system.

OBJECTIVE: The objective of current research is to design, develop, and optimize a cilnidipine (CLN) nanostructured lipid carrier (NLC)-based drug delivery system for the effective treatment of hypertension (HT). SIGNIFICANCE: Oral administration of CLN-loaded NLC (CLN NLC) containing glyceryl monostearate (GMS) as a solid and isopropyl myristate (IPM) as a liquid lipid may show remarkable lymphatic uptake through payer patches. METHODS: The emulsification probe sonication technique was used followed by optimization using 32 factorial designs. RESULTS: The optimized batch showed a mean particle size of 115.4 ± 0.22 nm with encapsulation efficiency of 98.32 ± 0.23%, polydispersity index (PDI) of 0.342 ± 0.03, and zeta potential (ZP, ζ) was -60.5 ± 0.24 which indicate excellent physical stability. In vitro studies showed a controlled release of CLN NLCs. Pharmacokinetics studies determined the Cmax of NLCs (373.47 ± 15.1) indicates 2.3-fold enhancement compared with plain drug (160.64 ± 7.63). Pharmacodynamic studies indicated that CLN NLCs were maintaining systolic blood pressure in a controlled manner without any signs of side effects. CONCLUSION: CLN NLCs significantly improved lymphatic delivery and proved to be effective in the treatment and management of HT. It has been proved that CLN NLCs are found to be better than any traditional CLN dosage form due to enhancement in solubility, absorption, bioavailability, intestinal permeability, avoidance of first-pass metabolism, P-glycoprotein efflux and reduction in dose-related side effects, achievement of controlled and sustained release action.

The antipsychotic chlorpromazine reduces neuroinflammation by inhibiting microglial voltage-gated potassium channels.

Neuroinflammation, the result of microglial activation, is associated with the pathogenesis of a wide range of psychiatric and neurological disorders. Recently, chlorpromazine (CPZ), a dopaminergic D2 receptor antagonist and schizophrenia therapy, was proposed to exert antiinflammatory effects in the central nervous system. Here, we report that the expression of Kv1.3 channel, which is abundant in T cells, is upregulated in microglia upon infection, and that CPZ specifically inhibits these channels to reduce neuroinflammation. In the mouse medial prefrontal cortex, we show that CPZ lessens Kv1.3 channel activity and reduces proinflammatory cytokine production. In mice treated with LPS, we found that CPZ was capable of alleviating both neuroinflammation and depression-like behavior. Our findings suggest that CPZ acts as a microglial Kv1.3 channel inhibitor and neuroinflammation modulator, thereby exerting therapeutic effects in neuroinflammatory psychiatric/neurological disorders.

The Adsorption of Chlorpromazine on the Surface of Gold Nanoparticles and Its Effect on the Toxicity to Selected Mammalian Cells.

Chlorpromazine (CPZ) is a first-generation neuroleptic with well-established antitumor and antiviral properties. Currently, numerous studies are focused on developing new methods for CPZ delivery; however, the knowledge regarding its conjugates with metal nanoparticles remains limited. The aim of this study was to prepare CPZ conjugates with gold nanoparticles (AuNPs) and evaluate their biological activity on human lymphocytes (HUT-78 and COLO 720L), as well as human (COLO 679) and murine (B16-F0) melanoma cells, in comparison to the effects induced by unconjugated CPZ molecules and AuNPs with well-defined properties. During the treatment of cells with CPZ, AuNPs, and CPZ-AuNP conjugates, changes in mitochondrial activity, membrane integrity, and the secretion of lipid peroxidation mediators were studied using standard biological assays such as MTT, LDH, and MDA assays. It was found that positively charged CPZ-AuNP conjugates more effectively reduced cell viability compared to AuNPs alone. The dose-dependent membrane damage was correlated with oxidative stress resulting from exposure to CPZ-AuNP conjugates. The activity of the conjugates depended on their composition and the size of the AuNPs. It was concluded that conjugating CPZ to AuNPs reduced its biological activity, while the cellular response to the treatment varied depending on the specific cell type.

Facile, eco-friendly and sensitive fluorimetric approach for detection of chlorpromazine: Application in biological fluids and tablet formulations as well as greenness evaluation of the analytical method.

Monitoring antipsychotic drugs in biological fluids, such as human serum and urine, is important for ensuring the safety and efficacy of psychiatric treatments. This process helps maintain therapeutic drug levels, minimize side effects, and optimize patient well-being. Chlorpromazine (CZ) is a widely prescribed antipsychotic drug used for conditions like schizophrenia, bipolar disorder, and acute psychosis. Almost all existing sensing techniques for CZ are either insensitive spectrophotometric methods or involve long and complex chromatographic procedures, limiting their routine use. In this work, we introduce a facile, green, and sensitive fluorimetric strategy with high reproducibility for detecting CZ in its pure form, tablet formulation, and spiked human plasma and urine without the need for derivatization reactions. The proposed method relies on the inhibition of the intramolecular photoinduced electron transfer (PET) effect by using 2.0 M acetic acid. This approach enables the linear detection of CZ from 3.0 to 600 ng/mL with remarkably low quantitation and detection limits of 1.51 and 0.49 ng/mL, respectively. Moreover, the developed method's greenness was evaluated.

