Neuroleptic Drugs Research Articles

Effects of Genetic Polymorphism in CYP2D6, CYP2C19, and the Organic Cation Transporter OCT1 on Amitriptyline Pharmacokinetics in Healthy Volunteers and Depressive Disorder Patients.

The tricyclic antidepressant amitriptyline is frequently prescribed but its use is limited by its narrow therapeutic range and large variation in pharmacokinetics. Apart from interindividual differences in the activity of the metabolising enzymes cytochrome P450 (CYP) 2D6 and 2C19, genetic polymorphism of the hepatic influx transporter organic cation transporter 1 (OCT1) could be contributing to interindividual variation in pharmacokinetics. Here, the impact of OCT1 genetic variation on the pharmacokinetics of amitriptyline and its active metabolite nortriptyline was studied in vitro as well as in healthy volunteers and in depressive disorder patients. Amitriptyline and nortriptyline were found to inhibit OCT1 in recombinant cells with IC50 values of 28.6 and 40.4 µM. Thirty other antidepressant and neuroleptic drugs were also found to be moderate to strong OCT1 inhibitors with IC50 values in the micromolar range. However, in 35 healthy volunteers, preselected for their OCT1 genotypes, who received a single dose of 25 mg amitriptyline, no significant effects on amitriptyline and nortriptyline pharmacokinetics could be attributed to OCT1 genetic polymorphism. In contrast, the strong impact of the CYP2D6 genotype on amitriptyline and nortriptyline pharmacokinetics and of the CYP2C19 genotype on nortriptyline was confirmed. In addition, acylcarnitine derivatives were measured as endogenous biomarkers for OCT1 activity. The mean plasma concentrations of isobutyrylcarnitine and 2-methylbutyrylcarnitine were higher in participants with two active OCT1 alleles compared to those with zero OCT1 activity, further supporting their role as endogenous in vivo biomarkers for OCT1 activity. A moderate reduction in plasma isobutyrylcarnitine concentrations occurred at the time points at which amitriptyline plasma concentrations were the highest. In a second, independent study sample of 50 patients who underwent amitriptyline therapy of 75 mg twice daily, a significant trend of increasing amitriptyline plasma concentrations with decreasing OCT1 activity was observed (p = 0.018), while nortriptyline plasma concentrations were unaffected by the OCT1 genotype. Altogether, this comprehensive study showed that OCT1 activity does not appear to be a major factor determining amitriptyline and nortriptyline pharmacokinetics and that hepatic uptake occurs mainly through other mechanisms.

Hemichorea Associated With Nonketotic Hyperglycemia: Rare Presentation of Uncontrolled Diabetes Mellitus

Abstract Introduction: Hemichorea is usually associated with a contralateral lesion in the central nervous system and can result from infection, genetic mutation, neoplasms, neurodegeneration, stroke, metabolic disease, drug-exposure, and autoimmune disease. Nonketotic hyperglycemic (NKH) hemichorea is mainly seen in elderly patients, especially females from East Asian origin with poor blood glucose control. The general treatment measures include improving control of blood glucose and the use of neuroleptic drugs. We report a unique case of hemichorea secondary to nonketotic hyperglycemia with negative imaging changes. Case Presentation: A 72-year-old woman with history of COPD, CKD stage III, CAD, diabetes type II for more than 30 years with poor glycemic control presented with sudden onset of uncontrolled involuntary dance like movements of left upper and lower extremities and left side of the face. These activities occurred while awake and disappeared during sleep. Neurological examination found that patient has a clear verbal ability, sanity, present involuntary dance-like movements of limbs, facial, jaw, and tongue. She had normal muscle strength and mild hypotonia. Other physical examination found no abnormalities. A CAT scan of the head showed high density in basal ganglia region and brain MRI(T1-weighted) showed and hyperintensity in the right basal ganglia. Laboratory tests showed that random blood sugar was 572 mg/dL, urine sugar (4+), and negative urine ketone, Hba1c was 14%. The patient’s subsequent thyroid function tests, autoantibodies, liver and kidney function tests, anti-neutrophilic cytoplasmic antibodies, ceruloplasmin, vitamins D and B12, and folic acid found to be normal. She was diagnosed with hemichorea associated with NKH. The treatments included improving blood glucose with IV insulin and symptomatic treatment of chorea with risperidone 2mg and clonazepam 1mg every night. On sixth day of admission patient’s involuntary movements improved. Blood sugar level normalized after a week. After 10 days, her dance-like symptoms disappeared completely. She tapered off risperidone and clonazepam within 3 months and continued to control blood sugar with premixed insulin after discharge. Conclusion: In conclusion, although uncommon, chorea/ballism associated with nonketotic hyperglycemia can be the first presenting sign of unknown diabetes mellitus or can occur after weeks or even months of poor glycemic control in diabetic patients. Timely neuro imaging examination and active blood glucose control can avoid misdiagnosis and delay in treatment.

