Neuroleptic Drugs Research Articles

Design and synthesis of N‑(benzylpiperidinyl)‑4‑fluorobenzamide: A haloperidol analog that reduces neuropathic nociception via σ1 receptor antagonism

AimsHaloperidol is a neuroleptic drug with high affinity towards the σ1 receptor (σ1R), acting as antagonist that decreases neuropathic pain, but has CNS side effects. This work describes the design and synthesis of a novel analog N‑(1‑benzylpiperidin‑4-yl)‑4‑fluorobenzamide (LMH-2), which produced antihyperalgesic and antiallodynic effects in rats with neuropathy induced by chronic constriction injury of the sciatic nerve (CCI), being more active than gabapentin (The most widely used drug for the treatment of neuropathic pain). Main methodsLMH-2 was designed as haloperidol analog. Its structure was characterized by spectroscopic (1H and 13C NMR) and spectrometric mass (electronic impact) techniques. Additionally, in silico predictions of pharmacokinetic, pharmacodynamic and toxicological properties were obtained, with promising results. A competitive binding assay using radioligands was employed to evaluate the in vitro affinity for σ1R, whereas in vivo antihyperalgesic and antiallodynic activities were investigated using Wistar rats with CCI. Key findingsLMH-2 showed high affinity for σ1R in an in vitro binding assay, with a Ki = 6.0 nM and a high σ1R/σ2R selectivity ratio. Molecular docking studies were carried out to determine the binding energy and to analyze LMH-2-protein interactions. Through an in silico pharmacological consensus analysis, LMH-2 was considered safe for in vivo evaluation. Thus, LMH-2 had dose-dependent antiallodynic and antihyperalgesic activities; its efficacy was comparable to that of gabapentin, but its potency was 2-times higher than this drug. SignificanceLMH-2 administration produced antihyperalgesic and antiallodynic effects by the antagonism of σ1R, suggesting its potential use as an analgesic drug for neuropathic pain.

P.201 Genetic variants associated with low dopaminergic activity relate to parameters included in the metabolic syndrome after treatment with antipsychotics

Neuropeptides play an important role in various neural pathways, being able to control a wide spectrum of physiological responses. Neuropeptide Y (NPY) and proopiomelanocortin (POMC) functions are quite well studied, however little is known about their action at the level of limbic structures. The present work was focused on the expression of the aforementioned peptides in this brain structure of rats treated with olanzapine, a second generation neuroleptic drug. The detailed purpose of this experiment was the evaluation of potential relationships between chronic olanzapine administration and NPY and POMC mRNA expression in the amygdala and hippocampal formation.The studies were carried out on adult, male Sprague-Dawley rats that were divided into 2 groups: control and experimental animals treated with olanzapine (28 day-long intraperitoneal injection). All individuals were sacrificed under anaesthesia, then the amygdaloid complexes and hippocampi were excised. Total mRNA was isolated from homogenized samples of both structures and the RT-PCR method was used for estimation of NPY and POMC gene relative expression.Prolonged olanzapine administration is reflected in qualitatively different changes in expression of NPY and POMC mRNA in the rat amygdala and hippocampus. Interestingly enough, olanzapine did not affect NPY expression, but significantly increased the POMC level in both examined regions.Olanzapine can affect amygdalar and hippocampal neuronal populations by the modulation of neuropeptide activity. Importantly, it may suggest the existence of an alternative mode of its action. Undoubtedly this hypothetic regulatory mechanism requires further pharmacological and neurostructural study.

P.287 Metabolic syndrome induced by antipsychotics and hematological abnormalities

Neuropeptides play an important role in various neural pathways, being able to control a wide spectrum of physiological responses. Neuropeptide Y (NPY) and proopiomelanocortin (POMC) functions are quite well studied, however little is known about their action at the level of limbic structures. The present work was focused on the expression of the aforementioned peptides in this brain structure of rats treated with olanzapine, a second generation neuroleptic drug. The detailed purpose of this experiment was the evaluation of potential relationships between chronic olanzapine administration and NPY and POMC mRNA expression in the amygdala and hippocampal formation.The studies were carried out on adult, male Sprague-Dawley rats that were divided into 2 groups: control and experimental animals treated with olanzapine (28 day-long intraperitoneal injection). All individuals were sacrificed under anaesthesia, then the amygdaloid complexes and hippocampi were excised. Total mRNA was isolated from homogenized samples of both structures and the RT-PCR method was used for estimation of NPY and POMC gene relative expression.Prolonged olanzapine administration is reflected in qualitatively different changes in expression of NPY and POMC mRNA in the rat amygdala and hippocampus. Interestingly enough, olanzapine did not affect NPY expression, but significantly increased the POMC level in both examined regions.Olanzapine can affect amygdalar and hippocampal neuronal populations by the modulation of neuropeptide activity. Importantly, it may suggest the existence of an alternative mode of its action. Undoubtedly this hypothetic regulatory mechanism requires further pharmacological and neurostructural study.

