Administration Of Chlorpromazine Research Articles

Chlorpromazine-Induced Neurological Symptoms Mimicking Stroke in an Elderly Patient with Intractable Hiccups: A Case Report

Background: Chlorpromazine, a widely utilized antipsychotic medication, has been recognized for its efficacy in treating intractable hiccups through its antagonistic action on histamine H1, dopamine D2, and muscarinic M1 receptors. Despite its therapeutic benefits, there is a spectrum of potential side effects, including neurological symptoms such as drug-induced stuttering, which poses diagnostic challenges and may lead to unnecessary investigations. Objective: This case study aims to explore the paradoxical effect of chlorpromazine, which, while effectively treating an 80-year-old male patient's intractable hiccups, induced slurred speech and drowsiness, symptoms that resolved upon cessation of the drug. Methods: A comprehensive evaluation was conducted, involving the patient's clinical presentation, treatment regimen, and the temporal relationship between medication administration and symptom onset. Investigations included a complete blood count, C-reactive protein, liver function tests, COVID-19 antigen test, cardiac workup, and brain MRI. Treatment response and side effects were meticulously documented, with follow-up to assess the resolution of symptoms. Results: Following the administration of chlorpromazine (50mg orally), the patient's hiccups ceased, but he subsequently developed slurred speech and drowsiness. These symptoms were not present upon initial examination and resolved completely following the discontinuation of chlorpromazine. The brain MRI conducted to explore potential neurological causes was found to be insignificant, reinforcing the diagnosis of drug-induced neurological symptoms. Conclusion: While chlorpromazine remains a valuable treatment for intractable hiccups, healthcare providers must be vigilant about its potential to induce neurological symptoms. This case highlights the importance of recognizing drug-induced side effects to avoid unnecessary diagnostic procedures and emphasizes the need for ongoing research into the mechanisms underlying such adverse reactions.

Proteasome localization and activity in pig brain and in vivo small molecule screening for activators.

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

Investigation of nuclear DNA content and cell cycle phases in rat liver cells under chlorpromazine administration

Hepatotoxicity of antipsychotic drugs remains an urgent problem of modern medicine. Therefore, the purpose of the study was to investigate the nuclear DNA content and cell cycle phases of rat liver cells under Сhlorpromazine administration at doses ranging from 3.5 mg/kg to 28 mg/kg for 30 and 60 days. The study was conducted on 60 sexually mature female rats. Chlorpromazine was administered once daily for 30 and 60 days at doses of 3.5 mg/kg, 7 mg/kg, 14 mg/kg, 21 mg/kg and 28 mg/kg. The DNA content in the nuclei of rat liver cells was determined by flow cytometry. Cytological analysis of cells was performed using FloMax software (Partec, Germany), where the percentage of nuclei in the G0G1 interval of the cell cycle, in the S phase, G2M interval, and the apoptosis index – SUB-G0G1 area on DNA histograms were determined. Statistical processing of the results was performed using the Mann-Whitney U test. The results of the study showed that Сhlorpromazine has a dose-dependent hepatotoxic effect: with an increase in the dose of this drug in rats from 7 to 28 mg/kg, the percentage of fragmented nuclei in liver tissue significantly increased, which is a sign of hepatocyte death by apoptosis. It was found that Сhlorpromazine at a dose of 3.5 mg/kg did not increase hepatocyte apoptosis, while at a dose of 21 and 28 mg/kg the drug showed the highest hepatotoxicity, increasing the level of apoptosis by 1.9 and 2.1 (p˂0.05) times, respectively. The hepatotoxic effect is enhanced by the use of Сhlorpromazine for 60 days, which is manifested in a significant increase in hepatocyte nuclear DNA fragmentation, which, in our opinion, should be taken into account when conducting long-term therapy in patients.