Raman microspectroscopic and quantum chemical investigations of neuroleptic drugs interactions with dipalmitoylphosphatidylcholine (DPPC) lipid

Raman microspectroscopic and quantum chemical studies are performed to get insights into the interaction of neuroleptic drugs with Dipalmitoylphosphatidylcholine (DPPC) lipid and specify their precise location in the lipid bilayer. Liposomes were formed by the thin-film hydration process, and perphenazine drug was added to DPPC at various molar percentages. The intensity ratio of the peak I2935/I2880 is indicative of the interaction of drugs with the alkyl chains and can provide the crucial information about the ratio between disorder and order that occurs in the conformation of the alkyl chain. The effect of chlorpromazine drug on liposomes is discussed. Our results suggest that penetration of drugs in the lipid bilayers results in a concentration dependent rise of the membrane flexibility. Quantum chemical calculations are also performed to plot electrostatic potential surface which provide insights at molecular level infarctions of perphenazine drug and DPPC. The strong interaction was found between both the lipophilic and the polar head groups of the phospholipids with drugs.

Worsening of myasthenia due to antiepileptic, antipsychotic, antidepressant, and sedative medication: An estimation of risk based on reporting frequency.

Many drugs can worsen myasthenia symptoms. The clinician usually relies on cautionary lists compiled according to case reports. We intended to provide a quantitative basis for a risk comparison within the groups of antiepileptic, antidepressant, neuroleptic, and sedative drugs. We extracted adverse drug reaction (ADR) counts (total and myasthenia related) for drugs from these groups and calculated the reporting odds ratio (ROR) within the drug groups from the World Health Organization pharmacovigilance database. For a given drug, the ROR was increased above 1 if the proportion of myasthenia-related ADRs for this drug was larger than the same proportion for the rest of drugs in that same group. If the 95% confidence interval of ROR was >1, this was taken as a signal for a higher risk of the given drug as compared to the average of the respective group. Gabapentin, sertraline, citalopram, lithium, and amisulpride had a signal for the ROR to be increased above 1 within their respective groups. Bupropion, desvenlafaxine, duloxetine, escitalopram, and paroxetine had ROR values <1. For all other drugs, 1 was within the ROR confidence interval. For gabapentin and lithium, the analysis of RORs confirmed case reports and cautionary lists. For a number of antidepressant drugs associated with a higher-than-average risk, no case reports exist substantiating our results. For these drugs, special attention should be paid to this risk. The remarkable difference between citalopram and escitalopram could prompt experimental work to confirm differential influence of the two preparations on neuromuscular transmission.

Isolation and Characterization of Anti Psychotic Compound From Cassia Occidentalis Leaf

The aim of the current work was mainly to find the neuroleptic effects of responsible compounds isolated from Cassia occidentalis leaves, on condiontioning avoidance and catalepsy induced psychotic wistar rats. Psychosis was induced by condiontioning avoidance and catalepsy induced in albino wistar rats. An isolated fraction of the ethanolic extract of Cassia occidentalis was ingested orally at 100 mg/kg, p.o dose. Haloperidol was considered as standard neuroleptic drug (10 mg/kg, p.o.). The isolated fractions from the column chromatography showing for the higher neuroleptic activity that facilitated for isolating the pure constituent, that was named trivially as name CO- 1.Precise analysis of the previous investigations with Ethanolic extract of Cassia occidentalis (ETCO) have encouraged us to isolate anti-psychotic responsible consituents from the leaves of Cassia occidentalis for managing the anti-psychotic activity. Collected pooled fractions were subjected to anti-psychotic activity in conditioning avoidance and catalepsy induced wistar rats. The fraction F from ETCO showed strong neuroleptic activity when compared with the commercial standard drug Haloperidol. To propose the constituents that possess anti psychotic activity related to F respectively. Besides, column chromatography analysis was performed with ‘F’ using different solvents and the isolated compound which is named as CO-1. This amorphous powder was extracted from the column with decomposition point. CO-1 is a phenolic compound that was confirmed by IR, Mass Spectrum and NMR analysis.

