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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. [ABSTRACT FROM AUTHOR]

Chlorpromazine (CPZ), an antipsychotic drug derived from phenothiazine, can cause a range of adverse effects in humans, notably visual problems and hematological disorders upon consumption of chlorpromazine‐contaminated water. In this regard, a novel electrochemical sensing platform based on a copper–aluminum‐layered double hydroxide (Cu–Al LDH)‐modified platinum electrode for the highly sensitive and selective detection of chlorpromazine in groundwater samples has been developed. The immobilized Cu–Al LDH showed an electrocatalytic effect on chlorpromazine reduction and oxidation. Among the employed electroanalytical techniques, only the square‐wave voltammetry‐assisted Pt/Cu–Al LDH electrode could detect chlorpromazine with a remarkable sensitivity of 0.065 µA µM−1 over a broad linear detection range of 0.01–760 µM, with low detection and quantification limits of 4.86 and 16.18 nM, respectively. Furthermore, the developed electrode can rapidly detect chlorpromazine within less than 10 s. In addition, the diffusion profiles of steady‐state concentrations of oxidized and reduced chlorpromazine within the immobilized Cu–Al were studied using the Legendre wavelet method. Moreover, the developed Pt/Cu–Al LDH electrode demonstrated satisfactory rates in the quantification of chlorpromazine in groundwater samples, yielding satisfactory recovery rates (97.63–102.57%), confirming the practicability of the fabricated electrode in real‐time monitoring of chlorpromazine levels in groundwater without requiring any sample pretreatment. [ABSTRACT FROM AUTHOR]

Soybean allergen entering the body is the initial step to trigger intestinal allergic response. However, it remains unclear how glycinin, the major soybean allergen, is transported through the intestinal mucosal barrier. The objective of this study was to elucidate the pathway and mechanism of glycinin hydrolysates transport through the intestinal epithelial barrier using IPEC‐J2 cell model. Purified glycinin was digested by in vitro static digestion model. The pathway and mechanism of glycinin hydrolysates transport through intestinal epithelial cells were investigated by cellular transcytosis assay, cellular uptake assay, immunoelectron microscopy and endocytosis inhibition assay. The glycinin hydrolysates were transported across IPEC‐J2 cell monolayers in a time/dose‐dependent manner following the Michaelis equation. Immunoelectron microscopy showed a number of glycinin hydrolysates appeared in the cytoplasm, but no glycinin hydrolysates were observed in the intercellular space of IPEC‐J2 cells. The inhibitors, colchicine, chlorpromazine and methyl‐β‐cyclodextrin, significantly inhibited the cellular uptake of glycinin hydrolysates. The glycinin hydrolysates crossed IPEC‐J2 cell monolayers through the transcellular pathway. Both clathrin‐ and caveolae‐dependent endocytosis were involved in the epithelial uptake of the hydrolysates. These findings provided potential targets for the prevention and treatment of soybean allergy. [ABSTRACT FROM AUTHOR]

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. [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]

Serotonin syndrome (toxicity), resulting from an excessive accumulation of serotonin in the central nervous system, it can occur due to various factors such as the initiation of medication, overdose or drug interactions. Diagnosing serotonin toxicity presents challenges as there are no definitive criteria. This review delves into the pathophysiology, incidence, clinical assessment and management of serotonin toxicity, stressing the significance of promptly recognizing and managing severe cases. Diagnosis relies primarily relies on clinical assessment due to the absence of specific laboratory tests. The Hunter Serotonin Toxicity criteria are commonly utilized but have only been validated in the overdose setting. Assessing the severity of toxicity is crucial for guiding management decisions. Supportive care, discontinuation of causative agents and symptomatic treatment are prioritized in management. Mild toxicity often requires withdrawal or reduction of the serotonergic agent, while more severe toxicity requires more aggressive resuscitative and supportive care. Severe serotonin toxicity characterized by hyperthermia and rigidity requires aggressive supportive measures, including benzodiazepines, intubation, paralysis and active cooling. Animal studies suggest potential benefits of 5‐HT2A receptor antagonists in preventing hyperthermia and fatalities, but only at high doses. Their clinical effectiveness remains uncertain, and evidence is predominately from case series and case reports. Although commonly used, serotonin antagonists like cyproheptadine lack conclusive evidence of efficacy. Other serotonin antagonists such as chlorpromazine and olanzapine have been explored but evidence is limited to case reports. Hence, the cornerstone of treating severe cases does not lie in ‘antidote’ administration or even diagnosis but in effective early resuscitative and supportive care. [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]

Chlorpromazine (CPZ), a first‐generation antipsychotic, is widely used in treating schizophrenia and other psychiatric disorders. However, CPZ is also associated with an increased likelihood of sudden cardiac death, and the underlying mechanisms remain unclear. In our study, we aimed to determine the CPZ‐induced changes in some members of the heat shock protein family in rat hearts and further explore the possible mechanisms of CPZ‐induced cardiotoxicity. Twenty‐four Sprague Dawley rats were randomly divided into three groups (n = 8 per group): control, low dose (33.216 mg/kg) and high dose (94.211 mg/kg). CPZ administration induced hypothermia in rats. Pathological changes, including ischaemia and hypoxia, were observed in rat hearts. Furthermore, the serum levels of cardiac Troponin T (c‐TN‐T) and brain natriuretic peptide (BNP) were elevated in the CPZ‐exposed groups. Meanwhile, the protein and gene expression of HSP70, HSP60, HSP27 and HSP10 significantly differed between the CPZ‐exposed and control groups. We conclude that acute CPZ exposure could lead to myocardial injury in rats, in which HSPs might play a crucial role. Further investigations are required to elucidate the underlying mechanisms. To explore the cardiotoxicity mechanism of chlorpromazine (CPZ), 24 Sprague Dawley rats were randomly divided into three groups (n = 8 per group): control, low dose (33.216 mg/kg) and high dose (94.211 mg/kg). Observed pathological changes in rat hearts included ischaemia and hypoxia, and the serum levels of c‐TN‐T and BNP were elevated in the CPZ‐exposed groups. The protein and gene expression of HSP70, HSP60, HSP27 and HSP10 significantly differed between the CPZ‐exposed and control groups. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance is a serious public health risk. Its severity is fueled on an unprecedented scale, necessitating the demand for novel antimicrobial scaffolds aimed at novel targets. Herein, we present cationic chlorpromazine peptide conjugates that are rationally intended to targetmultidrug‐resistant (MDR) bacteria. The most potent compound, CPWL, of all the conjugates evaluated, showed promising antibacterial activity against clinical, MDR S. aureus, with no cytotoxicity. The molecular docking experiments confirmed that CPWL possessed a very high affinity for S. aureus enoyl reductase (saFabI). Furthermore, CPWL antibacterial action against saFabI was further corroborated by MD simulation studies. Thus, our findings highlight cationic chlorpromazine as a promising scaffold for the development of saFabI inhibitors to target severe staphylococcal infections. [ABSTRACT FROM AUTHOR]