Morphological changes in the liver of rats after administration of chlorpromazine, depending on the dose and duration of administration

Chlorpromazine (CPZ) remains a widely used drug in psychiatric practice today. The drug has a hepatotoxic effect, but the possible mechanisms of this side effect have not yet been fully elucidated. The aim of the study was to determine morphological changes in rat liver tissue under chronic toxic effects of chlorpromazine, depending on the dose and duration of its administration. The study was conducted on 60 sexually mature male rats. CPP was administered intragastrically at different doses (3.5, 7.0, 14.0 and 21.0 mg/kg) for 30 and 60 days. The material was fixed in a 10 % solution of neutral formalin (pH 7.2-7.4) for 24-48 hours, then passed through alcohols of increasing concentration and embedded in paraffin. Serial sections (6-7 µm thick) were prepared from the paraffin blocks and stained with hematoxylin-eosin and picrofuchsin by Van Gieson to determine the degree of fibrotic changes in liver tissue, as well as with Giemsa III to detect fatty degeneration of hepatocytes. The microscopic structure of the hepatic parenchyma was studied using an OLIMPUS BX41 light microscope at 100, 200 and 400x magnification. Morphometric parameters of structural changes were determined using an ocular grid and Image Tulsa 3.6 software. The data were statistically processed by descriptive statistics using the Microsoft Office Excel 2010 spreadsheet processor. When CPZ was administered in different doses and duration, pathological changes of varying severity developed in the liver tissue of rats. In the liver tissue, signs of intracellular and intra-tubular cholestasis are found mainly in the central lobes, accompanied by focal desquamation and proliferation of the biliary epithelium, formation of small-focal, less frequently zonal necrosis of hepatocytes, inflammatory infiltration of portal tracts with its spread to the interlobular stroma and parenchyma. Mitotically active binucleated hepatocytes are the key to the reparative process. Periductal fibrosis develops in the portal sections, marginal proliferation of the bile ducts, hepatocytes with signs of granular and/or fatty dystrophy are noted. In the central veins and vessels of the portal areas, moderate initial sclerotic changes were found, signs of their capillarisation in sinusoids, and the endothelium of the vessels had focal destructive changes. In all portal zones, proliferation of bile ducts and formation of bile pseudo-ducts were observed. Thus, the analysis of the morphometric study data showed that within 60 days of CPZ administration there is a significant increase in the relative volume of connective tissue and stromal-parenchymal index due to a significant decrease in the volume of hepatocytes.

Role of the heat shock protein family in chlorpromazine-induced cardiotoxicity.

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.

Chlorpromazine as Treatment for Refractory Agitation Associated with Pediatric Delirium.

Delirium and agitation can be devastating and prolong the length of hospitalization. As part of our continuous improvement efforts, we implemented the use of intermittent chlorpromazine therapy to target refractory agitation associated with hyperactive or mixed delirium (RAA-D). The purpose of this study was to evaluate the effectiveness of chlorpromazine on RAA-D and delirium symptoms as well as any adverse effects in critically ill children. Retrospective chart review was conducted for children admitted to the pediatric intensive care unit who were treated with chlorpromazine for RAA-D from March 2017 to January 2019. The primary end point was to determine differences in Cornell Assessment for Pediatric Delirium (CAPD) and State Behavioral Scale (SBS) scores 24 hours before and after chlorpromazine administration. The secondary end points were the 24-hour cumulative dosing of narcotic and sedative agents before and after chlorpromazine administration and adverse events associated with chlorpromazine use. Twenty-six patients were treated with chlorpromazine for RAA-D; 16 (61.5%) were male with a median age of 14.5 months (IQR, 6-48). The mean CAPD (n = 24) and median SBS (n = 23) scores were significantly lower 24 hours after chlorpromazine use when compared to baseline scores, 12 vs 8.9 (p = 0.0021) and 1 vs -1, (p = 0.0005) respectively. No significant adverse effects were observed. Chlorpromazine use in critically ill children with RAA-D was helpful for managing symptoms without adverse events. Further investigation is needed to evaluate the use of chlorpromazine to treat RAA-D to avoid long-term use of an antipsychotic.