Effects of a Psychoeducation Program for People with Schizophrenia Aimed at Increasing Subjective Well-Being and the Factors Influencing Those Effects: a Preliminary Study.

There have been no intervention studies of psychoeducation programs for schizophrenia that focus on improving subjective well-being or studies to determine the factors influencing such effects. This study aimed to examine the effects of a psychoeducation program combining traditional psychoeducation with a focus on providing knowledge and information and a new intervention to raise patients' subjective well-being and to clarity the factors affecting the program's efficacy. Subjects were 117 patients who participated in a psychoeducation program for schizophrenia between 2012 and 2018. In addition to comparing subjective well-being (Subjective Well-being under Neuroleptic Drug Treatment Short Form, Japanese version, SWNS-J) and attitudes towards drugs (Drug Attitude Inventory-10, DAI-10) before and after the program, basic information such as psychiatric symptoms was surveyed. The factors influencing the effects of the program were assessed with multiple regression analysis. Scores for SWNS-J subscales and total SWNS-J score increased significantly after the program. Higher total scores on subjective well-being after the program were significantly associated with having less severe negative symptoms and higher total subjective well-being before the program, and with more positive attitudes toward drugs after the program. These results suggest that intervention with a focus on improving subjective well-being can be an effective part of psychoeducation programs for patients with schizophrenia. The results also suggest that the level of improvement in subjective well-being gained from the program may be higher in patients with milder negative symptoms and patients with a better understanding of drug treatment.

Electrophysiology and Behavioral Assessment of the New Molecule SMe1EC2M3 as a Representative of the Future Class of Triple Reuptake Inhibitors.

SMe1EC2M3 is a pyridoindole derivative related to the neuroleptic drug carbidine. Based on the structural similarities of SMe1EC2M3 and known serotonin (5-HT), norepinephrine, and dopamine reuptake inhibitors, we hypothesized that this compound may also have triple reuptake inhibition efficacy and an antidepressant-like effect. PreADMET and Dragon software was used for in silico prediction of pharmacokinetics and pharmacodynamics of SMe1EC2M3. Forced swim test was used to evaluate its antidepressant-like effects. Extracellular in vivo electrophysiology was used to assess 5-HT, norepinephrine, and dopamine reuptake inhibition efficacy of SMe1EC2M3. PreADMET predicted reasonable intestinal absorption, plasma protein binding, and blood-brain permeability for SMe1EC2M3. Dragon forecasted its efficiency as an antidepressant. Using behavioral measurements, it was found that SMe1EC2M3 decreased immobility time and increase swimming time during the forced swim test (FST). Electrophysiological investigations showed that SMe1EC2M3 dose-dependently suppressed the excitability of 5-HT neurons of the dorsal raphe nucleus (DRN), norepinephrine neurons of the locus coeruleus (LC), and dopamine neurons of the ventral tegmental area (VTA). The SMe1EC2M3-induced suppression of 5-HT, norepinephrine, and dopamine neurons was reversed by the antagonists of serotonin-1A (5-HT1A; WAY100135), α-2 adrenergic (α2, yohimbine), and dopamine-2 receptors (D2, haloperidol), respectively. We conclude that SMe1EC2M3 is prospective triple 5-HT, norepinephrine, and dopamine reuptake inhibitor with antidepressant-like properties, however future studies should be performed to complete the pharmacological profiling of this compound.

