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Japanese encephalitis virus (JEV) pathogenesis is driven by a combination of neuronal death and neuroinflammation. We tested 42 FDA-approved drugs that were shown to induce autophagy for antiviral effects. Four drugs were tested in the JE mouse model based on in vitro protective effects on neuronal cell death, inhibition of viral replication, and anti-inflammatory effects. The antipsychotic phenothiazines Methotrimeprazine (MTP) & Trifluoperazine showed a significant survival benefit with reduced virus titers in the brain, prevention of BBB breach, and inhibition of neuroinflammation. Both drugs were potent mTOR-independent autophagy flux inducers. MTP inhibited SERCA channel functioning, and induced an adaptive ER stress response in diverse cell types. Pharmacological rescue of ER stress blocked autophagy and antiviral effect. MTP did not alter translation of viral RNA, but exerted autophagy-dependent antiviral effect by inhibiting JEV replication complexes. Drug-induced autophagy resulted in reduced NLRP3 protein levels, and attenuation of inflammatory cytokine/chemokine release from infected microglial cells. Our study suggests that MTP exerts a combined antiviral and anti-inflammatory effect in JEV infection, and has therapeutic potential for JE treatment., (© 2024. The Author(s).)

Glioblastoma multiforme is the most common malignant primary brain tumor in adults. Despite new treatments developed including immunomodulation using vaccines and cell therapies, mortality remains high due to the resistance mechanisms presented by these tumor cells and the function of the blood-brain barrier that prevents the entry of most drugs. In this context of searching for new glioblastoma therapies, the study of the existing drugs to treat neurological disorder is gaining great relevance. The aim of this study was to determine, through a preliminary in vitro study on human glioblastoma (A172, LN229), anaplastic glioma (SF268) and neuroblastoma (SK-N-SH) cell lines, the possible antitumor activity of the active principles of several drugs (levomepromazine, haloperidol, lacosamide, valproic acid, levetiracetam, glatiramer acetate, fingolimod, biperiden and dextromethorphan) with the ability to cross the blood-brain barrier and that are commonly used in neurological disorders. Results showed that levetiracetam, valproic acid, and haloperidol were able to induce a relevant synergistic antitumor effect when associated with the chemotherapy currently used in clinic (temozolomide). Regarding the mechanism of action, haloperidol, valproic acid and levomepromazine caused cell death by apoptosis, while biperiden and dextromethorphan induced autophagy. Fingolimod appeared to have anoikis-related cell death. Thus, the assayed drugs which are able to cross the blood-brain barrier could represent a possibility to improve the treatment of neural tumors, though future in vivo studies and clinical trials will be necessary to validate it., (© 2022. The Author(s).)

Background: To assess potential benefits of quetiapine for persistent sleep disturbances in patients with posttraumatic stress disorder (PTSD) on stable combined SSRI and benzodiazepine therapy, who previously failed to respond to various benzodiazepine and non-benzodiazepine hypnotic adjuvant treatment as well as to first-generation antipsychotic add-on treatment., Subjects and Methods: Fifty-two male PTSD outpatients on stable combination treatment with SSRI and benzodiazepines, with persistent sleep disturbances not responding to prescription of zolpidem, flurazepam, nitrazepam, promazine, and levopromazine, were assessed for sleep disturbances improvements after prescription of quetiapine in the evening. Each patient met both ICD-10 and DSM-IV criteria for PTSD. Psychiatric comorbidity and premorbidity were excluded using the Mini-International Neuropsychiatric Interview (MINI). Improvement on the CAPS recurrent distressing dream item, reduction in the amount of time needed to fall asleep, prolongation of sleep duration, and reduction in average number of arousals per night in the last 7 days before the assessment period were used as efficacy measures., Results: All sleep-related parameters improved significantly at the end of a five-week follow-up: sleep duration increased by one hour (p<0.001), sleep latency decreased by 52.5 minutes (p<0.001), median number of arousals per night decreased from two to one (p<0.001), CAPS recurrent distressing dream item median decreased from five to four (p<0.001), and the number of patients dissatisfied with their sleep quality and quantity decreased from 45 to two (p<0.001)., Conclusion: Quetiapine prescribed in the evening may be successful therapy for persistent sleep disturbances in patients with PTSD and generally good response to an SSRI and benzodiazepine combination, who previously failed to respond to some of the usual hypnotic medication or addition of first-generation antipsychotics: zolpidem, flurazepam, nitrazepam, promazine, and levopromazine.

Background: Cytochrome P450 (CYP) enzymes are involved in the metabolism of many important endogenous substrates (steroids, melatonin), drugs and toxic xenobiotics. Their induction accelerates drug metabolism and elimination. The present study aimed at examining the inducing abilities of two antipsychotic drugs levomepromazine and clozapine for the main CYPs., Methods: The experiments were performed using cryopreserved human hepatocytes. The hepatotoxicity of levomepromazine and clozapine was assessed after exposure to the neuroleptics (LDH test). CYP activities were measured in the incubation medium using the CYP-specific reactions: caffeine 3-N-demethylation (CYP1A1/2), diclofenac 4'-hydroxylation (CYP2C9), perazine N-demethylation (CYP2C19) and testosterone 6β-hydroxylation (CYP3A4). In parallel, CYP mRNA levels were measured in neuroleptic-treated hepatocytes., Results: The results indicate that levomepromazine and clozapine induce the expression of main CYP enzyme CYP3A4 in human hepatocytes. Levomepromazine and clozapine at concentrations of 2.5 and 10 µM, respectively, caused a significant increase in the mRNA level and activity of CYP3A4. Both neuroleptics did not produce any changes in CYP1A1/2, CYP2C9 and CYP2C19., Conclusion: Levomepromazine and clozapine induce CYP3A4 in human hepatocytes in vitro. Further in vivo studies are advisable to confirm the CYP3A4 induction by levomepromazine and clozapine in the liver, and to assess the effect of these drugs on their own metabolism and on the biotransformation of other co-administered drugs which are the CYP3A4 substrates.