Background and Purpose: CaV3.1‐3 currents differentially contribute to neuronal firing patterns. CaV3 are regulated by G protein‐coupled receptors (GPCRs) activity, but information about CaV3 as targets of the constitutive activity of GPCRs is scarce. We investigate the impact of D5 recpetor constitutive activity, a GPCR with high levels of basal activity, on CaV3 functionality. D5 recpetor and CaV3 are expressed in the hippocampus and have been independently linked to pathophysiological states associated with epilepsy. Experimental Approach: Our study models were HEK293T cells heterologously expressing D1 or D5 receptor and CaV3.1‐3, and mouse brain slices containing the hippocampus. We used chlorpromazine (D1/D5 inverse agonist) and a D5 receptor mutant lacking constitutive activity as experimental tools. We measured CaV3 currents and excitability parameters using the patch‐clamp technique. We completed our study with computational modelling and imaging technique. Key Results: We found a higher sensitivity to TTA‐P2 (CaV3 blocker) in CA1 pyramidal neurons obtained from chlorpromazine‐treated animals compared with vehicle‐treated animals. We found that CaV3.2 and CaV3.3—but not CaV3.1—are targets of D5 receptor constitutive activity in HEK293T cells. Finally, we found an increased firing rate in CA1 pyramidal neurons from chlorpromazine‐treated animals in comparison with vehicle‐treated animals. Similar changes in firing rate were observed on a neuronal model with controlled CaV3 currents levels. Conclusions and Implications: Native hippocampal CaV3 and recombinant CaV3.2‐3 are sensitive to D5 receptor constitutive activity. Manipulation of D5 receptor constitutive activity could be a valuable strategy to control neuronal excitability, especially in exacerbated conditions such as epilepsy. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to elucidate the oral hygiene status and the factors associated with poor oral hygiene among patients with schizophrenia. Methods: The relationships of oral hygiene status (calculus index [CI], debris index [DI]), the mean number of decayed‐missing‐filled teeth (mean DMFT), and Revised Oral Assessment Guide (ROAG) with related factors (hospitalization, chlorpromazine equivalents [CPZE], age, Barthel Index [BI], frequency of cleaning teeth, and self‐oral hygiene ability) among 249 hospitalized schizophrenic patients were investigated. Results: The results for oral hygiene status were as follows: median (range); CI 0.5 (0–6.0), DI 1.7 (0–6.0), ROAG 10.0 (7.0–15.0); and mean DMFT 21.7 ± 7.3. The average CPZE was 524.4 ± 353.6 mg (mean ± SD), and the BI was 76.4 ± 30.7. There was a negative correlation between BI and DI (r = −0.34), and a positive correlation between age and mean DMFT (r = 0.57). Male patients tended to have worse oral conditions (ROAG) than females. The least‐squares multiple regression analysis revealed that BI for DI, age for mean DMFT, sex for ROAG, and self‐oral hygiene ability for CI, DI, and mean DMFT were factors related to oral health status. Conclusion: Patients with schizophrenia tended to have poor oral hygiene. BI, being male, and low activities of daily living were associated with poor oral hygiene. Furthermore, advanced age was associated with an increased risk of dental caries. [ABSTRACT FROM AUTHOR]

A retrospective cohort study examining psychiatric inpatients in New York state has found that use of second‐generation antipsychotics was associated with reduced risk of COVID‐19 infection. Conversely, use of valproic acid was associated with increased risk of COVID‐19. Study results were published online May 6, 2022, in JAMA Network Open. [ABSTRACT FROM AUTHOR]

Background and Purpose: Many psychotherapeutic drugs, including clozapine, display polypharmacology and act on GABAA receptors. Patients with schizophrenia show alterations in function, structure and molecular composition of the hippocampus, and a recent study demonstrated aberrant levels of hippocampal α5 subunit‐containing GABAA receptors. The purpose of this study is to investigate the effects of tricyclic compounds on α5 subunit‐containing receptor subtypes. Experimental Approach Functional studies of effects by seven antipsychotic and antidepressant medications were performed in several GABAA receptor subtypes by two‐electrode voltage‐clamp electrophysiology using Xenopus laevis oocytes. Computational structural analysis was employed to design mutated constructs of the α5 subunit, probing a novel binding site. Radioligand displacement data complemented the functional and mutational findings. Key Results: The antipsychotic drugs clozapine and chlorpromazine exerted functional inhibition on multiple GABAA receptor subtypes, including those containing α5‐subunits. Based on a chlorpromazine binding site observed in a GABA‐gated bacterial homologue, we identified a novel site in α5 GABAA receptor subunits and demonstrate differential usage of this and the orthosteric sites by these ligands. Conclusion and Implications: Despite high molecular and functional similarities among the tested ligands, they reduce GABA currents by differential usage of allosteric and orthosteric sites. The chlorpromazine site we describe here is a new potential target for optimizing antipsychotic medications with beneficial polypharmacology. Further studies in defined subtypes are needed to substantiate mechanistic links between the therapeutic effects of clozapine and its action on certain GABAA receptor subtypes. [ABSTRACT FROM AUTHOR]

Cerebral ischemia-reperfusion (I/R) incites neurologic damage through a myriad of complex pathophysiological mechanisms, most notably, inflammation and oxidative stress. In I/R injury, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) produces reactive oxygen species (ROS), which promote inflammatory and apoptotic pathways, augmenting ROS production and promoting cell death. Inhibiting ischemia-induced oxidative stress would be beneficial for reducing neuroinflammation and promoting neuronal cell survival. Studies have demonstrated that chlorpromazine and promethazine (C+P) induce neuroprotection. This study investigated how C+P minimizes oxidative stress triggered by ischemic injury. Adult male Sprague-Dawley rats were subject to middle cerebral artery occlusion (MCAO) and subsequent reperfusion. 8 mg/kg of C+P was injected into the rats when reperfusion was initiated. Neurologic damage was evaluated using infarct volumes, neurological deficit scoring, and TUNEL assays. NOX enzymatic activity, ROS production, protein expression of NOX subunits, manganese superoxide dismutase (MnSOD), and phosphorylation of PKC-δ were assessed. Neural SHSY5Y cells underwent oxygen-glucose deprivation (OGD) and subsequent reoxygenation and C+P treatment. We also evaluated ROS levels and NOX protein subunit expression, MnSOD, and p-PKC-δ/PKC-δ. Additionally, we measured PKC-δ membrane translocation and the level of interaction between NOX subunit (p47phox) and PKC-δ via coimmunoprecipitation. As hypothesized, treatment with C+P therapy decreased levels of neurologic damage. ROS production, NOX subunit expression, NOX activity, and p-PKC-δ/PKC-δ were all significantly decreased in subjects treated with C+P. C+P decreased membrane translocation of PKC-δ and lowered the level of interaction between p47phox and PKC-δ. This study suggests that C+P induces neuroprotective effects in ischemic stroke through inhibiting oxidative stress. Our findings also indicate that PKC-δ, NOX, and MnSOD are vital regulators of oxidative processes, suggesting that C+P may serve as an antioxidant. [ABSTRACT FROM AUTHOR]

Objective. This study is aimed at investigating the clinical efficacy of anisodamine combined with chlorpromazine on intractable hiccups after stroke. Methods. 150 patients admitted to Affiliated Hospital of the Hebei University of Engineering from 2017 to 2021 were selected as the research objects, all of which received the computed tomography (CT) examination. During CT examination, intelligent algorithms were used to segment the images. An unsupervised multilayer image threshold segmentation algorithm was proposed by using Kullback-Leibler (K-L) divergence and the modified particle swarm optimization (MPSO) algorithm. All patients were divided into three groups, with each group of 50 patients. Patients in the control group (group A) took the calcium tablets, vitamin C tablets, and vitamin B1 tablets orally. Patients in the control group (group B) received the acupoint injection of anisodamine, and those in the observation group (group C) received the acupoint injection of anisodamine combined with chlorpromazine. The therapeutic effect and patient satisfaction of the three groups were compared. Results. The two-dimensional (2D) K-L divergence was applied for the multilayer segmentation of images, which was helpful to obtain accurate images. The MPSO algorithm was adopted to reduce the computational complexity. The total efficiency of group C was 98%, that of group B was 56%, and that of group A was 22%. The total efficiency and satisfaction rate of group C were signally better than those of group A and group B (P < 0.05). Conclusion. The combination of 2D K-L divergence and MPSO algorithm could improve the accuracy of multilayer image segmentation and CT imaging. Acupoint injection of anisodamine combined with chlorpromazine had better efficacy than the injection of anisodamine alone for the treatment of intractable hiccups after stroke, with high safety and clinical promotion value. [ABSTRACT FROM AUTHOR]