Clinical features, neuroimaging findings and treatment outcomes in non ketotic hyperglycemic hemichorea-hemiballismus

Introduction: Nonketotic hyperglycemic hemichorea-hemiballism (NKHH) is an uncommon hyperkinetic movement disorder. It is the second most common etiology after stroke affecting basal ganglion. Only a few hundred cases are reported so far in literature. Objectives: The study attempts to systematically highlight clinical profile and neuroimaging findings in 15 patients of Nonketotic hyperglycemic hemichorea-hemiballism. Materials and Methods: Patients with hemichorea/ hemiballism associated with hyperglycemia were included in the study. The period of the study was from January 2008 to September 2018. Neurological examination, Demographic data, clinical, biochemical, and neuroimaging findings were captured from the medical records. Details of the involuntary hyperkinetic movements such as type and side(s) involved were noted. Treatment was aimed to control glycemic status and neuroleptic drugs. Descriptive statistics were used wherever necessary. Results: During the study period, 52 patients had hemichorea/ hemiballismus.27 patients had stroke affecting basal ganglia.6 patients had granuloma affecting basal ganglia. 4 patients had Wilson’s disease.15 patients had NKHH. Among 15 patients of NKHH, 9 patients were females and 6 were males. (Female to male 1.5:1).The mean age at the onset was 70.2 years (Range 58 -85). The mean serum glucose levels measured after the onset of NKHH was 439.93 mg/dL (Range 342-532).The mean glycated haemoglobin was 10.98% (Range 9.1-18.5.Neuroimaging showed involvement of striatum in 13 patients. Conclusion: NKHH is a rare hyperkinetic movement disorder. Elderly poorly controlled diabetics and female sex are most commonly affected. Neuroimaging findings are distinct. Further studies are needed to elucidate pathogenesis of this disease and for determining prognosticating factors. Keywords: Non ketotic, hyperglycemia, Hemichorea-hemiballism, Putamen, Striatum.

A half-century of participant observation in psychiatry. Part III: psychopharmacology.

The third part of the triptych of my 50-year activity in psychiatry is about psychopharmacology. This way of treatment changed the picture of contemporary psychiatry. The introduction of neuroleptic (antipsychotic) drugs and tricyclic antidepressants in the 1950s resulted in a therapeutic revolution and contributed to the ‛medicalization' of psychiatry and its therapeutic similarity to other non-surgical specialties. Adiscovery of prophylactic lithium activity in the1960s initiated the mood-stabilizing drugs.During the last half-century, the most dynamic was the 1990s when most antipsychotic and antidepressant drugs of the so-called new generation were introduced. The twenty-first century marks a debut of next antidepressant and antipsychotic drugs, some of the latter having long-acting injectable preparations. An interesting event was a demonstration of the antidepressant activity of ketamine. My research domain in psychopharmacology was lithium treatment of affective illnesses. Lithium makes the topic of many papers I authored, more than 150 of them are in the PubMed database. Many clinical and research aspects related to lithium administration have been reported as first in Polish literature and some are pioneering in the world. Recently, I wrote the book Lithium - the amazing drug in psychiatry which has also its English version. I have carried much research on antidepressant drugs, pharmacotherapy of treatment-resistant depression, and mood-stabilizing drugs for which I proposed a modern classification. I participated in European projects EUFEST and OPTIMISE on the optimization of using antipsychotic drugs in schizophrenia. I also performed much research on the antidepressant effect of ketamine and electroconvulsive therapy.