Antipsychotics are often the first-line treatment for behavioral and psychological symptoms of dementia. However, the potential anticholinergic effects of antipsychotics could counteract the therapeutic effects of cholinesterase inhibitors used to treat dementia. We investigated the inhibitory effects of 26 antipsychotics on [N-Methyl- 3 H]scopolamine specific binding in mouse cerebral cortex. At 10 -5  M, chlorpromazine, levomepromazine, prochlorperazine, timiperone, zotepine, pimozide, blonanserin, olanzapine, quetiapine, and clozapine inhibited [N-Methyl- 3 H]scopolamine binding by > 45%. Furthermore, the pK i values of chlorpromazine, levomepromazine, zotepine, olanzapine, and clozapine overlapped with their clinically achievable blood concentrations. Therefore, the anticholinergic properties of these antipsychotics could attenuate the effects of cholinesterase inhibitors., (Copyright © 2019 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Inhibition of cytochrome P450 (CYP) isoenzymes is the most common cause of harmful drug-drug interactions. The present study was aimed at examining the inhibitory effect of the phenothiazine neuroleptic levomepromazine on main CYP isoenzymes in human liver., Methods: The experiment was performed in vitro using the human cDNA-expressed CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 (Supersomes). CYP isoenzyme activities were determined using the CYP-specific reactions: caffeine 3-N-demethylation (CYP1A2), diclofenac 4'-hydroxylation (CYP2C9), perazine N-demethylation (CYP2C19), bufuralol 1'-hydroxylation (CYP2D6) and testosterone 6β-hydroxylation (CYP3A4). The rates of the CYP-specific reactions were assessed in the absence and presence of levomepromazine (1-50 μM). The concentrations of CYP-specific substrates and their metabolites formed by CYP isoenzymes were measured by HPLC with UV or fluorimetric detection., Results: Levomepromazine potently inhibited CYP2D6 (K(i) = 6 μM) in a competitive manner. Moreover, the neuroleptic moderately diminished the activity of CYP1A2 (K(i) = 47 μM) and CYP3A4 (K(i) = 34 μM) via a mixed mechanism. On the other hand, levomepromazine did not affect the activities of CYP2C9 and CYP2C19., Conclusion: The inhibition of CYP1A2, CYP2D6 and CYP3A4 by levomepromazine, demonstrated in vitro in the present study, should also be observed in vivo (especially the CYP2D6 inhibition by levomepromazine), since the calculated K(i) values are below or close to the presumed concentration range for levomepromazine in the liver in vivo. Therefore pharmacokinetic interactions involving levomepromazine and CYP2D6, CYP1A2 or CYP3A4 substrates are likely to occur in patients during co-administration of the above-mentioned substrates/drugs., (Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.)

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have distinct clinical features but a common pathology--cytoplasmic inclusions rich in transactive response element DNA-binding protein of 43 kDa (TDP43). Rare TDP43 mutations cause ALS or FTD, but abnormal TDP43 levels and localization may cause disease even if TDP43 lacks a mutation. Here we show that individual neurons vary in their ability to clear TDP43 and are exquisitely sensitive to TDP43 levels. To measure TDP43 clearance, we developed and validated a single-cell optical method that overcomes the confounding effects of aggregation and toxicity and discovered that pathogenic mutations shorten TDP43 half-life. New compounds that stimulate autophagy improved TDP43 clearance and localization and enhanced survival in primary murine neurons and in human stem cell-derived neurons and astrocytes harboring mutant TDP43. These findings indicate that the levels and localization of TDP43 critically determine neurotoxicity and show that autophagy induction mitigates neurodegeneration by acting directly on TDP43 clearance.

Human embryonic stem cells (hESCs) and induced pluripotent cells have the potential to provide an unlimited source of tissues for regenerative medicine. For this purpose, development of defined/xeno-free culture systems under feeder-free conditions is essential for the expansion of hESCs. Most defined/xeno-free media for the culture of hESCs contain basic fibroblast growth factor (bFGF). Therefore, bFGF is thought to have an almost essential role for the expansion of hESCs in an undifferentiated state. Here, we report identification of small molecules, some of which were neurotransmitter antagonists (trimipramine and ethopropazine), which promote long-term hESC self-renewal without bFGF in the medium. The hESCs maintained high expression levels of pluripotency markers, had a normal karyotype after 20 passages, and could differentiate into all three germ layers., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: Zuclopenthixol pharmacokinetics is incompletely characterised. We investigated potential interactions mediated through cytochrome P450 enzymes., Method: In vitro, we examined the impact of CYP2D6 and CYP3A4 inhibitors on zuclopenthixol metabolism in microsomes from six human livers. Subsequently, we compared dose-corrected serum zuclopenthixol concentrations in 923 samples from a therapeutic drug monitoring database from patients prescribed oral (n = 490) or injected (n = 423) zuclopenthixol alone or with fluoxetine, paroxetine, levomepromazine or carbamazepine., Results: In vitro fluoxetine, paroxetine, ketoconazole and quinidine all significantly inhibited zuclopenthixol metabolism. Ketoconazole and quinidine together abolished zuclopenthixol disappearance. Clinically, dose-corrected oral zuclopenthixol serum concentrations increased significantly, after adjustment, by 93%, 78% and 46% during co-treatment with fluoxetine, paroxetine and levomepromazine and decreased 67% with carbamazepine. Carbamazepine caused dose-dependent reductions in the oral zuclopenthixol concentration-dose ratio (P < 0.001), fluoxetine (P < 0.001) and paroxetine (P = 0.011) dose-dependent increases and levomepromazine an increase related to its serum concentration (P < 0.001). Results for injected zuclopenthixol were similar but not all reached statistical significance., Conclusion: The In vitro study suggests zuclopenthixol is metabolised primarily by CYP2D6 and CYP3A4. The clinical study supports this, demonstrating the impact of co-prescribed inhibitors or inducers. Guidelines should incorporate these interactions noting the potential for zuclopenthixol-related toxicity or treatment failure., (© 2010 John Wiley & Sons A/S.)

