Levomepromazine Research Articles

Comparison of Pharmacological Treatments for Agitated Delirium in the Last Days of Life

ContextAntipsychotics are often used in managing symptoms of terminal delirium, but evidence is limited. ObjectivesTo explore the comparative effectiveness of haloperidol with as-needed benzodiazepines (HPD) vs. chlorpromazine (CPZ) vs. levomepromazine (LPZ) for agitated delirium in the last days. MethodsA prospective observational study was conducted in two palliative care units in Japan. Adult cancer patients who developed agitated delirium with a modified Richmond Agitation-Sedation Scale (RASS-PAL) of one or more were included; palliative care specialist physicians determined that the etiology was irreversible; and estimated survival was 3 weeks or less. Patients treated with HPD, CPZ, or LPZ were analyzed. We measured RASS, NuDESC, Agitation Distress Scale (ADS), and Communication Capacity Scale (CCS) on Days 1 and 3. ResultsA total of 277 patients were enrolled, and 214 were analyzed (112 in HPD, 50 in CPZ, and 52 in LPZ). In all groups, the mean RASS-PAL score significantly decreased on Day 3 (1.37 to -1.01, 1.87 to -1.04, 1.79 to -0.62, respectively; P < 0.001); the NuDESC and ADS scores also significantly decreased. The percentages of patients with moderate to severe agitation and those with full communication capacity on Day 3 were not significantly different. The treatments were well-tolerated. While one-fourth of HPD group changed antipsychotics, 88% or more of CPZ and LPZ groups continued the initial antipsychotics. ConclusionHaloperidol with as-needed benzodiazepine, chlorpromazine, or levomepromazine may be effective and safe for terminal agitation. Chlorpromazine and levomepromazine may have an advantage of no need to change medications.

Methotrimeprazine is a neuroprotective antiviral in JEV infection via adaptive ER stress and autophagy

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.

Use of Levomepromazine for the Treatment of Emergence Agitation in Patients Receiving Mechanical Ventilation for SARS-CoV-2 Related Acute Respiratory Distress Syndrome

Purpose: To report our experience with the use of Levomepromazine (LMZ) for the treatment of delirium in patients treated for Acute Respiratory Distress Syndrome (ARDS) due to COVID-19. Methods: Retrospective series of patients admitted to the Intensive Care Unit (ICU) of a non-academic hospital and who requiring invasive mechanical ventilation for the treatment of ARDS due to SARS-CoV-2. Infection was confirmed by Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) testing, and patients presented delirium after withdrawal of neuromuscular blockade or sedation lightening treated with LMZ on top of other treatment. Results: Out of 34 ARDS patients admitted from 22 March 2020 to 23 January 2021, 11 (32.3%) died before neuromuscular blockade withdrawal, and of the remaining 23, 16 were treated with LMZ. The median time to initiation of LMZ was 6 days (interquartile, 5 to 8) from the start of sedation, and median duration of LMZ treatment was 5 (1 to 28) days. Median sedation score (as assessed by the Sedation Agitation Scale (SAS)) was 2 (1-4) at initiation and 3 (2-4) at discontinuation of LMZ, while median analgesia scores (Behavioral Pain Scale (BPS)) were respectively 3 (3-5) and 4 (3-5). Of the 16 patients treated with LMZ, 12 were weaned from mechanical ventilation immediately following discontinuation, without recurrence of delirium. No adverse effects related to LMZ use were observed. The 4 patients who could not be weaned from mechanical ventilation following LMZ required new neuromuscular blockade. Conclusions: Based on this retrospective series, LMZ seems to be useful for the management of delirium occurring after withdrawal of neuromuscular blockade or lightening of sedation in patients with ARDS due to SARS-CoV-2.

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.

Levomepromazine for difficult sedation in pediatric intensive care.