Thermodynamic Study on the Protonation and Complexation of the Neuroleptic Drug, Gabapentin with Na+, Ca2+ and Mg2+ at Various Temperatures and Ionic Strengths

The current work investigates the protonation constants of gabapentin (GP), 2-[1-(aminomethyl)cyclohexyl]acetic acid and the stability constants for the binding of GP to Ca2+ and Mg2+ in a wide range of temperature and ionic strength conditions [283.15 ≤ T/K ≤ 318.15 and ionic strengths of NaCl(aq), 0.12 ≤ I/mol·dm−3 ≤ 4.84]. The pH-potentiometric titration method was applied for gathering experimental data and determination of solution equilibrium constants. The ΔpK method was used for the determination of calcium and magnesium stability constants due to the low values which were predicted. A Debye–Huckel type equation, Specific Ion Interaction Theory, Pitzer and van’t Hoff equations were used for the modeling of ionic strength and temperature effects. Two species, ML and MHL, were found according to the best model for Ca2+ and Mg2+. Both protonation processes are exothermic based on the enthalpy values at 298.15 K and infinite dilution. A case study has been performed taking into account the speciation of GP in seawater.

The effect of levomepromazine on the healthy and injured developing mouse brain – An in vitro and in vivo study

Levomepromazine (LMP) is a phenothiazine neuroleptic drug with strong analgesic and sedative properties that is increasingly used off-label in pediatrics and is being discussed as an adjunct therapy in neonatal intensive care. Basic research points towards neuroprotective potential of phenothiazines, but LMP’s effect on the developing brain is currently unknown. The aim of the present study was to assess LMP as a pharmacologic strategy in established neonatal in vitro and in vivo models of the healthy and injured developing mouse brain. In vitro, HT-22 cells kept exposure-naïve or injured by glutamate were pre-treated with vehicle or increasing doses of LMP and cell viability was determined. In vivo, LMP’s effects were first assessed in 5-day-old healthy, uninjured CD-1 mouse pups receiving a single intraperitoneal injection of vehicle or different dosages of LMP. In a second step, mouse pups were subjected to excitotoxic brain injury and subsequently treated with vehicle or LMP. Endpoints included somatometric data as well as histological and immunohistochemical analyses. In vitro, cell viability in exposure-naïve cells was significantly reduced by high doses of LMP, but remained unaffected in glutamate-injured cells. In vivo, no specific toxic effects of LMP were observed neither in healthy mouse pups nor in experimental animals subjected to excitotoxic injury, but body weight gain was significantly lower following higher-dose LMP treatment. Also, LMP failed to produce a neuroprotective effect in the injured developing brain. Additional studies are required prior to a routine clinical use of LMP in neonatal intensive care units.

Pimozide Suppresses the Growth of Brain Tumors by Targeting STAT3-Mediated Autophagy.

Brain tumors are considered as one of the most aggressive and incurable forms of cancer. The majority of the patients with brain tumors have a median survival rate of 12%. Brain tumors are lethal despite the availability of advanced treatment options such as surgical removal, chemotherapy, and radiotherapy. In this study, we have evaluated the anti-cancer effects of pimozide, which is a neuroleptic drug used for the treatment of schizophrenia and chronic psychosis. Pimozide significantly reduced the proliferation of U-87MG, Daoy, GBM 28, and U-251MG brain cancer cell lines by inducing apoptosis with IC50 (Inhibitory concentration 50) ranging from 12 to 16 μM after 48 h of treatment. Our Western blotting analysis indicated that pimozide suppressed the phosphorylation of STAT3 at Tyr705 and Src at Tyr416, and it inhibited the expression of anti-apoptotic markers c-Myc, Mcl-1, and Bcl-2. Significant autophagy induction was observed with pimozide treatment. LC3B, Beclin-1, and ATG5 up-regulation along with autolysosome formation confirmed the induction of autophagy with pimozide treatment. Inhibiting autophagy using 3-methyladenine or LC3B siRNA significantly blocked the apoptosis-inducing effects of pimozide, suggesting that pimozide mediated its apoptotic effects by inducing autophagy. Oral administration of 25 mg/kg pimozide suppressed the intracranially implanted U-87MG tumor growth by 45% in athymic nude mice. The chronic administration of pimozide showed no general signs of toxicity, and the behavioral activity of the mice remained unchanged. Taken together, these results indicate that pimozide inhibits the growth of brain cancer by autophagy-mediated apoptosis.

Spotlight on Oculogyric Crisis: A Review.