Effects of chlorpromazine drug on DPPC lipid: Density functional theory study

ABSTRACT This work reports the interaction between neuroleptic drug, chlorpromazine, with dipalmitoylphosphtidylcholine (DPPC) lipid. Density functional theory was applied to assess the changes caused by chlorpromazine (CPZ) and to specify the exact location of the drug in the lipid. It is found that the incorporation of drugs in DPPC causes a concentration dependent increase of the membrane fluidity and they interact strongly with both the lipophilic part and the polar head group of the phospholipids. The results obtained from molecular electrostatic potential surface have shown that the amino groups interact with the negatively charged phosphate groups of the phospholipid molecules and the aromatic rings are directed towards the hydrophobic interior of the phospholipid membrane. The calculated HOMO and LUMO energy gap explains the charge transfer phenomenon within the molecule.

Neuroleptic Malignant Syndrome: An Undiagnosed Case

Neuroleptic malignant syndrome (NMS) was first described six decades ago after the introduction of neuroleptic drugs for the treatment of psychotic disorders..

The neuroleptic drug fluphenazine induces a significant UVA-mediated cytotoxic effect on three human cancer cell lines through apoptosis.

The cytotoxic activity of fluphenazine (FPZ) in combination with UVA light was evaluated on three human tumor cell lines, HeLa, MSTO-211H and A431. The photobiological effect was determined following irradiation treatment in the presence of/or after the removal of incubated FPZ. Under both conditions, FPZ proved to be very effective in killing tumor cells, with GI50 values in the micromolar range. However, when FPZ was present during irradiation, the photocytotoxicity was at least two times higher than that after its removal suggesting the contribution of the drug both outside and inside the cells. The uptake of FPZ was very fast and, after only 15 minutes of incubation, the compound was accumulated inside lysosomes, as evidenced through fluorescence microscopy. FPZ distribution covered also the nucleus and the cytoplasm without significant plasma membrane association. After irradiation, the membrane of lysosomes in which FPZ was accumulated lost its integrity suggesting that the released lysosomal enzymes played an important role in cell death, and mitochondria were damaged as well, following apoptosis. Indeed, cytofluorimetric studies demonstrated that apoptosis was the main mechanism of cell death. Finally, an extremely high production of ROS was found, indicating a significant photodynamic mechanism involved in the photocytotoxic effect of FPZ. Taken together, our data show that FPZ following UVA irradiation behaves as an effective photoantiproliferative compound inducing apoptosis on various human tumor cells.

The Persian version of the Calgary Depression Scale for Schizophrenia (CDSS-P).

Determining depression symptoms in schizophrenic patients is a challenging process because of a degree of similarity between depression symptoms and negative symptoms and the extrapyramidal side effects of neuroleptic drugs, but it is crucial to evaluate and measure depression among patients with schizophrenia for a better clinical outcome. The Calgary Depression Scale for Schizophrenia (CDSS) is a valid and reliable instrument used for the evaluation of depression in schizophrenia. This study aimed to determine the psychometric properties of the Persian version of CDSS in a sample of people with schizophrenia. Clinical interviews were conducted with 95 schizophrenic patients (40 inpatients and 55 outpatients), who were assessed with the Positive and Negative Syndrome Scale (PANSS), Hamilton Depression Rating Scale (HDRS-17 and HDRS-24 items), and the Calgary Depression Rating Scale (CDSS). Then an exploratory factor analysis was conducted to determine correlations between scales, Cronbach's alpha, and cutoff scores. The factor analysis led to the extraction of a unifactorial solution. The CDSS had significant relationships with PANSS Negative and PANSS General. However, it had no significant relationship with PANSS Positive and the PANSS Total. The CDSS also had significant relationships with HDRS-17 and HDRS-24. In addition, Cronbach's alpha of total score, test-retest reliability, and cutoff score were estimated at 0.86, 0.82, and 8 (sensitivity = 0.79 and specificity = 0.84), respectively. The findings support the CDSS unifactorial approach. Results also showed that the CDSS Persian version had acceptable psychometric properties; thus, it could be employed to evaluate depression among schizophrenic patients.

ID1 Is Critical for Tumorigenesis and Regulates Chemoresistance in Glioblastoma.