A comparison of activity data generated from cardiovascular telemetry studies - With quantitative open field locomotor studies in Wistar Han rats

Compound-mediated locomotion changes, conducted via open field infrared photobeam breaks, are an important common component of neurological assessments conducted in safety pharmacology studies. In addition to open field locomotor activity assessments, activity data (derived from changes in signal strength) from cardiovascular (CV) telemetry studies can also be an alternative method potentially used to assess locomotor effects. However, comparisons of these two methods have not been extensively characterized. The goal of this work was to compare these two methodologies to assess activity in rats using reference compounds known to have central nervous system (CNS)-stimulant (preladenant) or CNS-depressant (chlorpromazine) effects. Open field activity was conducted using the Kinder Scientific Motor Monitor system and data were collected for 30 min at each drug's expected time of maximum plasma exposure (Tmax). Telemetry-based CV assessment data were continuously acquired using DSI radiotelemetry instrumented animals for 24 h postdose (HPD). Drugs were administered during the lights-on period for both study types. Administration of preladenant caused increases in activity within 0.5–2 HPD for both methods. While administration of chlorpromazine caused decreases in activity in the infrared beam-based open field assessment (1.0–1.5 HPD), there was no effect on telemetry-derived activity during a similar time period. However, telemetry-derived decreases in activity were observed during the lights-off period (16–20 HPD), suggesting CNS-depressant compounds may be mischaracterized if the optimal dose administration time is not selected based on the light/dark cycle and pharmacokinetics. Overall, these results suggest that telemetry-based activity assessment is capable of detecting CNS-stimulant effects of compounds.

A dual dopaminergic therapy with L-3,4-dihydroxyphenylalanine and chlorpromazine for the treatment of blepharospasm, a focal dystonia: Possible implications for striosomal D1 signaling

Impairment of balanced activity between dopamine D1 and D2 receptor functions in the striatum, particularly in striatal functional subdivisions (i.e., striosome and matrix compartments), has been proposed to underlie dystonia genesis. This study was undertaken to examine the therapeutic effect of dual dopaminergic modulation with L-3,4-dihydroxyphenylalanine (L-DOPA) and chlorpromazine (CPZ) in patients with blepharospasm, a focal dystonia. For this purpose, Dopacol tablets™ (L-DOPA 50 mg plus carbidopa 5 mg) and Wintermin™ (CPZ phenolphthalinate 180 mg/g) were used. Clinical evaluations were performed before and after an 8-week drug treatment interval using the Visual Analog Scale (VAS), Blepharospasm Disability Index (BSDI), modified VAS (mVAS), and Jankovic Rating Scale (JRS). The data were analyzed using non-parametric statistics. Results showed that in patients (n = 7) with blepharospasm, dystonia symptoms were significantly alleviated by the administration of both Dopacol tablets™ (one tablet × 3/day) and CPZ (5 mg × 3/day), as determined using the VAS, BSDI, mVAS, and JRS. In contrast, there was no improvement of dystonia symptoms in patients (n = 7) who ingested Dopacol tablets™ (one tablet × 3/day) alone, nor in those (n = 7) who ingested CPZ (5 mg × 3/day) alone. Thus, dual pharmacotherapy with L-DOPA and CPZ can exert a therapeutic effect on blepharospasm, suggesting that dystonia symptoms can be attenuated through dopaminergic modulation with inducing an increase in striatal D1-signals. Since dopamine D1 receptors are heavily enriched in the striosome compartment in the “human” striatum, our results also suggest that striosomal loss of D1-signaling may be important in the pathogenesis of dystonia.

Hiccups as the first presentation of secondary adrenal insufficiency associated with advanced cervical cancer.