Developing patient-derived organoids to demonstrate JX24120 inhibits SAMe synthesis in endometrial cancer by targeting MAT2B.

Endometrial cancer (EC) is one of the most common gynecologic malignancies, which lacking effective drugs for intractable conditions or patients unsuitable for surgeries. Recently, the patient-derived organoids (PDOs) are found feasible for cancer research and drug discoveries. Here, we have successfully established a panel of PDOs from EC and conducted drug repurposing screening and mechanism analysis for cancer treatment. We confirmed that the regulatory ß subunit of methionine adenosyltransferase (MAT2B) is highly correlated with malignant progression in endometrial cancer. Through drug screening on PDOs, we identify JX24120, chlorpromazine derivative, as a specific inhibitor for MAT2B, which directly binds to MAT2B (Kd = 4.724 µM) and inhibits the viability of EC PDOs and canonical cell lines. Correspondingly, gene editing assessment demonstrates that JX24120 suppresses tumor growth depending on the presence of MAT2B in vivo and in vitro. Mechanistically, JX24120 induces inhibition of S-adenosylmethionine (SAMe) synthesis, leading to suppressed mTORC1 signaling, abnormal energy metabolism and protein synthesis, and eventually apoptosis. Taken together, our study offers a novel approach for drug discovery and efficacy assessment by using the PDOs models. These findings suggest that JX24120 may be a potent MAT2B inhibitor and will hopefully serve as a prospective compound for endometrial cancer therapy.

Comparison of intramuscular haloperidol and other short-acting injectable antipsychotics for management of acute agitation in an adult inpatient psychiatry unit.

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.

Prevalence of polypharmacy and factors impacting psychotropic prescribing patterns in women of childbearing potential at inpatient mental health services in Qatar.

AIMS: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Intractable Hiccups in a Patient With End-Stage Renal Disease: A Five-Month Ordeal Resolved Through Hemodialysis.

Hiccups, a common and usually self-limiting condition, are caused by involuntary, spasmodic contractions of the diaphragm and intercostal muscles, followed by the sudden closure of the glottis. While most cases resolve spontaneously, persistent hiccups (lasting 48 hours to one month) and intractable hiccups (lasting more than one month) require medical attention. Intractable hiccups, although rare, can significantly impair a patient's quality of life. The etiology of intractable hiccups is diverse, but they are often associated with serious underlying medical conditions, such as severe renal dysfunction and uremia. We present the case of a 72-year-old male patient with stage IV chronic kidney disease (CKD) who developed intractable, violent hiccups following a mild COVID-19 infection. Despite treatment attempts with chlorpromazine and baclofen, the hiccups persisted for five months and only resolved after the initiation of hemodialysis. Interestingly, the patient's renal function deteriorated significantly during the period of hiccup persistence, suggesting a possible link between the hiccups and the progression of CKD, likely exacerbated by COVID-19. This case highlights the challenges of managing intractable hiccups in patients with advanced CKD and emphasizes the importance of addressing underlying metabolic derangements in such complex clinical scenarios. Moreover, it contributes to the growing evidence supporting the role of dialysis in resolving intractable hiccups associated with severe renal dysfunction.

Electrochemical Synthesis of the In Human S-oxide Metabolites of Phenothiazine-Containing Antipsychotic Medications.

The tractable preparation of Phase I drug metabolites is a critical step to understand the first-pass 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.

Chlorpromazine overcomes temozolomide resistance in glioblastoma by inhibiting Cx43 and essential DNA repair pathways.

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.

Persistent hiccups after acute COVID-19 successfully treated with chlorpromazine: a case report.

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.

Spectroscopic studies under properties of chlorpromazine conjugated to gold nanoparticles.

Scientific studies have demonstrated that conjugates of anticancer drugs with metal nanoparticles (MeNPs) lead to a more effective deactivation of tumor cells compared to free drugs. Similarly, it has been established that conjugates of antibiotics with MeNPs exhibit higher biocidal activity against bacteria than their unbound counterparts. However, limited information is available regarding conjugates formed from drugs other than anticancer and antibiotics. Therefore, our research aims to develop synthesis methods for conjugates of chlorpromazine (CPZ), a neuroleptic, with gold nanoparticles (AuNPs). CPZ-AuNP conjugates were prepared through a ligand exchange reaction conducted on the surface of quasi-spherical, negatively charged citrate-stabilized TC-AuNPs with an average size of 55 ± 5 nm. UV-vis spectroscopy was employed to determine the stability range of the conjugates under controlled conditions of pH and ionic strength. Based on electrokinetic measurements, it was observed that the zeta potential of CPZ-AuNP conjugates strongly depends on the amount of CPZ adsorbed on the TC-AuNP surface. Additionally, the conjugates exhibited an isoelectric point at pH 8.8. Surface-enhanced Raman spectroscopy (SERS) and surface-enhanced infrared absorption spectroscopy (SEIRA) were employed to elucidate the adsorption structure of CPZ on TC-AuNPs. The interpretation of the spectra was conducted based on the Raman and FTIR spectra of CPZ, along with calculations performed using Density Functional Theory (DFT). The results indicated that CPZ primarily interacts with the TC-AuNP surface through the angularly oriented phenothiazine ring and the propylene bridge. Furthermore, it was demonstrated that the C-N-C fragment is perpendicular to the surface of the TC-AuNP with which it interacts. The findings from this analysis suggest the potential for further research on the use of these conjugates in biomedical applications.