Purpose: Codeine/paracetamol (C/P) and levomepromazine (L) are frequently co-administered for the treatment of acute back pain, but the efficacy/effectiveness of this combination drug therapy has not been evaluated. The demethylation of codeine to morphine is catalyzed by the polymorphic enzyme cytochrome P450 2D6 (CYP2D6), of which levomepromazine (methotrimeprazine) is a known inhibitor. The aim of this study was to investigate whether low-dose levomepromazine inhibits the formation of morphine from codeine in a patient population of homozygous extensive (EM) and heterozygous extensive (HEM) metabolizers of CYP2D6., Methods: Our patient cohort consisted of 29 patients hospitalized for acute back pain who were randomized to a 24-h treatment with either C/P (60 mg codeine + 1000 mg paracetamol) four times daily or to L+C/P (levomepromazine 5 + 5 + 5 + 10 mg + C/P) four times daily. After zero-urine sampling (baseline), the treatment was started and urine collected for 24 h. Blood samples were later genotyped for the CYP2D6*3, *4, and *6 polymorphisms by the PCR (LightCycler system) and for the *5 polymorphism using long PCR, to identify EM and HEM and to eliminate CYP2D6 poor metabolizers. Urine samples were analyzed using the CEDIA immunoassay and gas chromatography-mass spectrometry after enzymatic hydrolysis of glucuronide conjugates. O-demethylation ratios of codeine were calculated as hydrolyzed (total) concentrations of morphine/morphine + codeine., Results: Twenty-two of the patients fulfilled the inclusion criteria, of whom ten were EM (five C/P and five L+C/P) and twelve were HEM (six C/P and six L+C/P) for functional CYP2D6 alleles. In the EM group, the median O-demethylation ratio was significantly higher (P = 0.016, Mann-Whitney test) after the C/P treatment (0.092, range 0.041-0.096) than after the L+C/P treatment (0.031, range 0.009-0.042). However, there was no significant difference between these two treatments in either the HEM group [n = 12; 0.024 (range 0.011-0.042) vs. 0.026 (range 0.009-0.041), respectively; P = 1.00] or in the combined EM/HEM group [11 C/P + 11 L+C/P; 0.041 (range 0.011-0.096) vs. 0.030 (range 0.009-0.042), respectively; P = 0.122]., Conclusions: Our study revealed significant inhibition in the O-demethylation of codeine to morphine in homozygous EM of CYP2D6 treated with low-dose levomepromazine and codeine/paracetamol, compared to treatment with codeine/paracetamol only. No significant difference could be detected in HEM or in the mixed and heterogenous group of EM/HEM. In patients prescribed this drug combination, the amount of morphine generated by the O-demethylation of codeine may be insufficient for effective pain relief. The therapeutic effect of codeine in the treatment of acute back pain should be assessed with and without levomepromazine.

After discontinuation of neuroleptic agents, their effects are still present for a long time. The exact underlaying mechanisms are still unclear. In two previous studies we measured the concentrations and region-specific distribution of haloperidol (Kornhuber et al. 1999) and levomepromazine (Kornhuber et al. 2006) in postmortem human brain tissues. The aim of the present paper is to compare the results of these two studies. Even after short-term treatment, haloperidol and levomepromazine concentrations reach high levels in human brain tissue. Haloperidol concentrations in brain tissue are 10-30 times higher than the optimum serum concentrations in the treatment of schizophrenia. The brain-to-blood concentration ratio of levomepromazine is about 10. The estimated elimination half-life of these drugs in brain tissue are 6.8 days (haloperidol), 7.9 days (levomepromazine) and 27.8 days for the metabolite desmethyl-levomepromazine, respectively. After two half-lives (about 2 weeks), a considerable amount of drug remains in brain tissue. Haloperidol concentrations appeared to be homogeneously distributed across different brain areas, whereas levomepromazine shows a region-specific distribution, with highest values in the basal ganglia. The persistence of neuroleptic drugs in the human brain might explain their prolonged effects and side effects. The region-specific distribution of levomepromazine may increase our understanding of both the preferential toxicity of neuroleptic drugs against basal ganglia structures and higher basal ganglia volumes in patients treated with neuroleptics.