Background:Oculogyric crisis (OGC) is a form of acute dystonia characterized by sustained dystonic, conjugate, and upward deviation of the eyes. It was initially reported in patients with postencephalitic parkinsonism. But later, other factors such as medications, movement disorders, metabolic disorders, and focal brain lesions were also found to be associated with OGC.Methods:The literature regarding OGC was searched via PubMed, Google Scholar, and through citations in relevant articles till December 2019, with keywords including OGC, oculogyric eye movements, tonic eye movement, neuroleptics and OGC, antipsychotics and OGC, and all combinations of these. Only original articles (abstract or full text) that were published in the English language were reviewed.Results:Hypodopaminergic state is implicated in the pathogenesis of OGC. Common risk factors are younger age, male sex, severe illness, high neuroleptic dose, parenteral administration of neuroleptics, high potency of neuroleptic drugs, abrupt discontinuation of anticholinergic medication, and family history of dystonia.Conclusion:OGC is an acute dystonic reaction leading to tonic upward deviation of eyes. It is associated with various neurometabolic, neurodegenerative, and movement disorders and medications such as antipsychotics, antiemetics, antidepressants, antiepileptics, and antimalarials. OGC can adversely impact the compliance and prognosis of the primary illness. Hence, it needs to be managed at earlier stages with appropriate medication, primarily anticholinergics.

The Sigma-1 Receptor Ligands Chlorpromazine and Trifluoperazine Inhibit Na+ Transport in Frog Skin Epithelium

Using the voltage-clamp technique, it has been shown for the first time that the neuroleptic drugs chlorpromazine and trifluoperazine, which act as sigma-1 receptor antagonists, attenuate Na+ transport in the frog skin epithelium. The results suggest that sigma-1 receptors may be involved in the regulation of transepithelial Na+ transport in frog skin.

Impact of changes in social anxiety on social functioning and quality of life in outpatients with schizophrenia: A naturalistic longitudinal study

The prevalence of comorbid social anxiety disorder among patients with schizophrenia is currently attracting attention, and symptoms of social anxiety are reportedly associated with various clinical features. However, the contribution of social anxiety to social functioning and quality of life (QOL) over time remains obscure. The aim of this study was to examine the impact of changes in social anxiety symptoms on social functioning and QOL among outpatients with schizophrenia. Of the 207 outpatients who were eligible at baseline, 118 patients agreed with and completed a follow-up investigation at least 1 year (695.8 days on average) after the baseline study. Stepwise multiple regressions examining the change in social functioning using demographic data and changes in clinical variables as explanatory variables demonstrated that the changes in social anxiety and general psychopathology contributed to the change in the Social Functioning Scale, while the changes in clinical severity and negative symptoms contributed to the change in the Global Assessment of Functioning scale. Stepwise multiple regressions for the change in QOL demonstrated that the changes in social anxiety and depression contributed to the change in the World Health Organization QOL scale, Brief version, and the changes in social anxiety and positive symptoms contributed to the Subjective Well-being Under Neuroleptic Drug Treatment, Short Form. The results revealed that the changes in social anxiety symptoms were significantly associated with the change in functional outcome among patients with schizophrenia. Treatments targeting social anxiety seem to be key to achieving a full recovery in patients with schizophrenia.

Beneficial effects of an algal oil rich in ω-3 polyunsaturated fatty acids on locomotor function and D2 dopamine receptor in haloperidol-induced parkinsonism

ABSTRACT Introduction: Parkinson's disease (PD) is a chronic neurological disorder whose pathogenesis involves the loss of dopaminergic neurons and dopamine terminals, formation of Lewy bodies, and microgliosis. Its treatment includes dopamine-based drugs with limited results and adverse effects. Additionally, some neuroleptic drugs used for mental disorders produce side effects referred to as parkinsonism. Dietary interventions with ω-3 polyunsaturated fatty acids (ω-3 PUFA) have attracted attention since they play a key role in most of the processes associated with PD etiology. Objective: The purpose of our work was to investigate the effects of an ω-3 PUFA rich algal oil on locomotive alterations induced by haloperidol and D2 receptor protein and gene expression in Wistar rats. Methodology: Pre- and co-supplementation of algal oil (300 mg of ω-3 FA/kg/day for six weeks) and haloperidol (1.5 mg/kg/day for two weeks) were evaluated. Results: Haloperidol provoked locomotive alterations in the Open Field Test and a 43% diminution in D2 receptor in brain membranes; in pre-supplemented rats a 93% increase in D2 receptor protein expression and a partial maintenance of locomotory performance were observed, while in co-supplemented rats D2 receptor protein expression was maintained as in control rats, although locomotive behavior was found diminished as in haloperidol rats. Conclusions: These results confirm the beneficial effects of ω-3 PUFA over locomotory alterations and as neuroprotective and neurorestorative compounds and demonstrates a stimulatory action on D2 receptor presence, as a mechanism by which these fatty acids participate in brain health.