What is known and objective: The schizophrenia guidelines in Japan and many other countries describe clozapine as the first‐choice drug for patients with treatment‐resistant schizophrenia. However, there have been no reports to date on the effects of the introduction of clozapine on the prescription of other antipsychotics and concomitant drugs. Methods: In this study, we retrospectively investigated the prescription of antipsychotics and concomitant drugs before vs 6 months after and 12 months after switching to clozapine. Results and discussion: Clozapine was introduced to 62 patients with treatment‐resistant schizophrenia, and 51 patients continued on clozapine therapy. Six months after switching to clozapine, there was a significant decrease in the mean number of antipsychotic drugs (2.04 ± 0.75 vs 1.10 ± 0.30: p < 0.001) and in the mean chlorpromazine equivalent value (1024 ± 73 mg/day vs 781 ± 391 mg/day: p < 0.001) compared to before switching. Moreover, antipsychotic monotherapy increased from 24% to 90% after switching to clozapine. In addition, the number of concomitant benzodiazepines, anti‐parkinson drugs and antidepressants also significantly decreased 6 and 12 months after switching to clozapine (p < 0.001 for benzodiazepines and anti‐parkinson drugs, and p < 0.05 for antidepressants). What is new and conclusion: Our study suggests that switching to clozapine may reduce the use of antipsychotic combination therapy, and may also reduce the number of concomitant drugs. [ABSTRACT FROM AUTHOR]

The kinetic mechanism of oxidation of Chlorpromazine (CPZ) (2‐chloro‐10‐(3‐dimethylaminopropyl) phenothiazine) by hexachloroiridate (IV) in acidic aqueous medium has been studied spectrophotometrically using UV‐visible spectrophotometer at λmax 525 nm (ϵ, 10200 dm3 mol−1 cm−1). The title reaction is overall second order being first order with respect to each reactant, but to be complicated at higher substrate concentrations. Oxidant has been found as strong electron transfer species to the formation of chlorpromazine radical cation and further respected sulfoxide. The rate also increases with increasing concentration of hydrogen ion and reaction is catalyzed by perchlorate medium. The oxidation is unaffected to variation in ionic strength. Various proposals have been suggested on the basis of reactivity of Ir[IV] and radical cation species. The activation parameters have been evaluated by employing Eyring equation. The oxidation product of CPZ has been confirmed spectrally and a suitable mechanism has been proposed. [ABSTRACT FROM AUTHOR]

Objective: In paediatric migraine, ibuprofen, acetaminophen and triptans are safe, effective therapies but there is scant paediatric data informing second‐line emergency treatment. Methods: Retrospective cohort study of children diagnosed with migraine at a tertiary children's hospital ED. Results: There were 207 children with migraine over a 1 year period. 46% received simple oral analgesia. 25% intravenous chlorpromazine, of whom 45% received further analgesia. Conclusions: While intravenous chlorpromazine as second‐line agent was mostly safe, it had unclear efficacy given the requirement for further treatment and hospital admissions. [ABSTRACT FROM AUTHOR]

Objective: To compare the efficacy of intravenous chlorpromazine versus intravenous prochlorperazine for the treatment of acute migraine in adults presenting to the emergency department (ED). Background: Migraine is a common, incapacitating neurological condition. Although chlorpromazine and prochlorperazine are known to be safe, efficacious treatments for migraine, they have never been directly compared. Design: We performed a prospective, randomized, double‐blind clinical trial at a tertiary hospital in Melbourne, Australia. Adults aged 18–65 years, who presented with migraine, were eligible for recruitment. Sixty‐six patients were randomized to either chlorpromazine 12.5 mg or prochlorperazine 12.5 mg, both infused in 500 ml of sodium chloride 0.9% over 30 min. Headache severity score, nausea severity score, and the presence of photophobia and phonophobia were assessed at 0, 30, 60, and 120 min. Adverse effects and the need for rescue therapy were recorded. The primary outcome was a reduction in headache severity score from baseline at 60 min post‐commencement of the study medicine infusion. Results: Sixty‐five patients were included in the analysis. There was a median reduction in headache severity score at 60 min of 3.0 (interquartile range 1.0–4.0) in the chlorpromazine arm versus 2.0 (1.0–4.0) in the prochlorperazine arm (median difference −0.5 (95% confidence interval, −1.9 to 0.9)). We saw no evidence of a difference in secondary outcomes at 30, 60, or 120 min. Side effects were reported in 16/32 (50%) patients in the chlorpromazine group versus 7/33 (21%) in the prochlorperazine group (p = 0.020). Rescue therapy was required in 7/32 (22%) patients in the chlorpromazine group versus 12/33 (36%) in the prochlorperazine group (p = 0.277). Conclusions: Both chlorpromazine and prochlorperazine are efficacious treatments for acute migraine in adult patients presenting to the ED. This trial found no evidence of superiority of either agent over the other. Caution should be used when prescribing these medicines in the borderline hypotensive patient; in that circumstance, prochlorperazine should be preferentially used. [ABSTRACT FROM AUTHOR]

Immunochromatographic assays are good analytical tools for the detection of drug residues. We report a nanosphere-based time-resolved fluorescence immunoassay (nano-TRFIA) based on a monoclonal antibody and a portable TRFIA analyzer for the rapid quantification of chlorpromazine (CPZ) residues in pork. Under optimal conditions, the nano-TRFIA detected CPZ residues within 6 min of sample pretreatment. The results showed good linearity (R2 = 0.991), with a limit of detection (LOD) of 0.32 μg/kg, a wide dynamic range of 0.46–10.0 μg/kg, and coefficients of variation (CVs) of the overall intrabatch and interbatch assays of 7.34% and 7.65%, respectively. The nano-TRFIA was also used to detect CPZ at different spiked concentrations in pork, and the results were confirmed via ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The nano-TRFIA was evaluated for the analysis of six commercial pork samples, and the results agreed well with those obtained via UPLC-MS/MS, without significant differences (P > 0.05). Therefore, the proposed nano-TRFIA is a powerful alternative for the rapid and accurate quantification of CPZ residues in pork to meet the required Chinese maximum residue limits for veterinary drugs in foods. [ABSTRACT FROM AUTHOR]