The aim of the present study was to investigate the influence of classic and atypical neuroleptics on the activity of rat CYP2C6 measured as a rate of warfarin 7-hydroxylation. The reaction was studied in control liver microsomes in the presence of neuroleptics, as well as in microsomes of rats treated intraperitoneally for one day or two weeks (twice a day) with pharmacological doses (mg/kg) of the drugs (promazine, levomepromazine, thioridazine, perazine 10, chlorpromazine, haloperidol 0.3, risperidone 0.1, sertindole 0.05), in the absence of the neuroleptics in vitro. Some of the neuroleptics added in vitro to control liver microsomes decreased the activity of CYP2C6. Sertindole and levomepromazine (Ki = 25 and 31 microM, respectively) were the most potent inhibitors of the rat CYP2C6 among the drugs studied. Their effects were more pronounced than those of the other phenothiazines tested: thioridazine and chlorpromazine (Ki = 88 and 91 microM, respectively), promazine and perazine (Ki = 322 and 341 microM, respectively), risperidone (Ki = 414 microM) or haloperidol (Ki = 606 microM). The investigated neuroleptics--when given to rats in vivo for one day or two weeks--did not produce any indirect effect on CYP2C6 via other mechanisms, except for levomepromazine, which increased the activity of the enzyme after 24-h exposure. Therefore, the direct inhibitory effect of levomepromazine on CYP2C6 may be attenuated by an indirect mechanism at the beginning of the neuroleptic therapy. In summary, the obtained results show direct inhibitory effects of some phenothiazine neuroleptics and sertindole on the activity of CYP2C6 in vitro in rat liver microsomes. Considering relatively high pharmacological doses and therapeutic concentrations of phenothiazines, it seems that the inhibitory effect of levomepromazine (and other phenothiazines with Ki values below 100 microM) found in vitro may be of physiological and pharmacological importance in vivo.

This is a review of the uses of levomepromazine in psychiatry, based upon MEDLINE, PSYCLIT and EMBASE literature searches. The main indications for this drug in psychiatry are schizophrenia and schizoaffective disorder. Levomepromazine's sedative properties particularly fit it to use in psychiatric intensive care. There is also some evidence to suggest it has efficacy in drug-resistant psychosis, although this property of the drug does require further research. In other areas of medicine levomepromazine has been used in: alleviating bronchoconstriction; as a preoperative sedative; in terminal pain control and postoperative analgesia; and in the control of nausea. Some antimycobacterial properties have been recorded. The drug should not be prescribed to patients at high risk of accidental or suicidal overdose.

Objectives: To investigate the effects of levomepromazine and different desflurane concentrations upon electrocardiographic variables., Animals: Twenty adult mongrel dogs of both sexes weighing 6-28 kg., Methods: Dogs were divided into two groups of 10 animals. Group 1 received 1 mg kg(-1) i.v. of levomepromazine and 15 minutes later anesthesia was induced with propofol (3 mg kg(-1) i.v.). Desflurane end-tidal concentration was set at 1.6 MAC. After 30 minutes at this concentration, measurements were taken and the end-tidal concentration was reduced to 1.4 MAC. Thereafter, it was reduced to 1.2 and then 1.0 MAC at 15-minute intervals. The same procedure was followed for group 2, except that levomepromazine was replaced with 0.2 mL kg(-1) of 0.9% saline solution and more propofol was needed for induction (7 mg kg(-1)). The animals' body temperature was maintained between 38.3 and 39 degrees C using a heating pad. The electrocardiographic tracing was obtained from lead II throughout the experimental period. The measurements were taken immediately before the administration of levomepromazine or placebo (T1), 15 minutes after pre-medication (T2) and 30 minutes after the establishment of 1.6 MAC (T3). The other measurements were made at the concentrations of 1.4, 1.2, and 1.0 MAC, respectively (T(4-6)). The numerical data were submitted to analysis of variance plus F-test (p<0.05)., Results: The dogs that received levomepromazine had a decrease in heart rate. However, in both groups it increased with desflurane administration. Levomepromazine, in association with desflurane, did not induce significant electrocardiographic changes, and all mean values (except P-wave duration) were within the reference range for this species., Conclusions and Clinical Relevance: This study documented that levomepromazine, in association with desflurane, does not induce significant changes in electrocardiographic variables, suggesting that this drug combination has minimal effect on myocardial conduction.

The efflux pump of multidrug resistant mdr cells have different sensitivities to some stereoisomeric forms of CNS-active compounds. The ABC transporters of mdr cells were more sensitive to (-)butaclamol than to its stereoisomeric counterpart (8), which may function to alter the membrane structure. We suppose that the drug-accessible membrane structure possesses an important role in the induction (or prevention) of apoptosis. Therefore the apoptosis-inducing effect of three stereoisomeric pairs was studied on mouse lymphoma cells. In these experiments levo- and dextromepromazine had similiar effects. The cis- and trans-clopenthixol were less effective in apoptosis induction than the 12H-benzo(a)-phenothiazine used as a positive control. The effect of stereoisomeric pairs on induced apoptosis was studied when the cells were exposed to the stereoisomers for 60 minutes before subjection apoptosis induction by benzo(a)phenothiazine, a well-known apoptosis inducer. Then the pretreated cells were exposed to 12H-benzo(a)-phenothiazine for 60 minutes. The samples were washed and incubated for 24 hours. The cells were stained with annexin-V-FITC and propidium iodine and investigated by flow cytometry. The mdr cells with increased membrane integrity may result in the preferential killing of multidrug resistant cancer cells in the presence of some stereoisomers.

Levomepromazine (previously known as methotrimeprazine) has a broad range of beneficial effects in the terminal phase of many illnesses, resulting from its combined antipsychotic, anxiolytic and sedative actions. Levomepromazine can safely be administered in a continuous subcutaneous infusion with most other commonly used drugs in palliative care.