Sedation and analgesia using opioids and benzodiazepines is frequently required in critically ill children to minimize pain and anxiety. In some patients, difficult sedation occurs when tolerance or unacceptable side effects limit the efficacy of conventional analgo-sedative treatment. We describe seven patients (age range 1 to 17 yr) where difficult sedation was successfully managed with enteral levomepromazine (LMZ). LMZ is a neuroleptic antipsychotic agent that exhibits potent analgo-sedative properties without respiratory depression, through non-opioid and non-benzodiazepine pathways. We describe its use in our pediatric intensive care unit to control agitation in patients with known behavioral disorders who frequently pose a significant sedation challenge. We also illustrate its successful use in cases of withdrawal syndrome and delirium, and discuss the association of fever and its distinction from neuroleptic malignant syndrome in two patients. LMZ should be considered as a useful sedative in critically ill children where difficult sedation occurs and conventional agents are exhausted.

Studies on photodegradation of levomepromazine and olanzapine under simulated environmental conditions

The present study discusses the influence of sunlight on the photostability of levomepromazine (LV) and olanzapine (OLA) hydrochlorides in river water. Four samples of water from different rivers were used in the research. In their course, it turned out that levomepromazine easily underwent photooxidation under simulated environmental conditions, resulting in the generation of its sulphoxide. Olanzapine, on the other hand, appeared to be more resistant to sunlight, as its photodecomposition proceeded slowly, and only one product of its decomposition was detected spectrophotometrically during the process. The photodegradation was analyzed in detail using principal component analysis (PCA) and multivariate curve resolution alternating least squares (MCR-ALS) chemometric methods, and the outcomes verified by HPLC and GC-MS analysis. It can be stated that the rates of the observed processes heavily depended on the chemical composition of the fresh water used in the experiments.

Levomepromazine withdrawal

Levomepromazine withdrawal

Possible levomepromazine–clozapine interaction: Two case reports

Objective To report and comment upon two cases of suspected pharmacological interaction between the “classical” neuroleptic levomepromazine (LMP) and the “atypical” antipsychotic clozapine (CLZ). Case summary The patients who simultaneously took the two drugs had unusually low plasma levels of CLZ and its metabolites, even though they took high doses of CLZ. The patients were considered “non-responders” to the treatment by the psychiatrist. When LMP was withdrawn from the therapy, plasma concentrations of CLZ returned to therapeutic levels and one of the two patients experienced the anticipated therapeutic response. Discussion No information can be found in the literature regarding possible interactions between LMP and CLZ. However, the results of the two cases reported herein point out to a possible lack of therapeutic efficacy of CLZ therapy during this kind of polypharmacy. Conclusion While two cases are too few to draw any conclusion, it would be prudent on the part of psychiatrists to consider a possible drug interaction in patients receiving both CLZ and LMP who fail to respond to the therapy.

Phenothiazines suppress proliferation and induce apoptosis in cultured leukemic cells without any influence on the viability of normal lymphocytes. Phenothiazines and leukemia.