SummaryHiccups are a common symptom characterized by intermittent spasmodic contraction of the diaphragm. Most hiccups are transient, but some are refractory. Patients with intractable hiccups often have abnormalities of the diaphragm, medulla oblongata, and lesions affecting nerve fibers connecting them. Moreover, electrolyte abnormalities, including hyponatremia, are frequently observed in patients with intractable hiccups. Adrenal insufficiency (AI) is one of the causes of hyponatremia. However, hiccups are not commonly the first presentation. Herein, we describe a case of a 45-year-old woman complaining of refractory hiccups. The patient was initially diagnosed with hiccups associated with cervical cancer metastasis to the liver and peritoneum. The administration of chlorpromazine did not have a beneficial effect on her hiccup. Fasting hypoglycemia and hyponatremia were later found. Her serum cortisol level was low without an elevation of adrenocorticotropic hormone level. MRI of the pituitary gland showed metastatic lesion in the pituitary gland and stalk. Thus, the patient was diagnosed with secondary AI due to cervical cancer metastasis to the pituitary gland and stalk. Administration of hydrocortisone improved her hiccups with the normalization of serum sodium level. Therefore, differential diagnosis in advanced cancer patients with hiccups should include AI-induced hyponatremia.Learning pointsHiccups could be the first manifestation of adrenal insufficiency (AI).Hiccups in patients with AI are often mediated by hyponatremia.Hyponatremia is less frequent in secondary AI than in primary AI. However, hyponatremia can result from increased antidiuretic hormone due to loss of cortisol.The differential diagnosis should include AI-induced hyponatremia if hiccups occur in patients with advanced cancer, as metastasis to adrenal gland or pituitary gland could cause AI.

The Effectiveness of Chlorpromazine to Decrease the Level of Tumor Necrosis Factor-Alpha Serum in Schizophrenic Patients with Coronavirus Disease 2019

BACKGROUND: The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus-2. The COVID-19 pandemic has also had an impact on mental health, including those with schizophrenia (SCH). There were 131 inpatient schizophrenic patients who were confirmed positive for COVID-19 at Dadi Makassar Hospital, South Sulawesi, Indonesia, but all of these patients did not experience any clinical symptoms of COVID-19. Chlorpromazine as an antipsychotic also has antiviral and anti-inflammatory effects in schizophrenic patients with COVID-19, and the schizophrenic neuroinflammatory is very likely to occur in patients with COVID-19 infection. AIM: The researchers tried to examine the effectiveness of chlorpromazine on serum TNF-values in schizophrenic patients with COVID-19. METHODS: This research is a nested case–control study. The study was conducted on schizophrenic patients with mild and asymptomatic cases of COVID-19 at Dadi Mental Hospital with a sample of 40 patients compared to 42 schizophrenic patients who were not COVID-19. Study subjects received chlorpromazine 100 mg/day for 4 weeks. Serum tumor necrosis factor-alpha (TNF-α) concentrations were measured by enzyme-linked immunosorbent assays when COVID-19 was first confirmed and after 4 weeks. Positive and negative syndrome scale (PANSS) and clinical global impression SCH (CGI-SCH) examinations were also performed to measure the clinical symptoms of SCH. RESULTS: The comparison of baseline TNF-serum levels that increased in the schizophrenic group with COVID-19 was 9.33 pg/ml higher, compared to the schizophrenic group without COVID-19. The decrease in TNF-levels in the schizophrenic group with COVID-19 of 7.96 pg/ml (p &lt; 0.001) indicated an improvement in TNF-serum levels at week 4. Meanwhile, there was no significant decrease in serum TNF- levels in the non-COVID-19 schizophrenic group (p &gt; 0.05). CONCLUSION: The serum TNF-value of schizophrenic patients with COVID-19 is higher than schizophrenic patients without COVID-19. Coadministration of chlorpromazine, antipsychotics, and COVID-19 therapy reduces serum TNF- values in schizophrenic patients with COVID-19. The administration of chlorpromazine and antipsychotic in therapeutic doses reduced the total PANSS and CGI-SCH values.

The efficacy and safety of intravenous chlorpromazine treatment for sleep disturbance in patients with incurable cancer, with oral administration difficulty: a 1-week, prospective observational study.