The effect of three different stereoisomer pairs of CNS (central nervous system) active compounds was studied on the activity of human mdr1 p-glycoprotein. The methotrimeprazine, clopenthixol and butaclamol isomers had an antiproliferative effect (ID50) on the mdr1 expressing cells at 0.250 microgram/ml, while the parental cells were less sensitive having ID50 at 0.37-0.69 microgram/ml. Enantiomers of methotrimeprazine and clopenthixol had similar effectivity on the drug efflux of mdr cells. However, (-)butaclamol was found to inhibit mdr efflux-pump activity much more than the CNS active (+) isomer. Based on these results, tricyclic compounds does not seem to have stereoselectivity in methotrimeprazine and clopenthixol on the mdr reversal effect. In general, both active and inactive members of stereoisomers had a similar effect on the drug accumulation of the mdr cells. Therefore, hypothetically the CNS inactive member of stereoisomer pairs can be used as a resistance modifier without any risk in patients suffering from drug resistant cancer.

Bromperidol is a close structural analog of haloperidol. The authors studied the effects of levomepromazine and thioridazine, which are frequently added to other neuroleptics as sedatives, on plasma concentrations of bromperidol and its reduced metabolite. The subjects were 26 inpatients with schizophrenia receiving bromperidol, 12 to 24 mg/day, for 1 to 19 weeks. In 10 cases, 50 mg levomepromazine per day and in nine cases, 50 mg thioridazine per day were coadministered for 1 week. In seven cases, both drugs were coadministered with > or = 2-week intervals. Plasma concentrations of bromperidol and reduced bromperidol were measured by a high-performance liquid chromatographic method. Levomepromazine (n = 17) significantly (p < 0.001) increased plasma concentrations of bromperidol (7.3 +/- 4.1 versus 10.2 +/- 4.8 ng/ml) and reduced bromperidol (1.8 +/- 1.4 versus 4.5 +/- 3.3 ng/ml). Thioridazine (n = 16) did not significantly change plasma concentrations of bromperidol (9.1 +/- 5.7 versus 8.6 +/- 5.5 ng/ml), while those of reduced bromperidol could not be measured because of interfering peaks. The current study suggests that levomepromazine, but not thioridazine, increases plasma concentrations of bromperidol and reduced bromperidol by inhibiting the metabolism of these compounds.

The bioequivalence and absolute bioavailability of oblong and coated levomepromazine tablets were studied in 12 healthy volunteers. A 1-hour intravenous infusion served as the reference. Serum concentrations of levomepromazine were quantified with a specific high-performance liquid chromatographic method and electrochemical detection. The 2 oral formulations were bioequivalent. After oral administration of oblong and coated levomepromazine tablets the mean serum concentration versus time profiles were similar and the pharmacokinetic parameters showed wide interindividual variations. There was a 21% absolute bioavailability of levomepromazine, indicating a pronounced presystemic metabolism. The total serum clearance and the apparent volume of distribution at steady state were 48 +/- 14 l/min and 980 +/- 213 l, respectively. These pharmacokinetic parameters were also investigated with respect to the CYP2D6 polymorphism, i.e. via dextromethorphan phenotyping of 9 subjects, 3 subjects were poor metabolizers, and 6 extensive metabolizers. The Spearman's rank-ordered correlation analysis did not reveal a significant correlation between the pharmacokinetic parameters AUC, Cmax and t1/2 after oral administration of oblong and coated levomepromazine tablets and the metabolic ratios of dextromethorphan, suggesting that levomepromazine is not metabolized to any major extent by the isoenzyme CYP2D6.

Simulation of toxic brain edema-swelling allowed one to analyze the dynamics of blood protein alteration in presence of various neuroleptics. Alterations in blood protein fractions correlated with dynamics of nervous tissue impairments. All the drugs studied exhibited similar antiswelling action involving the gamma-globulin sub-system activation. At the same time, the neuroleptics with activating and depriving effects demonstrated an oppositely directed influence on blood albumins.

The influence of the major metabolites of the phenothiazine derivative, levomepromazine (methotrimeprazine), on hydroxylation of debrisoquine was examined in male Sprague-Dawley rats. The metabolic ratio of debrisoquine/4-hydroxy debrisoquine was first determined in rats after oral administration of 10 mg/kg of debrisoquine. Then the same dose of debrisoquine was co-administered with various doses of levomepromazine or one of its metabolites. Levomepromazine and its sulphoxidated, N-demethylated and O-demethylated metabolites caused highly significant and dose-dependent increases in the debrisoquine metabolic ratio. 3-Hydroxy levomepromazine had no significant effect on the metabolism of debrisoquine. This indicates that the non-hydroxylated metabolites of levomepromazine have relatively high affinities for the cytochrome P450 enzyme which converts debrisoquine to 4-hydroxy debrisoquine in the rat. Such metabolites may therefore be responsible for a considerable part of the inhibitory effect of debrisoquine hydroxylation previously reported in patients treated with phenothiazine neuroleptics.

The susceptibility of 66 strains of Candida albicans from patients was tested against ketoconazole (Ktz), chlorpromazine (Chl) levomepromazine (Lev), haloperidol (Hal) and the combination of Ktz with these calmodulin inhibitors, using Sabouraud's broth. The minimal inhibitory concentrations (MICs) for 66 strains of C. albicans were as follows: Chl 192 +/- 11.4 micrograms/ml, Lev 306 +/- 16.4 micrograms/ml, Hal 464 +/- 13.8 micrograms/ml compared with Ktz 34.46 +/- 3.9 micrograms/ml. The combination of Ktz and calmodulin inhibitors in various ratios (1:1,1:2,2:1) was found to exert synergistic effect and the mean values of the combinations were: Ktz+Chl 3.45 +/- 0.35, 3.78 + 0.36, 5.58 + 0.4 micrograms/ml; Ktz+Lev 10.8 +/- 2.19, 9.7 +/- 2.23, 10.5 + 2 micrograms/ml; Ktz+Hal 6.4 +/- 1.7, 6.8 +/- 1.6, 7.28 +/- 1.5 micrograms/ml. These results were significantly different (p < 0.001) from those of ketoconazole. These findings indicate that some calmodulin inhibitors increase the antifungal activity of Ktz against C. albicans in vitro.