Glioblastoma is the most common primary brain tumor in adults. While the introduction of temozolomide chemotherapy has increased long-term survivorship, treatment failure and rapid tumor recurrence remains universal. The transcriptional regulatory protein, inhibitor of DNA-binding-1 (ID1), is a key regulator of cell phenotype in cancer. We show that CRISPR-mediated knockout of ID1 in glioblastoma cells, breast adenocarcinoma cells, and melanoma cells dramatically reduced tumor progression in all three cancer systems through transcriptional downregulation of EGF, which resulted in decreased EGFR phosphorylation. Moreover, ID1-positive cells were enriched by chemotherapy and drove tumor recurrence in glioblastoma. Addition of the neuroleptic drug pimozide to inhibit ID1 expression enhanced the cytotoxic effects of temozolomide therapy on glioma cells and significantly prolonged time to tumor recurrence. Conclusively, these data suggest ID1 could be a promising therapeutic target in patients with glioblastoma. SIGNIFICANCE: These findings show that the transcriptional regulator ID1 is critical for glioblastoma initiation and chemoresistance and that inhibition of ID1 enhances the effect of temozolomide, delays tumor recurrence, and prolongs survival.

Abstract 256: Repurposing neuroleptic drug for brain tumor therapy

Abstract Brain tumor is considered as one of the most aggressive and incurable form of cancer. Majority of the brain tumors have a median survival rate of only 12%. Even though advanced treatments such as surgical removal, chemotherapy and radiotherapy are available, brain tumor persists to be lethal. Temozolomide (TMZ) is the main therapy for brain tumor but resistance to TMZ is the major cause of treatment failure. This resistance in tumor cells has frequently been linked to the expression of O6-methylguanine-DNA methyltransferase (MGMT). Pimozide (PMZ) is a neuroleptic drug used for the treatment of schizophrenia and chronic psychosis. In our study, we observed that pimozide significantly reduced the viability of U87MG, U251MG, DAOY and GBM28 cell lines with an IC50 ranging from 11µM to 20µM after 24 h of treatment. Pimozide induced apoptosis in these cell lines as evaluated by FITC/Annexin assay and further validated by the cleavage of caspase 3 as well as PARP. Western blot analysis resulted in the concentration dependent decrease in the expression of STAT3 signaling mainly targeting the anti-apoptotic markers BCl-XL, BCl-2 and Survivin etc in U87MG, U251MG, DAOY and GBM28 brain cancer cell lines. PMZ alone suppressed the growth of U87MG cells with an IC50 of 10µM, after 96 hours of treatment. On the other hand, treatment of U87MG cells with 750 µM of TMZ in combination with 10µM PMZ for 96 hours increased the killing of U87MG cells by 50% as compared to 10% when treated with TMZ. In addition, PMZ treatment reduced the survival of TMZ resistant U251R cells with an IC50 ranging from 15-20 µM after 24 h of treatment. Our results further demonstrated that oral administration of PMZ (25mg/kg) significantly inhibits the growth of brain tumors in an intracranial tumor model without any apparent signs of toxicity. It is important to note that PMZ is an FDA approved drug with no considerable toxicity. Overall, this study depicts that PMZ is a potential candidate to target brain tumors. Citation Format: Iti S. Kaushik, Alok Ranjan, Blake Schwettmann, Sanjay Srivastava. Repurposing neuroleptic drug for brain tumor therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 256.

Health Care Resource Utilization and Costs for Patients with Tardive Dyskinesia.

Tardive dyskinesia (TD) is an often-irreversible movement disorder affecting any part of the body. Patients experience debilitating symptoms that lower quality of life and increase mortality. Prolonged exposure to dopamine antagonists, which are frequently prescribed for psychiatric disorders as neuroleptic (antipsychotic) drugs, is a common cause of TD. The estimated prevalence of TD is 20%-50% among patients on antipsychotics, and the reported incidence of TD ranges from < 1% to 42%, depending on the antipsychotics studied. However, there are few real-world studies examining health care utilization and the economic burden of TD. To assess health care utilization and costs in a sample of patients with TD from the commercially insured and Medicare supplemental U.S. A retrospective analysis was conducted using Truven MarketScan Commercial and Medicare administrative claims data. Patients were included in the TD group if they had the first TD diagnosis (index date) between January 1, 2008, and September 30, 2014, with ≥ 1 inpatient or ≥ 2 outpatient nondiagnostic claims for TD (ICD-9-CM code 333.85). Patients without TD were randomly assigned an index date. Further inclusion criteria for all patients were ≥ 12 months of pre- and post-index medical and pharmacy continuous enrollment and no evidence of TD claims during the pre-index period. Patients with TD were directly matched to patients without TD within subgroups for schizophrenia, major depressive disorder, bipolar disorder, and other psychiatric disorders and propensity matched on other demographic and clinical factors. Descriptive statistics on the incidence of resource utilization and costs of health care were reported. Of 3,397 patients with TD, 834 met the selection criteria and were matched to 834 non-TD controls. Patients with TD generally had significantly greater utilization during the 12 months after TD diagnosis than in the 12 months before TD diagnosis. Their rates for health care utilization and costs were also substantially higher than for those without TD. During the post-TD-diagnosis time, inpatient admissions (55.5% vs. 26.1%; P < 0.001) and emergency room visits (61.5% vs. 50.6%; P < 0.001) occurred more for patients with TD than for patients without TD. Total health care costs were significantly greater for patients with TD than for those without TD ($54,656 vs. $28,777; P < 0.001). Patients diagnosed with TD demonstrate significantly higher health care utilization and costs compared with non-TD patients. This study was funded by Teva Pharmaceuticals (Petach Tikva, Israel). Truven Health Analytics, an IBM Watson Health Company, received payment from Teva Pharmaceuticals for the analysis in this study. Carroll is employed by Teva Pharmaceuticals and Irwin is employed by Truven Health Analytics, an IBM Watson Health Company.