Sleep disturbance is a common psychiatric disorder in patients with cancer. However, many patients with incurable cancer have difficulty receiving oral administrations, which limits treatment options during disease progression. The aim of the present study was to assess the efficacy and safety of intravenous chlorpromazine treatment for sleep disturbances in patients with incurable cancer, with oral administration difficulty. A prospective observational study was conducted among 52 patients with incurable cancer, with oral administration difficulty received daily intravenous chlorpromazine treatment for sleep disturbance from 2018 to 2020 at a single-unit university hospital. St. Mary's Hospital Sleep Questionnaire (SMHSQ) compared sleep before and after intravenous chlorpromazine administration. The primary endpoint was the efficacy rate of sleep quality [defined as a score of ≥4 (range, 1-6)] 7 days after receiving chlorpromazine. Beginning the day after receiving chlorpromazine, sleep quality significantly improved from a mean score of 1.6±0.7 to 4.3±1.2, and 80.8% [95% confidence interval (CI): 66.5-89.1%] and 69.2% (95% CI: 53.8-79.6%) of patients reported good sleep quality 3 and 7 days after receiving chlorpromazine, respectively. The patients reported increased total sleep time and fewer awakenings during sleep, and satisfaction with sleep and difficulty falling asleep improved. Some adverse events occurred [akathisia (n=2), dry mouth (n=2), and somnolence (n=3)]; all were Grade 1 (CTCAE ver5.0) and improved with chlorpromazine discontinuation. Systolic blood pressure and heart rate displayed no clinically problematic changes. Intravenous chlorpromazine has a high tolerability and effectively treats sleep disturbances in patients with incurable cancer with oral administration difficulties.

A Prepubertal Girl with Delusions of Pregnancy.

A Prepubertal Girl with Delusions of Pregnancy.

Involvement of clathrin-dependent endocytosis in cellular dsRNA uptake in aphids

RNAi is an essential technology for studying gene function in eukaryotes, and is also considered to be a potential strategy for pest control. However, the mechanism behind the cellular uptake of dsRNA in aphids, a group of important agricultural sucking pests, remains unknown. Here, using the pea aphid Acyrthosiphon pisum as model for aphids, we identified two core genes of clathrin-dependent endocytosis (CDE), Apchc and Apvha16. We confirmed that expression of Apchc, Apvha16 and RNAi core component genes (ApAgo2, ApDcr2 and ApR2d2) were simultaneously induced at 12 h after feeding dsRNA. By using an RNAi-of-RNAi approach, we demonstrated that suppression of Apchc and Apvha16 transcripts by RNAi significantly impaired RNAi efficiency of selected reporter genes (RGs), including ApGNBP1, Apmts and Aphb, suggesting the involvement of CDE in cellular dsRNA uptake in aphids. Further confirmation was also provided using two inhibitors, chlorpromazine (CPZ) and bafilomycin A1 (BafA1). Administration of CPZ and of BafA1 both led to an impaired silencing efficiency of the RGs in the pea aphid. Finally, these RNAi-of-RNAi results were reconfirmed in the peach aphid Myzus persicae. Taking these findings together, we conclude that CDE is involved in cellular dsRNA uptake in aphids.

Anti-hyperprolactinemic activities of aqueous extract of Uvaria chamae (P. Beauv) roots and associated biochemical changes in chlorpromazine-induced hyperprolactinemic female Wistar rats