The purpose of the present study was to investigate the effects of phenothiazines (at clinically relevant doses) on the viability and proliferation of leukemic cell lines and normal lymphocytes, and to investigate the possibility of specific induction of apoptosis in leukemic cells. Phenothiazines with different chemical structure and hydrophobicity were used: chlorpromazine (CPZ); levomepromazine (LVPZ); prometazine (PMZ); trifluoperazine (TFPZ); thioridazine (TRDZ). The leukemic cell lines used were: Daudi and Raji (derived from Burkitt's lymphoma), K-562 (derived from myelogenous leukemia), and BALL-1, MOLT-4, HPB-ALL and CCRF-HSB-2 (derived from acute lymphoblastic leukemia). The cytotoxicity of the phenothiazines was determined by a CellTiter-Glo luminescent cell viability assay, using ATP bioluminescence as a marker of cell viability as well as a marker of mitochondrial activity. The proliferation of leukemic cells was determined using a CellTiter-AQ cell proliferation assay which is based on the reduction of a methyl-tetrazolium compound to the formazan product. Apoptosis induction was estimated using phosphatidylserine (PSer) translocation to the cell surface and DNA fragmentation as characteristics of the process. Phenothiazines (at concentrations in the range 0.1-10 micro M) did not affect the viability of normal lymphocytes during a 24-h incubation. Moreover, about 15-20% increase in ATP bioluminescence was observed in normal cells during treatment with 40 micro M phenothiazines. In contrast, the phenothiazines manifested strong cytotoxicity and antiproliferative activity against leukemic cells. The most powerful drugs were TFPZ and TRDZ, followed by CPZ. They showed a significant cytotoxic effect against leukemic cells even at 5-10 micro M. The most sensitive cell lines were MOLT-4 and Raji, and the most resistant were HPB-ALL and CCRF-HSB-2. All phenothiazines induced PSer exposure on the surface of leukemic cells, but not of normal lymphocytes. TFPZ, TRDZ and CPZ also induced DNA fragmentation in almost all leukemic cell lines during a 48-h incubation. The strongest apoptotic agent was TRDZ. The apoptosis induction was not accompanied by a significant release of cytochrome c from the mitochondria into the cytoplasm of native cells. Moreover, the drugs markedly suppressed Ca(2+)-induced cytochrome c release in isolated mitochondria of leukemic cells. The results suggest that in clinically relevant doses (up to 20 micro M) some phenothiazines (TFPZ, TRDZ, CPZ) expressed a selective cytotoxicity and antiproliferative activity, and induced apoptosis in leukemic cells without any influence on the viability of normal lymphocytes. It is considered that the mechanism of apoptosis induction in phenothiazine-treated leukemic cells is associated with inhibition of mitochondrial DNA polymerase and decreased ATP production, which are crucial events for the viability of cancer cells.

Methotrimeprazine in the treatment of agitation in acquired brain injury patients

Medical management of the agitation associated with acquired brain injury (ABI) has been problematic. At least 12 distinct drugs are currently recommended in the medical literature. In recent years, on the ABI in-patient rehabilitation unit, methotrimeprazine (MTZ) has come to be the preferred drug and is used routinely for effective treatment of agitation. The objective of this paper is to describe the use and safety of MTZ in the rehabilitation of ABI patients. A retrospective chart review of all patients discharged from the ABI unit over a course of 2 years was conducted. In addition to demographics such a aetiology of ABI, sex, age, length of stay, Glasgow Coma Scale, length of posttraumatic amnesia and others, a detailed analysis was made of the multidisciplinary progress notes to determine the daily agitation status and the daily use of psychotropic medication. All notes on side effects and adverse reactions were carefully documented. 120 first admission recent ABI patients were discharged in the 2-year study period. Of these, 69 (57%) had some level of agitation and 56 (48%) were treated with MTZ, in doses of 2-50mg up to four times daily. Agitation was controlled in most cases. In only two cases were significant side effects noted. While MTZ has been used as a safe and effective neuroleptic in psychiatry for over 40 years, this is the first report of its use in treating agitation in ABI.

Fluorimetric and Photochemically Induced Fluorimetric Determination of Ethopropazine, Levomepromazine, Thioproperazine and Trifluoperazine

Fluorimetry and photochemically induced fluorimetry (PIF) are proposed for the quantitative analysis of four psychotropic drugs, including ethopropazine (EPZ), levomepromazine (LPZ), thioproperazine (TPZ) and trifluoperazine (TFZ). The influence of ultraviolet (UV) irradiation time on the fluorescence excitation and emission wavelengths and intensity was investigated in aqueous buffer solutions (pH 4 – 6) at room temperature (298 K). The selected UV irradiation times were between 10 and 50 s, depending on the compound. Linear calibration graphs were established over about two to four orders of magnitude, with relative standard deviations in the range 2.0 – 5.4%. PIF limits of detection were comprised between 2.6 and 8 ng ml−1, depending on the compound. The PIF method was found to be more sensitive and more reliable than conventional fluorimetry for the phenothiazine derivatives under study. PIF was applied to the determination of these compounds in urine and pharmaceutical samples. The mean recoveries ranged from 88 to 119%. bOn leave from the Departement of Analytical Chemistry, Faculty of Sciences, University of Extremadura, Badajoz (Spain).