Understanding Schizophrenia: Toward a Unified Biological and Psychodynamic Approach

Despite the advent of the neuroleptic drugs in the 1950s, schizophrenia continues to cause widespread economic burden and disability. Various psychoanalytic scholars have offered theories of schizophrenia as a mental illness, and research has consistently demonstrated psychotherapy’s effectiveness as a component of schizophrenia treatment. The contributions of the late Italian-American psychiatrist Silvano Arieti are reviewed here as an example of a unified biological and psychodynamic approach to schizophrenia. Clinical techniques for working analytically with schizophrenia patients are reviewed. Implications of an integrated approach to the disorder are discussed within the current climate of mental health.

QTc dispersion and interval changes in drug-free borderline personality disorder adolescents.

Emotional instability and dysregulation represent a core feature of borderline personality disorder (BPD) and abnormal patterns of sympathetic/parasympathetic activity have been repeatedly investigated in individuals with this disorder. Such abnormalities may represent the substrate for an arrhythmogenic risk that could materialize the following specific drug exposure. In this work, we decided to assess basal-corrected QT interval and dispersion (QTc and QTcd) for estimating such risk in a sample of drug-free adolescents with diagnosis of BPD. In this cross-sectional comparative study, we recruited n = 70 female adolescent BPD (14.7 ± 1.3years), free of medications, alcohol or recreational drugs. Furthermore, n = 70 matched female healthy controls (CTRL, 14.6 ± 1.5years) were enrolled. QTc and QTcd were manually assessed on a standard 12-lead ECG by a single experienced investigator who was unaware of clinical outcomes. QTcd was increased by 7ms on average in BPD vs. CTRL (+ 18%, p = 0.03). QTc was decreased by about 15ms on average in BPD vs. CTRL (p = 0.003). A mild correlation was found between QTc and QTcd in BPD (r = 0.25, p = 0.03) that was not present in CTRL. No correlation was found between either QTc or QTcd, and age in both groups. Mildly increased QTcd characterizes the cardiac activity regardless of drug exposure in female adolescents with BPD. This information may be of value to clinicians striving to use neuroleptic and antidepressant drugs with a lower risk of QTcd increase.