Ethnopharamcological relevanceThe age-long folkloric use of Uvaria chamae roots in the management of nipple discharge that is not related to pregnancy, childbirth or nursing but as a result of excessive production of prolactin (hyperprolactinemia) is yet to be substantiated with scientific data. Aim of the studyThis study investigated the anti-hyperprolactinemic activities of aqueous extract of Uvaria chamae roots (AEUCR) and associated biochemical changes in chlorpromazine (CPZ)-induced hyperprolactinemic female Wistar rats. Materials and methodsA total of sixty female rats (207.40 ± 2.69 g) were assigned into 6 groups: A-F. Animals in Group A received 0.5 ml of distilled water only whilst the 7 days CPZ-treated female rats (to induce hyperprolactinemia) in groups B, C, D, E, and F also received distilled water, 2.5 mg/kg body weight of bromocriptine (reference drug), 0.71, 1.41 2.83 mg/kg body weight of AEUCR for 28 days. ResultsAEUCR contained a total of 15 (75%) amino acids with seven (46.67%) being essential amino acids and eight (53.33%) as non-essential amino acids. Administration of CPZ increased (p < 0.05) the levels of prolactin and testosterone, and reduced (p < 0.05) the levels of estradiol, progesterone, follicle stimulating hormone (FSH), luteinizing hormone (LH), dopamine, triiodothyronine (T3) and tetraiodothyroxine (T4). Chlorpromazine also increased the levels of serum urea, creatinine, total protein, albumin, globulin, bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) of the animals. In contrast, AEUCR significantly (p < 0.05) reduced the CPZ-induced increases in the levels of prolactin and testosterone, and increased the levels of CPZ-induced reduction in the progesterone, estradiol, FSH, LH, dopamine, T3 and T4. The AEUCR also reversed (p < 0.05) the CPZ-induced related increases in the levels of urea, creatinine, total protein, albumin, globulin, bilirubin, ALT, AST and ALP similar to the trends in the distilled water- and bromocriptine-treated controls. The CPZ-induced remarkable increase in the size of lactating alveolus and lactiferous duct distribution in the mammary gland were restored to normal tubule-alveolar female pattern mammary glands, composed of branching ducts and small alveoli budding off the ducts. ConclusionThe study concluded that aqueous extract of Uvaria chamae root exhibited anti-hyperprolactinemic activity by restoring prolactin and dopamine levels and tubule-alveolar female pattern in female rats. It also ameliorated CPZ-induced changes in the liver and kidney function indices. This study justifies the folkloric use of Uvaria chamae root in the management of abnormal discharge by the nipples that is unrelated to pregnancy, childbirth and nursing.

Constitutive activity of dopamine receptor type 1 (D1R) increases CaV2.2 currents in PFC neurons.

Alterations in dopamine receptor type 1 (D1R) density are associated with cognitive deficits of aging and schizophrenia. In the prefrontal cortex (PFC), D1R plays a critical role in the regulation of working memory, which is impaired in these cognitive deficit states, but the cellular events triggered by changes in D1R expression remain unknown. A previous report demonstrated that interaction between voltage-gated calcium channel type 2.2 (CaV2.2) and D1R stimulates CaV2.2 postsynaptic surface location in medial PFC pyramidal neurons. Here, we show that in addition to the occurrence of the physical receptor-channel interaction, constitutive D1R activity mediates up-regulation of functional CaV2.2 surface density. We performed patch-clamp experiments on transfected HEK293T cells and wild-type C57BL/6 mouse brain slices, as well as imaging experiments and cAMP measurements. We found that D1R coexpression led to ∼60% increase in CaV2.2 currents in HEK293T cells. This effect was occluded by preincubation with a D1/D5R inverse agonist, chlorpromazine, and by replacing D1R with a D1R mutant lacking constitutive activity. Moreover, D1R-induced increase in CaV2.2 currents required basally active Gs protein, as well as D1R-CaV2.2 interaction. In mice, intraperitoneal administration of chlorpromazine reduced native CaV currents' sensitivity to ω-conotoxin-GVIA and their size by ∼49% in layer V/VI pyramidal neurons from medial PFC, indicating a selective effect on CaV2.2. Additionally, we found that reducing D1/D5R constitutive activity correlates with a decrease in the agonist-induced D1/D5R inhibitory effect on native CaV currents. Our results could be interpreted as a stimulatory effect of D1R constitutive activity on the number of CaV2.2 channels available for dopamine-mediated modulation. Our results contribute to the understanding of the physiological role of D1R constitutive activity and may explain the noncanonical postsynaptic distribution of functional CaV2.2 in PFC neurons.

