-
Biological & Pharmaceutical Bulletin 2021The clinical applications of antipsychotics for symptoms unrelated to schizophrenia, such as behavioral and psychological symptoms, in patients with Alzheimer's disease,...
The clinical applications of antipsychotics for symptoms unrelated to schizophrenia, such as behavioral and psychological symptoms, in patients with Alzheimer's disease, and the likelihood of doctors prescribing antipsychotics for elderly people are increasing. In elderly people, drug-induced and aging-associated urinary disorders are likely to occur. The most significant factor causing drug-induced urinary disorders is a decrease in urinary bladder smooth muscle (UBSM) contraction induced by the anticholinergic action of therapeutics. However, the anticholinergic action-associated inhibitory effects of antipsychotics on UBSM contraction have not been sufficiently assessed. In this study, we examined 26 clinically available antipsychotics to determine the extent to which they inhibit acetylcholine (ACh)-induced contraction in rat UBSM to predict the drugs that should not be used by elderly people to avoid urinary disorders. Of the 26 antipsychotics, six (chlorpromazine, levomepromazine (phenothiazines), zotepine (a thiepine), olanzapine, quetiapine, clozapine (multi-acting receptor targeted antipsychotics (MARTAs))) competitively inhibited ACh-induced contractions at concentrations corresponding to clinically significant doses. Further, 11 antipsychotics (perphenazine, fluphenazine, prochlorperazine (phenothiazines), haloperidol, bromperidol, timiperone, spiperone (butyrophenones), pimozide (a diphenylbutylpiperidine), perospirone, blonanserin (serotonin-dopamine antagonists; SDAs), and asenapine (a MARTA)) significantly suppressed ACh-induced contraction; however, suppression occurred at concentrations substantially exceeding clinically achievable blood levels. The remaining nine antipsychotics (pipamperone (a butyrophenone), sulpiride, sultopride, tiapride, nemonapride (benzamides), risperidone, paliperidone (SDAs), aripiprazole, and brexpiprazole (dopamine partial agonists)) did not inhibit ACh-induced contractions at concentrations up to 10 M. These findings suggest that chlorpromazine, levomepromazine, zotepine, olanzapine, quetiapine, and clozapine should be avoided by elderly people with urinary disorders.
Topics: Acetylcholine; Aging; Animals; Antipsychotic Agents; Chlorpromazine; Cholinergic Antagonists; Clozapine; Dibenzothiepins; Male; Mental Disorders; Methotrimeprazine; Muscle Contraction; Muscle, Smooth; Olanzapine; Quetiapine Fumarate; Rats, Wistar; Urinary Bladder; Urologic Diseases; Rats
PubMed: 34334499
DOI: 10.1248/bpb.b21-00363 -
Frontiers in Pharmacology 2020Drug repurposing is a rapid approach to identify therapeutics for the treatment of emerging infectious diseases such as COVID-19. To address the urgent need for...
Drug repurposing is a rapid approach to identify therapeutics for the treatment of emerging infectious diseases such as COVID-19. To address the urgent need for treatment options, we carried out a quantitative high-throughput screen using a SARS-CoV-2 cytopathic assay with a compound collection of 8,810 approved and investigational drugs, mechanism-based bioactive compounds, and natural products. Three hundred and nineteen compounds with anti-SARS-CoV-2 activities were identified and confirmed, including 91 approved drugs and 49 investigational drugs. The anti-SARS-CoV-2 activities of 230 of these confirmed compounds, of which 38 are approved drugs, have not been previously reported. Chlorprothixene, methotrimeprazine, and piperacetazine were the three most potent FDA-approved drugs with anti-SARS-CoV-2 activities. These three compounds have not been previously reported to have anti-SARS-CoV-2 activities, although their antiviral activities against SARS-CoV and Ebola virus have been reported. These results demonstrate that this comprehensive data set is a useful resource for drug repurposing efforts, including design of new drug combinations for clinical trials for SARS-CoV-2.
PubMed: 33708112
DOI: 10.3389/fphar.2020.592737 -
IBRO Reports Dec 2020Levomepromazine (LMP) is a phenothiazine neuroleptic drug with strong analgesic and sedative properties that is increasingly used off-label in pediatrics and is being...