Aminazine, 30 mg/kg, and tisercin, 30 mg/kg, were tested for their effects on the activities of angiotensin-converting enzyme (ACE), renin and the levels of aldosterone. Blood and lungs were taken 1 and 24 hours after intraperitoneal administration of the drugs to male rats. Tisercin was found to inhibit the activity of ACE and enhanced that of renin and elevated the levels of aldosterone in the serum and lung cytosol 24 hours following the agent administration. Aminazine depressed the activity of ACE and increased the serum levels of aldosterone 1 and 24 hours post-administration.

1. The effects of zopiclone 10mg (ZP), flunitrazepam 1mg (FN), triazolam 0.25mg (TZ) and levomepromazine 5mg (LP) on two models of sleep-wake schedule change-6 hours advanced shift: (A-shift), and 6 hours delayed: (D-shift)--were investigated in 6 healthy volunteers using polysomnography. 2. In A-shift with placebo, TST, SEI, %SR and REM/NREM decreased. ZP, FN and TZ shortened SL. All drugs increased TST and SEI. TZ and LP increased %SR and REM/NREM. 3. In D-shift with placebo, TST decreased, SWSL was prolonged, %S3+4 decreased, and %SR and REM/NREM increased. All drugs increased TST. ZP and LP shortened SWSL. All drugs increased %SWS. ZP, FN and TZ decreased %SR. ZP and FN decreased REM/NREM. 4. Daytime mental and physical conditions were worse than usual on more than half of the days in A- and D-shift. LP and FN caused some inadequate conditions on the following days. Significantly higher REM/NREM was observed in the nights before the days with worse mental conditions in D-shift, and lower REM/NREM in the nights before the days with worse physical conditions in A-shift. 5. It is concluded that TZ and ZP are superior to the others for A-shift and D-shift, respectively.

Based on the concept of glucocorticoid-receptor induction of angiotensin-converting enzyme (ACE), approaches to inhibiting enzyme induction with drugs that suppress the function of type II cytoplasmic glucocorticoid receptors, (genuine glucocorticoid receptors), are suggested. Three types of inhibiting the function of type II glucocorticoid receptors by drugs were distinguished. Type I is characterized by competition of the drugs with natural and synthetic glucocorticoids for interaction with glucocorticoid receptors (cortexolone, progesterone); type II is determined by irreversible inactivation of type II glucocorticoid receptors (aminazine, tisercin); type III is related to an increase of interaction of transcorticoid receptors with natural glucocorticoids which is accompanied by a reduction of the interaction of natural glucocorticoids with genuine glucocorticoid receptors (analgin, amidopyrine). It has been established that the drugs that provoke irreversible inactivation of the function of type II glucocorticoid receptors decrease ACE activity in blood plasma and in the lungs, that may serve the main reason for their high hypotensive effect in arterial hypertension. A concept is advanced, providing evidence for the use of the classical ACE inhibitors and of type II glucocorticoid receptor inhibitors.

The formation of three oxidative metabolites of imipramine, N-desmethylimipramine (desipramine), 2-hydroxyimipramine, and 10-hydroxyimipramine was studied in microsomes of an extensive metabolizer liver (KDL 26) and of a poor metabolizer liver (KDL 31) and in a homogenate of COS-1 cells in which the P450IID6 complementary deoxyribonucleic acid had been expressed. The following data support the role of P450IID6 in the 2-hydroxylation of imipramine: (1) The formation of 2-hydroxyimipramine was reduced to less than 20% of the control value when microsomes were incubated with serum containing inhibitory antibodies against P450IID6 (anti-LKM1), whereas no effect was seen with regard to formation of desipramine and 10-hydroxyimipramine, (2) quinidine and levomepromazine were potent competitive inhibitors of 2-hydroxylation of imipramine (ki approximately 70 nmol/L, and ki approximately 1 mumol/L, respectively) but had no effect on N-demethylation and 10-hydroxylation, and (3) in the COS-1 cell, homogenate, 10-hydroxyimipramine, 2-hydroxyimipramine, and desipramine were formed at rates of 48, 164, and 256 pmol per hour per milligram of homogenate protein, respectively. The P450 isozymes that are responsible for N-demethylation and 10-hydroxylation of imipramine have not yet been identified.

The in vivo inhibitory effect of five beta-adrenoceptor antagonists and levomepromazine on debrisoquine metabolism was assessed in 37 subjects. The debrisoquine phenotyping test was performed before and after 7 days' treatment with oxprenolol (40 mg three times daily), propranolol (20 mg three times daily), timolol (10 mg twice daily), pindolol (5 mg twice daily), metoprolol (50 mg twice daily) or levomepromazine (10 mg daily), each of which was given to six-seven subjects. No clear change in the urinary metabolic ratio of debrisoquine/4-OH-debrisoquine (MR) was seen with any of the single beta-adrenoceptor antagonist treatments, but the MR value increased significantly when all beta-adrenoceptor blocker treatments were considered together. Debrisoquine metabolism was clearly impaired after levomepromazine 10 mg daily for 7 days; the mean MR increased from 1.24 +/- 1.6 to 4.70 +/- 5.23 (P = 0.018) and the excretion of 4-hydroxydebrisoquine decreased from 0.92 +/- 0.46 mg to 0.31 +/- 0.19 mg (P = 0.043). Thus, levomepromazine changes MRs towards those characteristic of phenotypically poor metabolizers, but beta-adrenoceptor antagonists at the doses examined have only a marginal effect.