The role of olfactory transport in the penetration of manganese oxide nanoparticles from blood into the brain

There is no doubt that various nanoparticles (NPs) can enter the brain from the nasal cavity. It is assumed that NPs can penetrate from blood into the central nervous system (CNS) only by breaking the blood–brain barrier (BBB). The accumulation of NPs in CNS can provoke many neurological diseases; therefore, the understanding of its mechanisms is of both academic and practical interest. Although hitting from the surface of the lungs into the bloodstream, NPs can accumulate in various mucous membranes, including the nasal mucosa. Thus, we cannot rule out the ability of NPs to be transported from the bloodstream to the brain through the olfactory uptake. To test this hypothesis, we used paramagnetic NPs of manganese oxide (Mn3O4-NPs), whose accumulation patterns in the mouse brain were recorded using T1-weighted magnetic resonance imaging. The effect of intranasal application of endocytosis and axonal transport inhibitors on the brain accumulation patterns of intranasally or intravenously injected Mn3O4-NPs was evaluated. A comparative analysis of the results showed that the transport of Mn3O4-NPs from the nasal cavity to the brain is more efficient than their local permeation through BBB into CNS from the bloodstream, for example with the accumulation of Mn3O4NPs in the dentate gyrus of the hippocampus, and through the capture and transport of NPs from the blood by olfactory epithelium cells. Also, experiments with the administration of chlorpromazine, a specific inhibitor of clathrin-dependent endocytosis, and methyl-β-cyclodextrin, inhibitor of the lipid rafts involved in the capture of substances by endothelium cells, showed differences in the mechanisms of NP uptake from the nasal cavity and from the bloodstream. In this study, we show a significant contribution of axonal transport to NP accumulation patterns in the brain, both from the nasal cavity and from the vascular bed. This explains the accumulation of different sorts of submicron particles (neurotropic viruses, insoluble xenobiotics, etc.), unable to pass BBB, in the brain. The results will add to the understanding of the pathogenesis of various neurodegenerative diseases and help studying the side effects of therapeutics administered intravenously.

Evaluation of molecularly imprinted polymers for chlorpromazine and bromopromazine prepared by multi-step swelling and polymerization method—The application for the determination of chlorpromazine and its metabolites in rat plasma by column-switching LC

Monodisperse molecularly imprinted polymers (MIPs) for chlorpromazine (CPZ) and bromopromazine (BPZ), MIPCPZ and MIPBPZ, were prepared using methacrylic acid as a functional monomer and ethylene glycol dimethacrylate as a crosslinker by multi-step swelling and polymerization. The retention and molecular-recognition properties of MIPCPZ and MIPBPZ were evaluated using a mixture of potassium phosphate buffer and acetonitrile or a mixture of water and acetonitrile including ammonium formate as a mobile phase in reversed-phase LC. On MIPBPZ, CPZ, BPZ and imipramine (IMP) gave the maximal retention factors at a mobile-phase pH 8, while the maximal imprinting factors were obtained at a mobile-phase pH 7. Each MIP recognized a template molecule the most, while CPZ metabolites, desmethyl CPZ (DM-CPZ), CPZ sulfoxide (CPZ-SO) and 7-hydroxy CPZ (7−OH-CPZ), were moderately recognized on MIPCPZ and MIPBPZ. Furthermore, both MIPs gave the similar retention and molecular-recognition for CPZ and its metabolites. For avoiding the template-leakage problems, MIPBPZ was used as the pretreatment column for the determination of CPZ and its metabolites in rat plasma in column-switching LC with UV detection. In addition to DM-CPZ and CPZ-SO, didesmethyl CPZ (DDM-CPZ) and CPZ N-oxide (CPZ-NO) were speculated as the metabolite in rat plasma after administration of CPZ using LC-ESI-TOF-MS, while 7-OH-CPZ was not detected. The column-switching LC method was validated and applied for the determination of CPZ and its metabolites, DM-CPZ, DDM-CPZ, CPZ-SO and CPZ-NO, in rat plasma after intravenous and oral administration of CPZ using IMP as an internal standard.