Metabolism of levomepromazine in man.

The phenothiazine drug, levomepromazine (LM), is used in the treatment of psychiatric disorders and as an analgesic. A single 50 or 100 mg dose of LM was given to healthy male volunteers, and urine samples were collected for 24 h. The urine was treated with beta-glucuronidase, purified by solid-phase extraction, and analyzed on a GC-MS system for identification of LM metabolites. Mass spectra suggesting 14 different LM metabolites were obtained from the samples. Our of these, 13 spectra could be ascribed to specific metabolites, 5 of which have not previously been identified. All these 5 metabolites were hydroxylated at the phenothiazine nucleus. Although the applied method did not determine the positions of hydroxyl groups on phenothiazine nuclei. 3 of the 5 metabolites were identified as O-desmethyl 3-hydroxy LM, O-desmethyl 7-hydroxy LM, and N,O-didesmethyl 7-hydroxy LM, based on their chromatographic properties. In addition two metabolites, one being hydroxylated on the phenothiazine nucleus, and one being O-demethylated and hydroxylated on the nucleus, were found. It is suggested that these were 8-hydroxy LM and O-desmethyl 8-hydroxy LM. The concentrations of 3-hydroxy LM (free+conjugated) appeared to be much higher than the concentrations of any other metabolite in the samples.

Thrombocytopenia associated with levomepromazine: A case report

AbstractCases of blood dyscrasia related to neuroleptic therapy have been reported. However thrombocytopenia associated with levomepromazine (LPZ) has never been reported, to the best of our knowledge. We describe here a patient treated with LPZ who has developed haemorrhagic vesicles and severe thrombocytopenia. Appropriate management and prompt substitution of LPZ by sulpride led to a full clinical recovery.

Levomepromazine receptor binding profile in human brain—implications for treatment—resistant schizophrenia

The receptor binding profile of levomepromazine (LMP) in human brain was compared with that of clozapine (CLOZ) and chlorpromazine (CPZ). LMP showed significantly greater binding affinity for both alpha-1 and serotonin-2 binding sites than either CLOZ or CPZ, and significantly greater binding to alpha-2 sites than CPZ. A potent pharmacological effect at these receptor sites may explain the beneficial effect of LMP on psychotic symptoms and akathisia in treatment-resistant schizophrenia recently described in 2 open studies. LMP requires further appraisal as a potentially useful neuroleptic in the management of treatment-resistant schizophrenia.

Is levomepromazine a useful drug in treatment-resistant schizophrenia?

Levomepromazine (LMP) unexpectedly improved 16 of 23 chronic treatment-resistant schizophrenic patients who were hospitalized in most cases for at least 2 years and who manifested positive symptoms, irritability and, in many cases, restlessness, hostility, uncooperativeness, poor concentration and aggressive behavior. Improvement led to discharge in 7 (6 to a foster home), placement on a waiting list for a foster home in 4 and improved behavior and autonomy in 5 patients. Five subjects developed seizures and 1 agranulocytosis. Whether improvement with LMP is caused by unique antischizophrenic properties or by diminished liability to induce side effects such as akathisia, a formal controlled study of LMP in treatment-resistant schizophrenia is merited.

Effect of methotrimeprazine on respiration.

Effect of methotrimeprazine on respiration.

The antisialogogue effect of phenothiazine derivatives: comparison of promazine, levomepromazine, trifluoperazine, proclorperazine, methdilazine and prothipendyl.

The antisialogogue effect of phenothiazine derivatives: comparison of promazine, levomepromazine, trifluoperazine, proclorperazine, methdilazine and prothipendyl.