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 and models of the healthy and injured developing mouse brain. , 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. , 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. , cell viability in exposure-naïve cells was significantly reduced by high doses of LMP, but remained unaffected in glutamate-injured cells. , 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.
PubMed: 33024879
DOI: 10.1016/j.ibror.2020.09.003 -
Levomepromazine and clozapine induce the main human cytochrome P450 drug metabolizing enzyme CYP3A4.Pharmacological Reports : PR Feb 2021Cytochrome P450 (CYP) enzymes are involved in the metabolism of many important endogenous substrates (steroids, melatonin), drugs and toxic xenobiotics. Their induction...
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.
Topics: Antipsychotic Agents; Cells, Cultured; Clozapine; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Enzyme Induction; Hepatocytes; Humans; Liver; Methotrimeprazine; RNA, Messenger
PubMed: 32888176
DOI: 10.1007/s43440-020-00157-4 -
BioRxiv : the Preprint Server For... Aug 2020Drug repurposing is a rapid approach to identifying therapeutics for the treatment of emerging infectious diseases such as COVID-19. To address the urgent need for...
Drug repurposing is a rapid approach to identifying therapeutics for the treatment of emerging infectious diseases such as COVID-19. To address the urgent need for treatment options, we carried out a quantitative high-throughput screen using a SARS-CoV-2 cytopathic assay with a compound collection of 8,810 approved and investigational drugs, mechanism-based bioactive compounds, and natural products. Three hundred and nineteen compounds with anti-SARS-CoV-2 activities were identified and confirmed, including 91 approved drug and 49 investigational drugs. Among these confirmed compounds, the anti-SARS-CoV-2 activities of 230 compounds, including 38 approved drugs, have not been previously reported. Chlorprothixene, methotrimeprazine, and piperacetazine were the three most potent FDA approved drugs with anti-SARS-CoV-2 activities. These three compounds have not been previously reported to have anti-SARS-CoV-2 activities, although their antiviral activities against SARS-CoV and Ebola virus have been reported. These results demonstrate that this comprehensive data set of drug repurposing screen for SARS-CoV-2 is useful for drug repurposing efforts including design of new drug combinations for clinical trials.
PubMed: 32839771
DOI: 10.1101/2020.08.18.255877 -
BMJ Supportive & Palliative Care Sep 2020Anticipatory prescribing (AP) of injectable medications in advance of clinical need is established practice in community end-of-life care. Changes to prescribing...
BACKGROUND
Anticipatory prescribing (AP) of injectable medications in advance of clinical need is established practice in community end-of-life care. Changes to prescribing guidelines and practice have been reported during the COVID-19 pandemic.
AIMS AND OBJECTIVES
To investigate UK and Ireland clinicians' experiences concerning changes in AP during the COVID-19 pandemic and their recommendations for change.
METHODS
Online survey of participants at previous AP national workshops, members of the Association for Palliative Medicine of Great Britain and Ireland and other professional organisations, with snowball sampling.
RESULTS
Two hundred and sixty-one replies were received between 9 and 19 April 2020 from clinicians in community, hospice and hospital settings across all areas of the UK and Ireland. Changes to AP local guidance and practice were reported: route of administration (47%), drugs prescribed (38%), total quantities prescribed (35%), doses and ranges (29%). Concerns over shortages of nurses and doctors to administer subcutaneous injections led 37% to consider drug administration by family or social caregivers, often by buccal, sublingual and transdermal routes. Clinical contact and patient assessment were more often remote via telephone or video (63%). Recommendations for regulatory changes to permit drug repurposing and easier community access were made.
CONCLUSIONS
The challenges of the COVID-19 pandemic for UK community palliative care has stimulated rapid innovation in AP. The extent to which these are implemented and their clinical efficacy need further examination.