We have examined the mixed micellar behavior of {amphiphilic drug; chlorpromazine hydrochloride (CPZ) + cationic surfactant; cetyltrimethylammonium bromide (CTAB)} at varying mole fractions of CPZ (αCPZ = 0.2, 0.4, 0.6, and 0.8) in (0.1, 0.3, and 0.5) mol kg−1 glycine(aq) solutions at 298.15, 308.15, and 318.15 K, by using conductometric, volumetric, isentropic compressibility, UV–visible absorbance, fluorescence, and dynamic light scattering (DLS) techniques. The critical micelle concentration (CMC) values obtained from above measurements have been utilized to calculate the thermodynamic parameters (ΔG°m, ΔH°m, and ΔS°m) and degree of ionization (α) at studied temperatures and concentrations. The partial specific volume (φv), partial specific isentropic compression (φκ), and isentropic compressibility (κs) have been calculated from the experimental density and speed of sound measurements and the results have been used to elucidate different interactions occurring in these systems. These results are further supported by UV–visible absorbance and fluorescence spectroscopic studies. The hydrodynamic diameters (Dh) of the mixed micellar system have been measured from the DLS studies. Thermodynamic and spectroscopic studies depict the dominance of hydrophobic/hydrophilic‐hydrophobic interactions between the alkyl (R = C16H33) chain of CTAB or hydrophobic tricyclic scaffolding of CPZ/Br−/N+‐CH3 group of CTAB or hydrophilic group i.e., tertiary amine portion of CPZ with hydrophobic group of glycine. [ABSTRACT FROM AUTHOR]

Objective: This study describes the approaches, medications used, and time of care for migraineurs, who have been in emergency departments (ED) from 2 different regions of Brazil. Methods: Retrospective, cross‐sectional, observational, non‐randomized study of migraine patients seen at 2 headache centers in Brazil. Results: Eighty‐four migraine patients (15 men and 69 women) were divided into 2 groups: chronic (19%, n = 16) and episodic migraineurs (81%, n = 68). In the ED, medications were used in the following order of frequency: dipyrone or metamizole (89.3%, 75/84), nonsteroidal anti‐inflammatory drugs (57.1%; 48/84) opioids (51.1%; 43/84), metoclopramide (29.8%; 25/84), dexamethasone (28.6%; 24/84), chlorpromazine (13.1%; 11/84), and subcutaneous sumatriptan (7.1%; 6/84). The average time in the care center was 8.2 hours, but only 23 patients (27.4%) left the hospital with greater than 50% relief in headache severity. Conclusions: Dipyrone and nonsteroidal anti‐inflammatories were the most used drugs, but nearly half received opioids. More efficient drugs were poorly used. Considering the number of patients leaving the hospital with headache relief, a changing treatment paradigm should be carried out in Brazil. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to describe a group of patients with chronic headache disorders (CH) and medication overuse headache (MOH) treated with intravenous chlorpromazine (IVC). We hypothesized that IVC is an effective and safe addition to well‐known treatment strategies for CH and MOH management. Introduction: Up to 4% of the general population could experience CH. Most cases occur in women, in association with MOH. To date, evidence to support different treatment strategies is lacking. Although IVC is frequently used in the emergency room (ER), documentation on its use as supportive treatment for CH and for withdrawal management of MOH is poor. Methods: A retrospective cohort of patients hospitalized to receive treatment for CH in a specialized neurological center in Argentina was analyzed. Results: A total of 35 CH patients were included. Of the 35 patients, 33 (94%) patients also presented MOH. Patients reported only minor side effects to IVC administration (mainly drowsiness and symptomatic hypotension). Three months after inpatient treatment, the number of ER visits made by these patients decreased from an average of 2.8 in the 3 months prior to hospitalization to 0.7 after it (72%, P =.009). Headache frequency decreased in 20/34 (59%) patients during the same time period. Pain levels had dropped from a mean of 8 points at admission (in the scale of 1‐10) to 2 points at discharge. In the first 3 months of follow‐up, the average number of days per month in which patients experienced headache decreased from 28.9 to 15.4 days (53.3%, P <.0001). Conclusion: In this particular group of inpatients, there were no significant safety issues with IVC administration and the study might suggest that the efficacy of IVC as an add‐on treatment for CH and MOH. [ABSTRACT FROM AUTHOR]

We report a simple and sensitive voltammetric sensor for the determination of chlorpromazine (CPZ) based on Ni−Al layered double hydroxide (NiAlLDH) modified glassy carbon electrode (GCE). NiAlLDH was simply electrodeposited on GCE surface in a very short time. The response linear range was 1×10−3–1×10−9 mol L−1, with a detection limit of 1×10−9 mol L−1. The NiAlLDH film showed well defined and well separate peaks for dopamine, ascorbic acid, uric acid and CPZ in the same solution. The proposed electrode was used to measure the active pharmaceutical ingredient of CPZ tablet as a real sample. [ABSTRACT FROM AUTHOR]

Nanocomposite of nanoscale zero‐valent iron (nZVI) and layered double hydroxide (LDH) was used as modifier for boron‐doped diamond electrode in determination of anti‐psychotic drug chlorpromazine (CPZ). nZVI nanoparticles were prepared by liquid phase reduction of ferric chloride with sodium borohydride on the surface of NiAl LDH matrix owing to the strong exchange and confinement efficiency of LDH. The structure, binding and surface properties of the nZVI@LDH nanocomposite were monitored using powder X‐ray diffractometry, FT‐IR spectroscopy, scanning and transmission microscopy and BET techniques. The electrochemical properties of the modified electrode were investigated by CV and EIS, performed in a phosphate buffer containing ferro/ferricyanide as redox probe. The modified electrode exhibited excellent electrochemical performance compared with unmodified electrode. As regard potential application of the nanocomposite surface to the CPZ detection, square‐wave voltammetric signals showed a good linear correlation over CPZ concentrations in a broad range from 0.1 to 8.0 μM with low detection limit of 0.005 μM. Nevertheless, these results suggest that the proposed nanocomposite modifier surface provides exceptional synergy and significant enhancement effect to the voltammetric response of CPZ and thus could be applied as highly efficient and stable platform of sensors in clinical analysis. [ABSTRACT FROM AUTHOR]

Chlorpromazine may induce abnormal skin hyperpigmentation in exposed areas, described as slate‐gray, purple, or blue‐grayish discoloration. A 58‐year‐old man with schizophrenia, had been taking chlorpromazine for 5 years, and his sun‐exposed skin areas exhibited a blue‐grayish color. Large deposits of brown pigment and granular basophilic material were seen in the dermis with light microscopy. HMB‐45 and anti‐Melan‐A antibody immunostaining labeled some pigment in the dermis. Transmission electron microscopy identified deposits among dermal collagen bundles collagen in both transverse and longitudinal sections. In the latter, an arboriform aspect of deposits was quite clear, and some melanophages were also seen. The three‐dimensional examination of the dermis with scanning electron microscopy also identified deposits, which at higher magnification demonstrated an appearance in the shape of leaves, grass‐like, interspersed with normal collagen. These results suggest a complex pathogenic mechanism, including deposition of dermal melanin together with drug itself and potentially additional unknown metabolites. [ABSTRACT FROM AUTHOR]

A retrospective cohort study involving Medicaid‐insured children and young adults receiving second‐generation antipsychotics has found an increased risk of mortality only in the young‐adult group that received high doses of the medication. There was no association between antipsychotic use and increased mortality risk for children aged 5 to 17 or for young adults aged 18 to 24 taking lower doses of antipsychotics. [ABSTRACT FROM AUTHOR]