Repurposing neuroleptic drug for brain tumor therapy

Brain tumor is considered as one of the most aggressive and incurable form of cancer. Majority of the brain tumors have a median survival rate of only 12%. Even though advanced treatments such as surgical removal, chemotherapy and radiotherapy are available, brain tumor persists to be lethal. Temozolomide (TMZ) is the main therapy for brain tumor but resistance to TMZ is the major cause of treatment failure. This resistance in tumor cells has frequently been linked to the expression of O6‐methylguanine‐DNA methyltransferase (MGMT). Pimozide (PMZ) is a neuroleptic drug used for the treatment of schizophrenia and chronic psychosis. In our study, we observed that pimozide significantly reduced the viability of U87MG, U251MG, DAOY and GBM28 cell lines with an IC50 ranging from 11μM to 20μM after 24 h of treatment. Pimozide induced apoptosis in these cell lines as evaluated by FITC/Annexin assay and further validated by the cleavage of caspase 3 as well as PARP. Western blot analysis resulted in the concentration dependent decrease in the expression of STAT3 signaling mainly targeting the anti‐apoptotic markers BCl‐XL, BCl‐2 and Survivin etc in U87MG, U251MG, DAOY and GBM28 brain cancer cell lines. PMZ alone suppressed the growth of U87MG cells with an IC50 of 10μM, after 96 hours of treatment. On the other hand, treatment of U87MG cells with 750 μM of TMZ in combination with 10μM PMZ for 96 hours increased the killing of U87MG cells by 50% as compared to 10% when treated with TMZ. In addition, PMZ treatment reduced the survival of TMZ resistant U251R cells with an IC50 ranging from 15–20 μM after 24 h of treatment. Our results further demonstrated that oral administration of PMZ (25mg/kg) significantly inhibits the growth of brain tumors in an intracranial tumor model without any apparent signs of toxicity. It is important to note that PMZ is an FDA approved drug with no considerable toxicity. Overall, this study depicts that PMZ is a potential candidate to target brain tumors.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Enhancing Adamantylamine Solubility through Salt Formation: Novel Products Studied by X-ray Diffraction and Solid-State NMR

The reactivity of the neuroleptic drug adamantylamine toward aliphatic carboxylic acids, sulfone derivatives, and aromatic amino acids was screened for the first time using simple mechanochemical methods. Seven new molecular salt structures were reported exhibiting improved physicochemical properties. To carefully characterize these compounds, multiple complementary techniques were combined: single crystal and powder X-ray diffraction, 13C/15N solid-state NMR, and Fourier transform infrared-attenuated total reflectance spectroscopies, employed to solve cocrystal/salt ambiguities. In all molecular salts, the crystal packing is supported on a common synthon, a N–H+(ADA)···O–(coformer) charge assisted hydrogen bond. Different supramolecular arrangements were obtained induced by the size of the counterions as well as their complementary functional groups. Two salts, with glutaric and methanesulfonic acids, presented higher solubility than the commercially available pharmaceutical product.

Tolerability of Midazolam to treat acute agitation in elderly demented patients: A systematic review.

Behavioural disorders are difficult to manage in elderly demented patients because of the lack of appropriate drugs or difficulties surrounding the route of administration. The tolerability of Midazolam is well described in the emergency management of agitation for young patients, when administered intramuscularly or intravenously. However, very little data are available on the use of oral Midazolam for this indication and in the elderly population. A literature review was conducted, and studies were included if involving adults, receiving Midazolam, alone or in combination, whatever the route, dosage or indication and if they reported adverse events related to the use of Midazolam. Forty-one articles were included. Eleven different adverse events were identified from the studies. Hypotension and desaturation were the two most frequent adverse events reported. Adverse reactions appear to be more common in older patients but also when Midazolam was used in combination with other drugs. The frequency of these adverse effects was lower than those reported for neuroleptic drugs. The oral route appears to be appropriate to provide a rapid and well-tolerated response. Further studies will be needed to confirm the good tolerance of oral Midazolam in the management of acute agitation in elderly demented patients.

Chlorpromazine toxicity is associated with disruption of cell membrane integrity and initiation of a pro-inflammatory response in the HepaRG hepatic cell line

Chlorpromazine (CPZ) is a neuroleptic drug and prototype compound used to study intrahepatic cholestasis. The exact mechanisms of CPZ induced cholestasis remain unclear. Rat hepatocytes, or a sandwich culture of rat and human hepatocytes, have been the most commonly used models for studying CPZ toxicity in vitro. However, to better predict outcomes in pre-clinical trials where cholestasis may be an unwanted consequence, a human in vitro model, based on human HepaRG cells, capable of real-time, non-invasive and label free monitoring, alongside molecular investigations would be beneficial. To address this we used the human hepatic HepaRG cell line, and established concentrations of CPZ ranging from sub-toxic, 25 μM and 50 μM, to toxic 100 μM and compared them with untreated control. To assess the effect of this range of CPZ concentrations we employed electrical cell-substrate impedance sensing (ECIS) to measure viability and cell membrane interactions alongside traditional viability assays, immunocytostaining and qRT-PCR to assess genes of interest within adaptive and inflammatory pathways. Using these methods, we show a concentration dependant response to CPZ involving pro-inflammatory pathway, loss of tight junctions and membrane integrity, and an adaptive response mediated by Cytochrome P450 (CYP) enzyme activation and up-regulation of membrane phospholipid and xenobiotic transporters. In conclusion, structural changes within the membrane caused by sub-toxic and toxic concentrations of CPZ negatively impact the function of the cellular membrane. Damage to efflux transport proteins caused by CPZ induce cholestasis alongside downstream inflammation, which activates compensatory responses for cell survival. Lay summaryChlorpromazine is a drug used to treat patients with schizophrenia, which has a known association with liver damage. Here we show that it causes inflammation and alters the cell membranes in liver and bile duct cells similar to what is seen within a human population. The initiation of the inflammatory response and changes to cellular structure may provide insight into the damage and disease process and inform medical treatment.