Chlorpromazine overdose: a case series.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. DISCUSSION: 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. CONCLUSIONS: 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.

Modulation of NLRP3 inflammasome-related-inflammation via RIPK1/RIPK3-DRP1 or HIF-1α signaling by phenothiazine in hypothermic and normothermic neuroprotection after acute ischemic stroke.

BACKGROUND: Inflammation and subsequent mitochondrial dysfunction and cell death worsen outcomes after revascularization in ischemic stroke. Receptor-interacting protein kinase 1 (RIPK1) activated dynamin-related protein 1 (DRP1) in a NLRPyrin domain containing 3 (NLRP3) inflammasome-dependent fashion and Hypoxia-Inducible Factor (HIF)-1α play key roles in the process. This study determined how phenothiazine drugs (chlorpromazine and promethazine (C + P)) with the hypothermic and normothermic modality impacts the RIPK1/RIPK3-DRP1 and HIF-1α pathways in providing neuroprotection. METHODS: A total of 150 adult male Sprague-Dawley rats were subjected to 2 h middle cerebral artery occlusion (MCAO) followed by 24 h reperfusion. 8 mg/kg of C + P was administered at onset of reperfusion. Infarct volumes, mRNA and protein expressions of HIF-1α, RIPK1, RIPK3, DRP-1, NLRP3-inflammation and cytochrome c-apoptosis were assessed. Apoptotic cell death, infiltration of neutrophils and macrophages, and mitochondrial function were evaluated. Interaction between RIPK1/RIPK3 and HIF-1α/NLRP3 were determined. In SH-SY5Y cells subjected to oxygen/glucose deprivation (OGD), the normothermic effect of C + P on inflammation and apoptosis were examined. RESULTS: C + P significantly reduced infarct volumes, mitochondrial dysfunction (ATP and ROS concentration, citrate synthase and ATPase activity), inflammation and apoptosis with and without induced hypothermia. Overexpression of RIPK1, RIPK3, DRP-1, NLRP3-inflammasome and cytochrome c-apoptosis were all significantly reduced by C + P at 33 °C and the RIPK1 inhibitor (Nec1s), suggesting hypothermic effect of C + P via RIPK1/RIPK3-DRP1pathway. When body temperature was maintained at 37 °C, C + P and HIF-1α inhibitor (YC-1) reduced HIF-1α expression, leading to reduction in mitochondrial dysfunction, NLRP3 inflammasome and cytochrome c-apoptosis, as well as the interaction of HIF-1α and NLRP3. These were also evidenced in vitro, indicating a normothermic effect of C + P via HIF-1α. CONCLUSION: Hypothermic and normothermic neuroprotection of C + P involve different pathways. The normothermic effect was mediated by HIF-1α, while hypothermic effect was via RIPK1/RIPK3-DRP1 signaling. This provides a theoretical basis for future precise exploration of hypothermic and normothermic neuroprotection.

Adverse hematological profiles associated with chlorpromazine antipsychotic treatment in male rats: Preventive and reversal mechanisms of taurine and coenzyme-Q10.

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.

Highly sensitive and novel dual-emission fluorescence nanosensor utilizing hybrid carbon dots-quantum dots for ratiometric determination of chlorpromazine.

Herein, a ratiometric fluorimetric nanosensor is introduced for the sensitive and selective analysis of chlorpromazine (CPZ) via employing blue-emitting B-doped carbon dots (B-CDs) as the reference fluorophore and green-emitting CdTe capped thioglycolic acid (TGA) quantum dots (TGA-CdTe-QDs) as the specific recognition probe. The sensor exhibits dual emission centered at 440 and 560 nm, under a single excitation wavelength of 340 nm. Upon the addition of ultra-trace amount of CPZ, the fluorescence signal of TGA-CdTe-QDs declines due to electron transfer process from excited TGA-CdTe-QDs to CPZ molecules, whereas the fluorescence peak of B-CDs is unaffected. Therefore, a new fluorimetric platform was prepared for the assay of CPZ in the range of 2.2 × 10-10 to 5.0 × 10-9 M with a detection limit of 1.3 × 10-10 M. Moreover, the practicability of the designed strategy was investigated for the detection of CPZ in biological samples and the results demonstrate that it possesses considerable potential to be utilized in practical applications.

Novel Tetracyclic Azaphenothiazines with the Quinoline Ring as New Anticancer and Antibacterial Derivatives of Chlorpromazine.

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.