Purpose - Since the development of antipsychotic drugs in the 1950s, a variety of studies and case reports have been published that suggest an association between exposure to typical antipsychotics and venous thromboembolisms (VTE). Therefore, when starting treatment with antipsychotics, especially low-potency typical antipsychotics and clozapine, health-care providers must account for the patient's existing VTE risk factors. Design/methodology/approach - In this case report, the authors describe the development of a pulmonary embolism associated with use of chlorpromazine in the treatment of an acute manic episode in a 51-year-old female patient with bipolar disorder type 1. Findings - The patient was brought to the emergency room by the police on a legal hold for bizarre behaviors at a bus stop, which included incessantly yelling at bystanders. The patient was found to have disorganized thoughts, poor sleep, rapid speech, labile mood, distractibility, auditory hallucinations and grandiose delusions. During the course of her stay, the patient received extensive IM chlorpromazine for extreme agitation, in addition to chlorpromazine 200 mg IM Q8H, which was later decreased to chlorpromazine 100 mg chlorpromazine IM/PO Q8H. On day 4 of the treatment, the patient experienced difficulty breathing, hypoxia and tachycardia and was found to have bilateral expiratory wheezes. CT angiography showed sub-segmental pulmonary embolus and the patient was transferred to MICU service. The patient was then intubated and started on heparin by the medical team. Over the course of the next day, her respiratory distress resolved and the patient was extubated. Originality/value - It is possible that chlorpromazine may indeed increase VTEs, and there are various physiological postulations regarding the mechanism of action. However, multiple confounding variables existed in the authors' report, including venous stasis and the use of restraints, tobacco and valproic acid. Each of these variables has been shown to increase VTE occurrence. Further controlled studies are necessary to identify the true relationship between antipsychotics and VTEs. [ABSTRACT FROM AUTHOR]

Chlorpromazine is known to produce both systemic phototoxic and photoallergic reactions. However, it may also cause photoallergic contact dermatitis and, albeit exceptionally, allergic contact dermatitis (ACD). We present a series of photoallergic contact dermatitis and ACD to chlorpromazine diagnosed at a tertiary centre cutaneous allergy unit between 1980 and 2019. [ABSTRACT FROM AUTHOR]

Summary: What is known and objective: Based on spontaneous reports from Spain, it is claimed that the British, Irish and Scandinavians are at a greater risk of dipyrone‐induced agranulocytosis. This report examines the evidence. Comment: Although interethnic differences in drug response are well known, there are no reliable epidemiologic data to support the above claim. Available information on chlorpromazine suggests variable ethnic sensitivities to drug‐induced agranulocytosis. Agranulocytosis induced by at least four drugs has been associated with variant HLA alleles. Preliminary evidence also suggests that the presence of specific variant HLA alleles may sensitize individuals to dipyrone‐induced agranulocytosis. There are historical reasons to suspect that the three populations referred to may share some key genetic features, including the potentially culprit variant HLA alleles, that predispose them to dipyrone‐induced agranulocytosis. What is new and conclusion: The possibility that the British, Irish and Scandinavians show higher susceptibility than other populations to dipyrone‐induced agranulocytosis cannot be ruled out. If this complication is linked to specific HLA allele(s), populations with higher frequency of variant HLA allele(s) may be at a greater risk. If confirmed, screening for the risk allele may be useful in reducing the risk of dipyrone‐induced agranulocytosis. [ABSTRACT FROM AUTHOR]

Aim: Pneumonia is a major cause of death in patients with schizophrenia. Preventive strategies based on identifying the risk factors are needed to reduce pneumonia‐related mortality. This study aimed to clarify the risk factors for pneumonia in patients with schizophrenia. Methods: We retrospectively reviewed the clinical files of consecutive patients with schizophrenia admitted to Tokyo Metropolitan Matsuzawa Hospital during a four‐year period from January 2014 to December 2017. We analyzed the clinical differences between patients with and without pneumonia. Results: Of the 2209 patients enrolled, 101 (4.6%) received the diagnosis of pneumonia at the time of hospital admission while 2108 (95.4%) did not have pneumonia. Multivariable analysis to determine the risk factors related to pneumonia showed that the use of atypical antipsychotics had the highest odds ratio among the predictive factors (2.7; 95% confidence interval [CI] 1.0‐17.7; P = 0.046), followed by a total chlorpromazine equivalent dose ≥600 mg (2.6; 95% CI 1.7‐4.0; P < 0.001), body mass index <18.5 kg/m2 (2.3; 95% CI 1.6‐3.6; P < 0.001), smoking history (2.0; 95% CI 1.3‐3.1; P < 0.001), and age ≥50 years (1.7; 95% CI 1.2‐2.6; P = 0.002). Conclusions: We found that advanced age, underweight, smoking habit, use of atypical antipsychotics, and large doses of antipsychotics were risk factors for pneumonia in patients with schizophrenia. Among these factors, it was unclear whether the use of antipsychotics was a direct cause of pneumonia due to is uncertain because our retrospective study design. However, our result might be a good basis of further study focused on reducing pneumonia‐related fatalities in schizophrenic patients with pneumonia. We found that the advanced age, underweight, smoking habit, and the dose and category of antipsychotics were related to the development of pneumonia in patients with schizophrenia. Preventive strategies for reducing pneumonia should be elaborated with careful consideration of these risk factors. [ABSTRACT FROM AUTHOR]

This systematic review evaluates the safety and efficacy of intravenous (IV) lidocaine for the treatment of acute pain in adult patients. The PubMed database was searched for randomized controlled trials, retrospective cohort studies, case series, and case reports evaluating the use of IV lidocaine for the treatment of acute pain in adult patients, published between January 1970 and January 2018. The primary outcome was pain reduction via the Visual Analog Scale, Verbal Rating Scale, or Numeric Rating Scale among patients treated with IV lidocaine and placebo or active controls. Safety outcomes included both nonserious and serious adverse events. A total of 347 titles and abstracts were screened, and after full‐text review, 13 studies met the inclusion criteria involving 512 patients. The four active controls studied were IV morphine, IV ketorolac, IV dihydroergotamine (DHE), and IV chlorpromazine (CPZ). The dosing of IV lidocaine varied among studies between a weight‐based dose of a 1‐ to 2‐mg/kg bolus, a fixed‐bolus dose of 50–100 mg, and a 1‐mg/kg/hour continuous infusion. Monitoring of serum lidocaine concentrations was not done routinely. Intravenous lidocaine had superior efficacy to morphine for renal colic and critical limb ischemia, superior efficacy to DHE for acute migraine, and equivalent efficacy to ketorolac for acute radicular lower back pain. However, lidocaine was less effective than CPZ for the treatment of acute migraine. The most common adverse event reported among all studies were neurologic effects such as altered mental status and slurred speech. Due to the inconsistency in dosing, length of administration, and lack of serum monitoring, the absolute safety of IV lidocaine for acute pain is unknown. Larger, prospective studies are needed before the routine use of IV lidocaine can be recommended for all types of acute pain. [ABSTRACT FROM AUTHOR]

We report the case of a person who went into cardiac arrest after being given chlorpromazine for hiccups and was subsequently diagnosed with congenital Long QT Syndrome. Long QT Syndrome is an uncommon, congenital condition that carries a high risk of sudden cardiac death. Clinicians need to recognize the risk that chlorpromazine may prolong the QTc and prepare to manage potential complications. [ABSTRACT FROM AUTHOR]