Ultrasound-guided phrenic nerve block for intraoperative persistent hiccups: a case report

BackgroundContinuous hiccups during surgery not only affect the surgical procedure, they can also cause adverse effects for the patient. Apart from active investigation of the cause of the hiccups, their timely termination is also necessary.Case presentationWe reported a case of a 70-year-old woman with continuous intraoperative hiccups that appeared during vaginal hysterectomy under low continuous epidural anesthesia. After the ineffectiveness CO2 repeated inhalation and intravenous administration of chlorpromazine and methoxychlorpromide, we performed unilateral phrenic nerve block under ultrasound guidance. Hiccups were terminated without any related complications.ConclusionsDuring intraoperative continuous hiccups, ultrasound guided phrenic nerve block may be a suitable treatment option when physical methods and drug therapy are not effective. However, given the absence of a vital risk related to hiccups, this block should imply the complete absence of any respiratory contraindication and a prolonged postoperative respiratory monitoring.

Iron overload prevents oxidative damage to rat brain after chlorpromazine administration.

The hypothesis tested is that Fe administration leads to a response in rat brain modulating the effects of later oxidative challenges such as chlorpromazine (CPZ) administration. Either a single dose (acute Fe overload) or 6 doses every second day (sub-chronic Fe overload) of 500 or 50mg Fe-dextran/kg, respectively, were injected intraperitoneally (ip) to rats. A single dose of 10mg CPZ/kg was injected ip 8h after Fe treatment. DNA integrity was evaluated by quantitative PCR, lipid radical (LR·) generation rate by electron paramagnetic resonance (EPR), and catalase (CAT) activity by UV spectrophotometry in isolated brains. The maximum increase in total Fe brain was detected after 6 or 2h in the acute and sub-chronic Fe overload model, respectively. Mitochondrial and nuclear DNA integrity decreased after acute Fe overload at the time of maximal Fe content; the decrease in DNA integrity was lower after sub-chronic than after acute Fe overload. CPZ administration increased LR· generation rate in control rat brain after 1 and 2h; however, CPZ administration after acute or sub-chronic Fe overload did not affect LR· generation rate. CPZ treatment did not affect CAT activity after 1-4h neither in control rats nor in acute Fe-overloaded rats. However, CPZ administration to rats treated sub-chronically with Fe showed increased brain CAT activity after 2 or 4h, as compared to control values. Fe supplementation prevented brain damage in both acute and sub-chronic models of Fe overload by selectively activating antioxidant pathways.

Factors Associated with the Effectiveness of Intravenous Administration of Chlorpromazine for Delirium in Patients with Terminal Cancer.

Delirium in patients with terminal cancer is irreversible and increases treatment resistance, which leads to a deterioration in quality of life. To investigate factors affecting the effectiveness and safety of intravenous chlorpromazine for irreversible delirium in patients with terminal cancer. Multiple regression analysis for factors affecting treatment effectiveness was carried out based on a retrospective comparison between responders and nonresponders to intravenous chlorpromazine. Ninety-seven patients with terminal cancer who were treated with intravenous chlorpromazine for irreversible delirium were included. The rate of patients with ≥50% improvement in mean Nursing Delirium Screening Scale score from pretreatment to day three of chlorpromazine treatment was 0.48 (95% confidence interval [CI]: 0.38-0.58). Factors affecting chlorpromazine treatment effectiveness were hyperactive delirium (odds ratio [OR]: 6.25, 95% CI: 1.14-34.5) and longer survival (OR: 1.096, 95% CI: 1.05-1.14). The mean chlorpromazine dose was low, at 17.9 mg/day. Adverse events were reported in 11 patients (11.3%) by day three of chlorpromazine treatment, and all were observed in patients who survived less than two weeks after chlorpromazine treatment. Patients who died, who had decreased blood pressure during chlorpromazine administration, and who showed acute akathisia all displayed shock index ≥1. Intravenous administration of low-dose chlorpromazine may be an effective and safe treatment option for delirium in patients with terminal cancer who have hyperactive delirium, longer predictive prognosis, and shock index <1.