T-wave morphology descriptors in patients with bulimia nervosa

Bulimia nervosa (BN) is associated with increased risk of cardiovascular disease and arrhythmias. Some reports found abnormal electrocardiographic markers of arrhythmias in BN, while others did not. This study investigated novel parameters of T-wave morphology that were reported to be associated with adverse cardiovascular outcomes in other patient groups, among patients with BN under medical care. Thirty-five BN patients and 76 healthy controls were included. Total cosine R to T (TCRT) and T-wave Morphology Dispersion (TMD) parameters were computed according to accepted standards for an average beat and a random beat. Patients were followed for 11.1 ± 0.1years for the emergence of arrhythmias or events of sudden death. Twenty-five (71.4%) BN patients were hospitalized when enrolled, for a mean duration of 1.1 ± 0.2months. The rest were ambulatory patients. The BN group had lower blood pressure, more smokers, and used antidepressants, neuroleptic drugs and benzodiazepines more than controls did. Other demographic parameters were comparable between groups. TCRT and TMD parameters were statistically similar and within the normal ranges reported by other research groups. None of the BN patients had prolonged QTc interval or electrolyte abnormalities on inclusion. During the follow-up period, no clinical symptoms suggestive of arrhythmias were reported, and no cardiovascular-related hospitalizations or deaths occurred in either group. Medically treated BN patients have normal T-wave morphology parameters and hence, low risk for repolarization-associated malignant ventricular arrhythmias. The prognostic importance of these novel repolarization parameters remains to be explored among untreated patients, those who ingest emetic substances and patients with electrolyte imbalance. Level III.

The effect of neuroleptic drugs on DPPC/sphingomyelin/cholesterol membranes

The hydrophobic nature of neuroleptic drugs renders that these molecules interact not only with protein receptors, but also with the lipids constituting the membrane bilayer. We present a systematic study of the effect of seven neuroleptic drugs on a biomembrane model composed of DPPC, sphingomyelin, and cholesterol. Differential scanning calorimetry (DSC) measurements were used to monitor the gel-fluid phase transition of the lipid bilayer at three pH values and also as a function of drug concentration. The implementation of a new methodology to mix lipids homogeneously allowed us to assemble bilayers completely free of organic solvents. The seven neuroleptics were: trifluoperazine, haloperidol decanoate, clozapine, quetiapine, olanzapine, aripiprazole, and amisulpride. The DSC results show that the insertion of the drug into the bilayer produces a fluidization and a disordering of the bilayer. The bilayer perturbation is qualitatively the same for all the studied drugs, but quantitatively different. The driving force for the neuroleptic drug to place itself in the lipid bilayer is entropic in nature, signaling to the importance of the size and geometry of the drugs. The drug protonated species produce stronger effects than their non-protonated forms. At high concentrations two of the neuroleptics revert the fluidization effect and another completely abolishes the gel-fluid transition. The DSC data and the associated discussion contribute to the understanding of the interactions between neuroleptic drugs and lipid membranes.

Photomutagenicity of chlorpromazine and its N-demethylated metabolites assessed by NGS

The human genome is constantly attacked by endogenous and exogenous agents (ultraviolet light, xenobiotics, reactive oxygen species), which can induce chemical transformations leading to DNA lesions. To combat DNA damage, cells have developed several repair mechanisms; however, if the repair is defective, DNA lesions lead to permanent mutations. Single-cell gel electrophoresis (COMET assay) is a sensitive and well-established technique for quantifying DNA damage in individual cells. Nevertheless, this tool lacks relationship with mutagenesis. Therefore, to identify errors that give rise to mutations it would be convenient to test an alternative known procedure, such as next generation sequencing (NGS). Thus, the present work aims to evaluate the photomutagenicity of neuroleptic drug chlorpromazine (CPZ), and its N-demethylated metabolites using COMET assay and to test NGS as an alternative method to assess photomutagenesis. In this context, upon exposure to UVA radiation, COMET assay reveals CPZ-photosensitized DNA damage partially repaired by cells. Conversely with this result, metabolites demethylchlorpromazine (DMCPZ) and didemethylchlorpromazine (DDMCPZ) promote extensive DNA-photodamage, hardly repaired under the same conditions. Parallel assessment of mutagenesis by NGS is consistent with these results with minor discrepancies for DDMCPZ. To our knowledge, this is the first example demonstrating the utility of NGS for evaluating drug-induced photomutagenicity.