Electrically evoked release of dopamine from the caudate nucleus is reduced by the dopamine receptor agonists, apomorphine and bromocriptine, and facilitated by neuroleptic drugs, which act as dopamine autoreceptor antagonists. The potencies of chlorpromazine, fluphenazine, levomepromazine and their hydroxy-metabolites in modulating electrically evoked release of dopamine were examined by superfusion of rabbit caudate nucleus slices pre-incubated with 3H-dopamine. O-Desmethyl levomepromazine, 3-hydroxy- and 7-hydroxy metabolites of chlorpromazine and levomepromazine facilitated electrically evoked release of 3H-dopamine, having potencies similar to that of the parent compounds. 7-Hydroxy fluphenazine was less active than fluphenazine in this system. These results indicate that phenolic metabolites of chlorpromazine and levomepromazine, but not of fluphenazine, may contribute to effects of the drugs mediated by presynaptic dopamine receptors.

A description is given of a technique named "Protected Sleep", which produces a deep and residual analgesia and neurolepsia, without interfering with spontaneous respiration. A deep, stable and reliable neuroanesthesia is achieved by means of a partial pharmacodynamic blockage of the neuro-humoral reaction system. It is recognisable by the following features: 1 degree a smooth transition through pre-, per- and post-operative stages, avoiding in particular immediate awakening; 2 degrees a relative arterial hypotension, low venous pressure good peripheral circulation and tissular perfusion; 3 degrees light hypothermia; 4 degrees completely spontaneous respiration. This last factor is, to our way of thinking, of great importance: The venous return remains physiologically unchanged during inspiration in the peroperative as well as in the pre- and postoperative phases, enabling the maintenance of a constant, low venous pressure. Furthermore, should danger exist, the preservation of spontaneous respiration facilitates the immediate control of the respiratory centre. In this way we can obtain: 1. An almost perfect bloodless surgical field with good conditions for dissecting. 2. A low cerebro-spinal fluid pressure. 3. Decreased brain volume. 4. Absence of postoperative haemorrage. 5. Little of no postoperative oedema. 6. Little or no postoperative hyperthermia. "Protected sleep" is a pharmacodynamic technique realised mainly through administration of a combined and sufficient dose of pethidine, N-allyl-normorphine and levome promazine. For induction, a given dose of diazepam is combined with a single dose of succinyl-choline, to facilitate intubation, followed by a large dose of the narco-neuro-leptanalgesic mixture. For maintenance, nitrous oxide, oxygen, methoxyflurane and additional doses of the mentioned mixture are administered. Undirectional gas flow, without rebreathing, is provided, using the Ruben valve. In this paper on neuroanaesthesia, the technique of "Protected Sleep" and the pre-, per- and postoperative management and positioning of the neurosurgical patient are described in detail.

The influence of antidepressants on the brain and pituitary content of immunoreactive beta-endorphin (ir-beta E) and dynorphin (ir-DYN) was studied in rats. Chronic administration of the first and second generation antidepressants imipramine, citalopram and rolipram, and of the antidepressant neuroleptics levomepromazine and chlorprothixene elevated the level of ir-beta E in the hypothalamus. Imipramine and levomepromazine also increased the level of ir-DYN in this tissue. Imipramine administered chronically potentiated stress-induced as well as morphine analgesia. The results obtained suggest that chronic antidepressants enhance the brain opioid system activity and increase the sensitivity of opiate receptors.

This paper deals with the microbiological assay of chloropromazine, levomepromazine and promethazine, whose bacteriostatic power was measured in the diffusion test against four different strains of Bacillus subtilis. The four strains proved to be equally sensitive to solutions of phenothiazine derivatives containing more than 0.5 mg/ml. There was no difference between the four strains as referred to the median percentual error in the chlorpromazine determination. The median percentual error has been very high (around 20%) in the levomepromazine determination using Bacillus subtilis ATCC 9945. When promethazine was used against the four strains of Bacillus subtilis a very high percentual error (around 20%) has been obtained, therefore, they are not recommended for the promethazine determination.

Chlorpromazine, levopromazine and promethazine exerted a bacteriostatic effect on Gram-positive bacteria at 20-60 mug/ml, on Gram-negative bacteria at 130-180 mug/ml concentration. Of the three compounds, chlorpromazine had the most marked bactericidal effect on cultures of Bacillus anthracis growing in minimal medium. In addition, chlorpromazine had a significant bactericidal effect on the resting cells of Escherichia coli suspended in saline. Pseudomonas aeruginosa was resistant to phenothiazines. Experiments have failed to derive resistant mutants from the highly sensitive B. anthracis. An effective R-factor elimination was observed at chlorpromazine concentrations of 50 mug/ml, practically not affecting the growth of multiple resistant E. coli.