Abstract: In this study, a novel ‘fiber‐in‐tube’ configuration was applied to electrochemically controlled fiber‐in‐tube solid‐phase microextraction of antipsychotic drugs (perphenazine and chlorpromazine) from biological samples. To prepare an electrochemically controlled fiber‐in‐tube solid‐phase microextraction column, first eight stainless‐steel wires were placed into the stainless‐steel column. Then, a nanostructured Cu‐Cr‐Al ternary layered double hydroxide/polythiophene coating was prepared on the inner surface of the stainless‐steel tube and on the surfaces of the stainless‐steel wires by a facile in situ electrodeposition method. The nanostructured coating exhibited enhanced long lifetime, good mechanical stability, high porosity, and large specific surface area compared with polythiophene and Cu‐Cr‐Al layered double hydroxide coatings. Under the optimal conditions, the limits of detection were in the range of 0.07–0.8 μg/L. This method showed good linearity for perphenazine and chlorpromazine in the ranges of 0.3–300 and 0.2–300 μg/L, respectively, with coefficients of determination more than 0.9982. The inter‐ and intra‐assay precisions (RSD%, n = 3) were in the ranges of 3.0–5.1 and 2.5–4.5% at three concentration levels of 5, 25 and 50 μg/L, respectively. Finally, the method was applied for the analysis of the drugs in human urine and plasma samples. [ABSTRACT FROM AUTHOR]

Background and Objective. In this study, turbo-ion spray as an interface of tandem mass spectrometry (MS/MS) was performed for sensitive and accurate quantification of chlorpromazine, haloperidol, levomepromazine, olanzapine, risperidone, and sulpiride in plasma samples. Methods. Separation was performed by gradient reversed phase high-performance liquid chromatography using a mobile phase containing ammonium formiate 2 mM, pH 2.7, and acetonitrile flowing through a Restek PFP Propyl C18 analytical column (50 mm×2.1 mm i.d.) with particle size of 5 µm, at a flow rate of 800 µL/min. Positive ion fragments were detected in multiple reaction monitoring (MRM) mode. Sample preparation was achieved by solid phase extraction (SPE) (Oasis HLB). Results. Mean extraction recoveries ranged from 82.75% to 100.96%. The standard calibration curves showed an excellent linearity, covering subtherapeutic, therapeutic, and toxic ranges. Intraday and interday validation using quality control (QC) samples were performed. The inaccuracy and imprecision were below 12% at all concentration levels. The limits of detection (LOD) and quantification (LOQ) for all analytes were under therapeutic ranges for all tested analytes. Thus, the proposed method was sensitive enough for the detection and determination of subtherapeutic levels of these antipsychotics in plasma samples. No interference of endogenous or exogenous molecules was observed and no carryover effects were recorded. Conclusion. According to the results, the proposed method is simple, specific, linear, accurate, and precise and can be applied for antipsychotic analysis in clinical routine. This method was applied for the determination of the tested antipsychotics in plasma samples taken from 71 individuals. [ABSTRACT FROM AUTHOR]

Short‐term treatment with large doses of corticosteroids can result in acute weakness of muscles in processes that have not yet been fully characterized. Corticosteroids have been shown to exert direct inhibitory action on the muscle‐type nicotinic acetylcholine receptor (AChR), and therefore can promote pharmacological muscle denervation. The mechanism of hydrocortisone (HC) blockage of AChR has not been fully established yet. It is uncommon for an electrically neutral molecule, for example, HC, to induce voltage‐dependent changes in AChR kinetics. Our experiments aimed to determine the source of voltage‐dependency in HC action. Wild‐type (WT) and αD200Q receptors were transiently expressed in HEK293 cells. Recordings were performed in either the presence or absence of HC. We showed that the D‐to‐Q substitution is capable of suppressing the voltage dependency in the HC‐induced block. We conclude that the distance between αD200 and the agonist‐binding site depends on the membrane potential. The voltage‐dependent changes of the αD200 position have not been considered yet. To our knowledge, the ability to induce voltage‐dependency in blocker action has not been shown previously for an amino acid located outside the transmembrane portion of the receptor. Possible mechanisms of HC block (allosteric and knocking) in WT and αD200Q receptors are discussed. [ABSTRACT FROM AUTHOR]

Abstract: Endocytosis is an essential function of cells, with key roles in the internalisation of nutrients, signal molecules and also drugs. Endocytic processes are therefore widely investigated in the context of drug delivery, and inhibitors of endocytic pathways have been used to provide information regarding uptake mechanisms of drug carrier materials. Here we describe studies in which two established inhibitors of clathrin dependent and independent endocytosis, chlorpromazine and methyl‐β‐cyclodextrin respectively, were employed to probe endocytic pathways of three cell lines chosen to represent tumour‐relevant or associated phenotypes: 3 T3 (fibroblasts), HCT 116 (colon cancer) and MGLVA‐1 (gastric cancer). For clathrin mediated endocytosis the data highlight that chlorpromazine inhibition of transferrin internalization, via clathrin dependent endocytosis, is cell and time dependent. We also show that inhibition of uptake is transient with a resumption of transferrin internalization after a maximal inhibition period. The same endocytosis inhibitors were used to probe the internalization of 50 and 100 nm carboxylated polystyrene nanoparticles (C‐PS‐NPs) as model drug delivery carriers. Flow cytometry data indicated that internalisation of C‐PS‐NPs varied considerably with the incubation time of cells with chlorpromazine or methyl‐β‐cyclodextrin, and that the effects were also markedly cell‐line dependent. These data highlight that the effects of endocytosis inhibitors on the internalisation pathways even of relatively simple nanoparticles are complex and interdependent. We suggest that mechanistic investigations of the endocytic processes which govern practical applications of nanoparticles for diagnostic and therapeutic applications should be considered on a cell, time and concentration basis. [ABSTRACT FROM AUTHOR]

Objective: To assess the impact of a multi-strategic, interdisciplinary intervention on antipsychotic and benzodiazepine prescribing in residential aged care facilities (RACFs). Design, setting: Prospective, longitudinal intervention in Australian RACFs, April 2014 - March 2016.Participants: 150 RACFs (with 12 157 residents) comprised the main participant group; two further groups were consultant pharmacists (staff education) and community pharmacies (prescribing data). Data for all RACF residents, excluding residents receiving respite or end-stage palliative care, were included.Intervention: A multi-strategic program comprising psychotropic medication audit and feedback, staff education, and interdisciplinary case review at baseline and 3 months; final audit at 6 months.Main Outcome Measure: Mean prevalence of regular antipsychotic and benzodiazepine prescribing at baseline, and at 3 and 6 months. Secondary measures: chlorpromazine and diazepam equivalent doses/day/resident; proportions of residents for whom drug was ceased or the dose reduced; prevalence of antidepressant and prn (as required) psychotropic prescribing (to detect any substitution practice).Results: During the 6-month intervention, the proportion of residents prescribed antipsychotics declined by 13% (from 21.6% [95% CI, 20.4-22.9%] to 18.9% [95% CI, 17.7-20.1%]), and that of residents regularly prescribed benzodiazepines by 21% (from 22.2% [95% CI, 21.0-23.5%] to 17.6% [95% CI, 16.5-18.7]; each, P < 0.001). Mean chlorpromazine equivalent dose declined from 22.9 mg/resident/day (95% CI, 19.8-26.0) to 20.2 mg/resident/day (95% CI, 17.5-22.9; P < 0.001); mean diazepam equivalent dose declined from 1.4 mg/resident/day (95% CI, 1.3-1.5) to 1.1 mg/resident/day (95% CI, 0.9-1.2; P < 0.001). For 39% of residents prescribed antipsychotics and benzodiazepines at baseline, these agents had been ceased or their doses reduced by 6 months. There was no substitution by sedating antidepressants or prn prescribing of other psychotropic agents.Conclusions: The RedUSe program achieved significant reductions in the proportions of RACF residents prescribed antipsychotics and benzodiazepines.Trial Registration: Australian New Zealand Clinical Trials, ACTRN12617001257358. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is characterized by deregulated activation of T and B cells, autoantibody production, and consequent formation of immune complexes. Liposomes with nonbilayer phospholipid arrangements (NPA), induced by chlorpromazine, procainamide, or manganese, provoke a disease resembling human lupus when administered to mice. These mice produce anti-NPA IgM and IgG antibodies and exhibit an increased number of TLR-expressing spleen cells and a modified gene expression associated with TICAM1-dependent TLR-4 signaling (including IFNA1 and IFNA2) and complement activation. Additionally, they showed a diminished gene expression related to apoptosis and NK cell activation. We hypothesized that such gene expression may be affected by miRNAs and so miRNA expression was studied. Twelve deregulated miRNAs were found. Six of them were common to the three lupus-like models. Their validation by qRT-PCR and TaqMan probes, including miR-342-3p, revealed that miR-155-5p and miR-200a-3p expression was statistically significant. Currently described functions for these miRNAs in autoimmune diseases such as SLE reveal their participation in inflammation, interferon production, germinal center responses, and antibody maturation. Taking into account these findings, we propose miR-155-5p and miR-200a-3p, together with the anti-NPA antibodies, as key players in the murine lupus-like models and possible biomarkers of the human SLE. [ABSTRACT FROM AUTHOR]