Pseudotumour cerebri associated with mycoplasma pneumoniae infection and treatment with levofloxacin: a case report

BackgroundIdiopathic intracranial hypertension (IIH), also known as pseudotumour cerebri syndrome (PTCS), is characterized by the presence of signs and symptoms of raised intracranial pressure without evidence of any intracranial structural cause and with normal cerebrospinal fluid microscopy and biochemistry.Obesity, various systemic diseases and endocrine conditions, and a number of medications are known to be risk factors for PTCS. The medications commonly associated with PTCS are amiodarone, antibiotics, corticosteroids, cyclosporine, growth hormone, oral contraceptives, vitamin A analogues, lithium, phenytoin, NSAIDs, leuprolide acetate, and some neuroleptic drugs. In relation to antibiotics, quinolones may cause intracranial hypertension, and most reported cases of quinolone-induced intracranial hypertension were associated with nalidixic acid, ciprofloxacin, ofloxacin, or pefloxacin. Literature reports of levofloxacin-induced PTCS are rare. Some authors recently hypothesized that Mycoplasma pneumoniae may trigger PTCS.Case presentationWe report on a 14-year-old overweight White Italian boy who suffered headache, diplopia, and severe bilateral papilloedema after a Mycoplasma pneumoniae infection, exacerbated on levofloxacin intake. A spontaneous improvement in headache and a reduction in diplopia was seen during hospitalisation. Oral acetazolamide therapy led to the regression of papilloedema in about five months. No permanent eye damage has been observed in our patient to date.ConclusionsPTCS pathophysiology may be multifactorial and its specific features and severity may be a consequence of both constitutional and acquired factors interacting synergistically. It may be useful for paediatricians to know that some antibiotics may have the potential to precipitate PTCS in patients who already have an increased CSF pressure due to a transitory imbalanced CSF circulation caused by infections such as Mycoplasma pneumoniae, with headache being the first and most sensitive, but also the least specific, symptom.

Comparison of treatment costs at the Psychiatric Ward in Gryfice between 2016 and 2017, after the introduction of olanzapine long-acting injectable in hospital treatment

Objectives. The aim of this study was to compare the costs of treatment at the Psychiatric Ward in Gryfice between 2016 and 2017, after the introduction of olanzapine long-acting injectable in hospital treatment. Material and methods. Analysis of numerical data of the costs of treatment at the Psychiatric Ward in Gryfice (60 inpatient beds) between 2016 and 2017, data from the central hospital pharmacy – internal expenditure of medicines (OLAI, clozapine and zuclopentixol – acetate and decanoate). In 2016, two patients were treated with olanzapine long-acting injectable; in 2017, it was 25 patients, who met the diagnosis criteria for schizophrenia according to ICD-10 and the indications for the refund of the drug (recurrence of psychotic symptoms as a result of documented persistent lack of cooperation). Results. Compared with 2016, in 2017, there were 104 fewer patients hospitalised (–7%); the number of patient-days decreased by 254 (–1.1%) and the number of patients diagnosed as schizophrenia lowered by 32 (–18.5%). The cost of pharmacological treatment decreased both per patient (reduction by 6.7%) and per patient-day (reduction by 12, 2%). The use of other drugs also decreased. Conclusions. Introduction of olanzapine long-acting injectable in hospital treatment is economically beneficial in the short term. In 2017, as compared to 2016, a reduction in the cost of pharmacological treatment was achieved at the Psychiatric Ward in Gryfice (both per patient and per patient-day). The consumption of other neuroleptic drugs, such as clozapine and zuclopenthixol (acetate and decanoate), decreased, too.