The experiment on adrenalectomized rats has shown that the concentration rates of 3.5.10(-4)M aminazine and 7.0.10(-4)M tizercine reduce 3H-acetonide triamcinolone-receptor interaction, and the concentration rate of 7.0.10(-4) tizercine increases 3H-cortisol receptor interaction in liver cytosol. The concentration rates of 3.5.10(-7)M aminazine and 3.5.10(-5)M tizercine suppress 3H-uridine inclusion into the acid-resisting mRNA thymocyte fraction. Associated introduction of aminazine and tizercine with acetonide triamcinolone (10(-8)M) increases the inhibiting effect on 3H-uridine inclusion into mRNA thymocytes. This suggests that aminazine and tizercine suppress matrix activity of DNA thymocytes through their effect on glucocorticoid receptors of type II.

The interactions of Methotrimeprazine (MTM) with the CNS opiate receptor, with naloxone, and with morphine were investigated. MTM (16--256 nM) did not compete with 3H-naloxone for specific binding sites in mouse brain homogenates. In vivo, MTM induced analgesia was not antagonized by naloxone. After 14 days administration of MTM partial tolerance developed to the activity effect but not the analgesic effect. After 14 days administration of morphine, tolerance developed to both the activity effect and the analgesic effect.

Levomepromazine, chlorpromazine (10 and 30 mg/kg), etaperaxine, haloperidol (3 and 10 mg/kg) inhibited the exploratory-motor reactions of rats and the brain Na, K-ATPase activity an hour after their administration. The effects of tranquilizers as well as of antidepressants on the exploratory reactions and on the enzyme activity were not found to stand in a clearcut relation to each other. The stimulating effect of amphethamine (3 mg/kg) was accompanied by activation and suppressive action (10 mg/kg)--by inhibition of the enzyme. It is suggested that the inhibition of the brain Na, K-ATPase activity by psychotropic drugs may play a role in the mechanism of their sedative action.

Methotrimeprazine (MTM) (0.5 mg/kg) and meperidine (1.5 mg/kg) was administered to four groups of 10 patients each. Two of these groups (I and II) received MTM or meperidine 12 minutes before, two other groups (III and IV), 3 minutes after, induction of thiopental anesthesia. N2O-O2 was administered after thiopental induction, and fractional doses of meperidine and muscle relaxants were used as required for maintenance of anesthesia. The preliminary administration of MTM or meperidine decreased the induction dose of thiopental by about 60 percent. When administered before thiopental, both had similar effects on heart rate, but whereas MTM moderately decreased, meperidine moderately increased systolic and diastolic blood pressure MTM had little or no effect on respiratory rate, which was significantly depressed by meperidine. When given after an induction dose of thiopental, the circulatory effects of MTM and meperidine were similar. Respiratory measurements were little affected by MTM but were markedly depressed by meperidine. The mug/kg/min maintenance doses of meperidine were about the same in the four groups. Postanesthetic recovery of consciousness was delayed in the two MTM groups. The incidence of postoperative nausea and vomiting was less in the MTM than in the meperidine groups. MTM appears to have several advantages over meperidine as a component of balanced anesthesia, but is not desirable if rapid postanesthetic recovery or early ambulation is important. Its use is indicated in patients in whom even transient respiratory depression is undesirable and in those in whom prolonged postoperative sedation is desired.

Summarized results of the experiments (conducted in 1981-1984) demonstrate seasonal rhythms of some behavioural effects (catalepsy and depression of locomotor activity) of haloperidol (0.5 mg/kg) and levomepromazine (5 mg/kg) in white rats. In intact rats neuroleptics were more effective in depressing high than low motor activity. Catalepsy induced by single administration of neuroleptics was more pronounced in spring and autumn months. A certain negative correlation exists between seasonal variations of neuroleptic catalepsy and the speed of monoamine (dopamine and serotonin) metabolism in the brain of intact rats.

Administration of antidepressants (imipramine, citalopram) or antidepressant neuroleptics (levomepromazine, chlorprothixene) for 14-24 days enhanced by 20-30% the density of [3H]prazosin binding sites in the membranes from the cerebral cortex of the rat, without significant change in their affinity.

1. Perphenazine, promethazine and levomepromazine induced sedation in young pullets following intramuscular injections. 2. The best results were obtained with perphenazine at a dose rate of 1-5 mg/kg.

The duration of the analgesic effect of levomepromazine was prolonged in mice when associated with propranolol. The administration of morphine to animals treated with propranolol resulted in an increase of morphine toxicity with death of some animals.

Although the anterior hypothalamus has been implicated in the control of aggression in various rodent species, little is known about the neurochemical mechanisms mediating this control. It has been established that flank marking, which occurs with high frequency during agonistic encounters in hamsters, is dependent upon vasopressin-sensitive neurons in the anterior hypothalamus. The present study was undertaken to determine whether intraspecific aggression in this species is similarly influenced by vasopressin in this area of the hypothalamus. Adult male hamsters, surgically implanted with guide cannulae aimed at the anterior hypothalamus, were microinjected with three different concentrations of the V1-receptor antagonist d(CH2)5Tyr(Me)AVP or a vehicle control of 0.9% NaCl. Sixty minutes after each microinjection a smaller male hamster was introduced into the home cage of the treated hamster. The resident hamsters showed a significant dose-dependent reduction in the number of biting attacks on the intruders over the 10 minute test period. The V1-receptor antagonist also caused a significant increase in the resident hamster's latencies to attack the intruder. However, the resident hamsters' total contact time with the intruder was unaffected by drug treatment suggesting that the reduction of aggression was not due to a generalized effect upon social behavior. The specificity of the drug treatment was further supported by the observation that it did not affect resident hamsters' sexual motivation or ability to mount a receptive female. These data suggest that vasopressin-sensitive neurons in the anterior hypothalamus are involved in the control of intraspecific aggression in male hamsters.