Roman chamomile ( Chamaemelum nobile or Anthemis nobilis) has traditionally been used for health care, health maintenance and medicinal purposes, and the essential oil obtained from the flowers is used as a basic ingredient for aromatherapy. Roman chamomile essential oil (CHA) produces psychostimulant-like effects, such as the ambulation-promoting effect, on mouse behaviour. However, mechanisms underlying the effects of CHA remain unclear. The present study aimed to identify the constituents responsible for the ambulation-promoting effect of CHA and to elucidate a possible neuronal mechanism. GC/MS analysis revealed that isobutyl angelate, isoamyl angelate and 2-methylbutyl isobutyrate were the major constituents of CHA. These compounds significantly promoted mouse ambulation, and were thus identified as the major active constituents for the ambulatory effect of CHA. The ambulatory effects were attenuated by chlorpromazine and haloperidol, suggesting that the neurotransmitter dopamine is involved in the ambulation-promoting effects of these constituents similar to already-known psychostimulants. The results suggest that CHA can change a mental condition, at least in part, through the CNS effects of the constituents identified in the current study. The results also suggest that mental effects of CHA are largely different from those of other Roman chamomile preparations due to the composition difference. [ABSTRACT FROM AUTHOR]

Background and Purpose: Visceral hypersensitivity is responsible for pathogenesis of irritable bowel syndrome (IBS). Therefore, its prevention can help avoid abdominal pain and discomfort in IBS. To find candidate drugs for visceral hypersensitivity, we screened existing medicines for their ability to prevent visceral sensitivity induced by colorectal distension (CRD) in rats and identified chlorpromazine, a typical antipsychotic drug, as a candidate compound. In this study, we investigated the effect of chlorpromazine on visceral hypersensitivity.Experimental Approach: Visceral sensitivity (visceromotor response) was monitored by measuring the electrical activity of the abdominal external oblique muscle contraction in response to CRD using a barostat apparatus. Visceral hypersensitivity was induced by a colonic instillation of sodium butyrate or acetic acid in neonates.Key Results: Oral administration of chlorpromazine suppressed butyrate-induced visceral hypersensitivity to CRD. Interestingly, atypical antipsychotic drugs, quetiapine and risperidone, ameliorated butyrate-induced visceral hypersensitivity, whereas the typical antipsychotic drugs, haloperidol and sulpiride, did not. Pharmacological analysis using specific inhibitors showed that a selective 5-HT2A receptor antagonist, ketanserin, suppressed butyrate-induced visceral hypersensitivity, whereas a selective dopamine D2 receptor antagonist, L-741626, did not. Furthermore, the 5-HT2A receptor agonist AL-34662 stimulated visceral sensitivity to CRD in healthy control rats but not in butyrate-treated rats. These findings suggest that increased 5-HT levels in the colon contribute to the induction of visceral hypersensitivity.Conclusions and Implications: Our results indicate that chlorpromazine ameliorates visceral hypersensitivity and that the 5-HT2A receptor is a potential therapeutic target for treating abdominal pain and discomfort in IBS. [ABSTRACT FROM AUTHOR]

This study investigated the modulatory and chemopreventive benefit of amlodipine ( AML), a dihydropyridine calcium channel antagonist, against neurobehavioural abnormalities ( NAs) associated with chlorpromazine ( CPZ) toxicity in mice. Adult mice were divided into five groups of six animals/group. Group 1 (control) was administered saline (10 mL/kg i.p.). Group 2 received CPZ (2 mg/kg i.p.). Groups 3 and 4 received bromocriptine ( BMC, 2.5 mg/kg s.c.) and AML (1 mg/kg s.c.), respectively, while group 5 received their combination. Groups 3-5 later received CPZ 30 min after initial treatments. Animals were subjected to neurobehavioural tests and euthanized 18 h later. CPZ-induced NAs were characterized by significant increase ( P < 0.001) in cataleptic behaviour and lowered ( P < 0.05) spontaneous activity reaction time in mice. There were also significant ( P < 0.001) increases in malondialdehyde levels and decreased locomotion plus learning and memory parameters ( P < 0.05-0.001). AML pretreatment alone did not alleviate CPZ-induced motor deficits in the mice. While pretreatment with BMC alone attenuated CPZ-associated catalepsy, its combination with AML further protected mice against NAs. Furthermore, BMC pretreatment did not affect CPZ-induced increase in malondialdehyde level, but AML or BMC+ AML significantly ( P < 0.05) decreased malondialdehyde in the CPZ-treated rats. Reduced glutathione levels and activities of superoxide dismutase and catalase remained elevated in all treatment groups. In conclusion, data from this study suggest possible chemopreventive benefit of AML alone or in combination with BMC against CPZ-associated neurobehavioural deficits. The ameliorative effect of AML may be related to its antioxidant and/or calcium channel blocking property. [ABSTRACT FROM AUTHOR]

Objective The effect of antipsychotic medication on brain structure remains unclear. Given the prevalence of weight gain as a side-effect, body mass index ( BMI) change could be a confounder. Method Patients with first-episode psychosis ( n = 78) and healthy controls ( n = 119) underwent two 1.5T MRI scans with a 1-year follow-up interval. siena ( fsl 5.0) was used to measure whole-brain volume change. Weight and height were measured at both time points. Antipsychotic medication use at baseline and follow-up was converted into chlorpromazine equivalent dose and averaged. Results Patients did not show significantly larger brain volume loss compared with healthy controls. In the whole sample ( n = 197), BMI change was negatively associated with brain volume change (β = −0.19, P = 0.008); there was no interaction effect of group. Among patients, higher antipsychotic medication dosage was associated with greater brain volume loss (β = −0.45, P < 0.001). This association was not affected by adjusting for BMI change. Conclusion Weight gain was related to brain volume reductions to a similar degree among patients and controls. Antipsychotic dosage-related reductions of brain volume were not confounded by BMI change. Generalizability to contexts involving severe weight gain needs to be established. Furthermore, disentangling effects of medication from illness severity remains a challenge. [ABSTRACT FROM AUTHOR]