The antipsychotic drug pimozide inhibits IgE-mediated mast cell degranulation and migration

BackgroundMast cells (MCs) mediate a key role in allergic diseases. Detailed studies of how the neuroleptic drug pimozide affects MC activity are lacking. The aim of this study was to investigate pimozide inhibition of immunoglobulin E (IgE)-mediated MC activation and MC-mediated allergic responses. MethodMCs were stimulated with anti-dinitrophenyl (DNP) IgE antibodies and DNP-horse serum albumin (HSA) antigen (Ag), and anti-allergic pimozide effects were detected by measuring β-hexosaminidase levels. Morphological changes were observed histologically. In vivo pimozide effects were assessed in passive cutaneous anaphylaxis (PCA) and ovalbumin (OVA)-sensitized active systemic anaphylaxis mouse (ASA) model experiments. Levels of phosphorylated (p-) SYK (spleen tyrosine kinase) and MAPKs (mitogen-activated protein kinases) were detected in western blots. ResultsWe found that pimozide inhibited MC degranulation, reduced MC release of β-hexosaminidase dose-dependently in activated RBL-2H3 (IC50: 13.52 μM) and bone marrow derived MC (BMMC) (IC50: 42.42 μM), and reduced MC morphological changes. The IgE/Ag-induced migration effect was suppressed by pimozide treatment dose-dependently. Pimozide down-regulated IgE/Ag-induced phosphorylation of SYK and MAPKs in activated MCs. Moreover, pimozide attenuated allergic reactions in PCA and ASA model mice, and decreased MC populations among splenic cells. ConclusionsThe antipsychotic drug pimozide can suppress IgE-mediated MC activation in vitro and in vivo and should be considered for repurposing to suppress MC-mediated diseases.

Symptomatic Characteristics of Parkinson's Disease Induced by Neuroleptic Drugs, Based on a Functional Neuroimaging Diagnosis.

Objective When patients take neuroleptics, the distinction between Parkinson's disease (PD) and drug-induced parkinsonism (DIP) based solely on clinical features can become difficult. At present, 123I-FP-CIT SPECT (DAT-SPECT) and 123I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy are widely used to supplement the differential diagnosis of parkinsonism. This study assessed the clinical symptoms and neurological findings in the patients suspected of having DIP based on DAT-SPECT findings. Methods Twenty-three patients (11 men, 12 women, age: 52-81 years old) presenting with DIP were recruited. All patients underwent neurological examinations, including brain magnetic resonance imaging and DAT-SPECT. Patients who showed abnormal DAT-SPECT results underwent MIBG myocardial scintigraphy. Results Eleven patients showed a reduction in the ligand uptake on DAT-SPECT (DAT-positive group), and nine of these patients showed a low delayed heart-to-mediastinum (H/M) ratio on MIBG myocardial scintigraphy. The remaining 12 patients showed normal results on DAT-SPECT (DAT-negative group). All patients in the DAT-positive group had asymmetric motor symptoms, whereas only 4 in the DAT-negative group exhibited this clinical feature (p=0.001). A detailed medical history showed that 7 of the 11 patients in the DAT-positive group had prodromal symptoms for PD. However, only 1 patient in the DAT-negative group exhibited these symptoms (p= 0.009). Although two patients in the DAT-negative group showed poor improvement, they showed a normal H/M ratio on MIBG and no response to levodopa. Conclusion The patients in the DAT-positive group might have prodromal symptoms that were worsened by neuroleptic drugs. The results of detailed history-taking and neurological findings seem to indicate cases of compromised dopaminergic transmission before the administration of neuroleptic drugs.

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.