Studies on Schizophrenia so far reveal a complex picture of neurological malfunctioning reported to be strongly associated with DAOA. Detailed sequence analyses proved DAOA as a primate specific gene having conserved gene desert region on both upstream and downstream region. The analyses of 10 MB chromosomal region of primates, birds, rodents, and reptiles having DAOA evidenced the conserved part in primates and in the rest of species, while DAOA is only present in primates. DAOA has four isoforms having one interaction partner DAO. Protein-protein analyses of four DAOA isoforms with DAO were performed individually and find potential interacting residues computationally. It was observed that molecular docking of approved FDA drugs revealed efficient results but there was no common drug with effective binding to all DAOA isoforms. Library of compounds was constructed by virtual screening of 2D similarity search against recommended SZ drugs in conjunction with their physiochemical properties. Molecular docking resulted in six novel compounds exhibiting maximum binding affinity with selected four DAOA isoforms. However not the entire schizophrenic population responds to the single drug and interestingly in this study six novel compounds having promising results and same binding site to that DAOA that may be used to interact with DAO against four DAOA isoforms were observed. [ABSTRACT FROM AUTHOR]

Background Hiccups are familiar to everyone, but remain poorly understood. Acute hiccups can often be terminated by physical manoeuvres. In contrast, persistent and intractable hiccups that continue for days or months are rare, but can be distressing and difficult to treat. Aim To review the management of hiccups, including a systematic review of reported efficacy and safety of pharmacological treatments. Methods Available articles were identified using three electronic databases in addition to hand searching of published articles. Inclusion criteria were any reports of pharmaceutical therapy of 'hiccup(s)', 'hiccough(s)' or 'singultus' in English or German. Results Treatment of 341 patients with persistent or intractable hiccups was reported in 15 published studies. Management was most effective when directed at the underlying condition. An empirical trial of anti-reflux therapy may be appropriate. If the underlying cause is not known or not treatable, then a range of pharmacological agents may provide benefit; however, systematic review revealed no adequately powered, well-designed trials of treatment. The use of baclofen and metoclopramide are supported by small randomised, placebo-controlled trials. Observational data suggest that gabapentin and chlorpromazine are also effective. Baclofen and gabapentin are less likely than standard neuroleptic agents to cause side effects during long-term therapy. Conclusions This systematic review revealed no high quality data on which to base treatment recommendations. Based on limited efficacy and safety data, baclofen and gabapentin may be considered as first line therapy for persistent and intractable hiccups, with metoclopramide and chlorpromazine in reserve. [ABSTRACT FROM AUTHOR]

Conventional two-dimensional (2D) monolayer cultures of HepaRG cells allow in vitro maintenance of many liver-specific functions. However, cellular dedifferentiation and functional deterioration over an extended culture period in the conventional 2D HepaRG culture have hampered its applications in drug testing. To address this issue, we developed tethered spheroids of HepaRG cells on Arg-Gly-Asp (RGD) and galactose-conjugated substratum with an optimized hybrid ratio as an in vitro three-dimensional (3D) human hepatocyte model. The liver-specific gene expression level and drug metabolizing enzyme activities in HepaRG-tethered spheorids were markedly higher than those in 2D cultures throughout the culture period of 7 days. The inducibility of three major cytochrome P450 (CYP) enzymes, namely CYP1A2, CYP2B6 and CYP3A4, was improved in both mRNA and activity level in tethered spheroids. Drug-induced cytotoxic responses to model hepatotoxins (acetaminophen, chlorpromazine and ketoconazole) in tethered spheroids were comparable to 2D cultures as well as other studies in the literature. Our results suggested that the HepaRG-tethered spheroid would be an alternative in vitro model suitable for drug safety screening. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Chlorpromazine is a phenothiazine-derived antipsychotic drug ( APD) that inhibits clathrin-mediated endocytosis ( CME) in cells by an unknown mechanism. We examined whether its action and that of other APDs might be mediated by the GTPase activity of dynamin. Eight of eight phenothiazine-derived APDs inhibited dynamin I ( dynI) in the 2-12 µ m range, the most potent being trifluoperazine ( IC50 2.6 ± 0.7 µ m). They also inhibited dynamin II ( dynII) at similar concentrations. Typical and atypical APDs not based on the phenothiazine scaffold were 8- to 10-fold less potent (haloperidol and clozapine) or were inactive (droperidol, olanzapine and risperidone). Kinetic analysis showed that phenothiazine-derived APDs were lipid competitive, while haloperidol was uncompetitive with lipid. Accordingly, phenothiazine-derived APDs inhibited dynI GTPase activity stimulated by lipids but not by various SH3 domains. All dynamin-active APDs also inhibited transferrin (Tfn) CME in cells at related potencies. Structure-activity relationships ( SAR) revealed dynamin inhibition to be conferred by a substituent group containing a terminal tertiary amino group at the N2 position. Chlorpromazine was previously proposed to target AP-2 recruitment in the formation of clathrin-coated vesicles ( CCV). However, neither chlorpromazine nor thioridazine affected AP-2 interaction with amphiphysin or clathrin. Super-resolution microscopy revealed that chlorpromazine blocks neither clathrin recruitment by AP-2, nor AP-2 recruitment, showing that CME inhibition occurs downstream of CCV formation. Overall, potent dynamin inhibition is a shared characteristic of phenothiazine-derived APDs, but not other typical or atypical APDs, and the data indicate that dynamin is their likely in-cell target in endocytosis. [ABSTRACT FROM AUTHOR]

We report a multi-objective de novo design study driven by synthetic tractability and aimed at the prioritization of computer-generated 5-HT2B receptor ligands with accurately predicted target-binding affinities. Relying on quantitative bioactivity models we designed and synthesized structurally novel, selective, nanomolar, and ligand-efficient 5-HT2B modulators with sustained cell-based effects. Our results suggest that seamless amalgamation of computational activity prediction and molecular design with microfluidics-assisted synthesis enables the swift generation of small molecules with the desired polypharmacology. [ABSTRACT FROM AUTHOR]

A hiccup is a myoclonic jerk of the diaphragm, and cases of hiccups may last for more than 48 hours (persistent hiccups) or even more than 2 months (intractable hiccups). Current pharmacologic treatment of persistent or intractable hiccups mainly includes antidopaminergic drugs. We describe the case of a 60-year-old man with a recent diagnosis of right insular ischemic stroke who presented with frequent, intense, and disabling hiccups for more than 1 month. As diagnosis of poststroke hiccups was assumed, the patient was treated over the next 6 months with adequate doses of various antipsychotic drugs commonly used for the treatment of hiccups; however, all were discontinued because of adverse effects. Indeed, dyskinesia after chlorpromazine (up to 75 mg/day for 4 wks), as well as somnolence and dyskinesia after haloperidol (up to 6 mg/day for 6 wks), somnolence after gabapentin (up to 1800 mg/day for 8 wks), and severe somnolence and hypotension after baclofen (up to 50 mg/day for 6 wks) were reported. The patient was then prescribed tetrabenazine at a starting dose of 12.5 mg twice/day (25 mg/day), with a nearly complete remission of the hiccup symptomatology after ~6 weeks, when a daily dose of 150 mg was reached. We therefore hypothesize that a supratentorial lesion may disrupt the modulation of dopaminergic pathways involved in the regulation of medullar centers responsible for the hiccup reflex. To our knowledge, this is the first case report of poststroke hiccups responding to tetrabenazine. The dramatic response of our patient to tetrabenazine monotherapy suggests that this drug may be a valuable pharmacologic alternative for patients with hiccups after stroke who are intolerant or unresponsive to classic antipsychotic agents. [ABSTRACT FROM AUTHOR]