Topics: Administration, Buccal; Administration, Sublingual; Analgesics, Non-Narcotic; Analgesics, Opioid; Betacoronavirus; COVID-19; Caregivers; Coronavirus Infections; Drug Administration Routes; Fentanyl; General Practitioners; Hospice Care; Hospices; Humans; Hypnotics and Sedatives; Ireland; Lorazepam; Methotrimeprazine; Muscarinic Antagonists; Nurse Specialists; Palliative Care; Palliative Medicine; Pandemics; Physicians; Pneumonia, Viral; Practice Guidelines as Topic; Practice Patterns, Physicians'; SARS-CoV-2; Surveys and Questionnaires; Telemedicine; Terminal Care; Transdermal Patch; United Kingdom
PubMed: 32546559
DOI: 10.1136/bmjspcare-2020-002394 -
Journal of Chromatography. A Aug 2020The separation of the enantiomers of mepromazine, promethazine, thioridazine and alimemazine was studied by nonaqueous capillary electrophoresis in the presence of...
Chiral separation of four phenothiazines by nonaqueous capillary electrophoresis and quality by design-based method development for quantification of dextromepromazine as chiral impurity of levomepromazine.
The separation of the enantiomers of mepromazine, promethazine, thioridazine and alimemazine was studied by nonaqueous capillary electrophoresis in the presence of cyclodextrins using 1 M acetic acid and 50 mM ammonium acetate in methanol as background electrolyte. Heptakis(2,3-di-O-acetyl-6-O-sulfo)-β-cyclodextrin, heptakis(2,3-di-O-methyl-6-O-sulfo)-β-cyclodextrin (HDMS-β-CD) and octakis(2,3-di-O-methyl-6-O-sulfo)-γ-cyclodextrin were the most effective chiral selectors for mepromazine, promethazine and alimemazine. Subsequently, a method for the determination of dextromepromazine as chiral impurity of levomepromazine was developed employing quality by design principles. Using HDMS-β-CD as selector, a fractional factorial resolution V+ design was employed for evaluating the knowledge space, while a central composite face centered design provided further method optimization and the basis for the computation of the design space by Monte Carlo simulations. The final experimental conditions included a 30/40.2 cm fused-silica capillary with 75 µm inner diameter and a background electrolyte composed of 0.75 M acetic acid and 55 mM ammonium acetate in methanol containing 27.5 mg/mL HDMS-β-CD. The applied voltage was 22 kV and the capillary temperature was 15°C. Following method robustness testing via a Plackett-Burman design, the method was validated for dextromepromazine in the range of 0.01 to 3.0 % relative to a concentration of 0.74 mg/mL levomepromazine and applied to the analysis of reference standards of the European Pharmacopoeia and commercial tablets. The assay also allowed the detection of levomepromazine sulfoxide although the quantitation of the compound was hampered by the poor peak shape of the late migrating diastereomer.
Topics: Electrophoresis, Capillary; Methotrimeprazine; Phenothiazines; Probability; Reference Standards; Reproducibility of Results; Stereoisomerism
PubMed: 32540073
DOI: 10.1016/j.chroma.2020.461232 -
Soudni Lekarstvi 2020We present here a fatal case of heatstroke, involving olanzapine and levomepromazine medications. A male in his sixties was found dead in his storage room in the...
We present here a fatal case of heatstroke, involving olanzapine and levomepromazine medications. A male in his sixties was found dead in his storage room in the middle of August, with a high rectal temperature. Autopsy revealed congestion of the lungs without any specific findings. Quantitative toxicological analysis demonstrated concentrations of olanzapine, levomepromazine, 7-aminonitrazepam, and 7-aminoflunitrazepam in a femoral blood sample of 0.433 µg/mL, 0.177 µg/mL, 0.604 µg/mL, and 0.041 µg/mL, respectively. The concentration of olanzapine exceeded toxic levels; however, levomepromazine level was within the therapeutic range. Due to the blocking mechanism of both olanzapine and levomepromazine against muscarinic receptors, they might depress sweating and impair heat dissipation. Based on autopsy findings, results of toxicological examination, and investigation by the authorities, we concluded that the cause of death was heatstroke under the influence of olanzapine and levomepromazine.
Topics: Autopsy; Fatal Outcome; Heat Stroke; Humans; Male; Methotrimeprazine; Middle Aged; Olanzapine; Psychotropic Drugs
PubMed: 33736437
DOI: No ID Found -
Australian Journal of General Practice Dec 2019Evidence exists for the use of palliative sedation for people approaching the last days of life with refractory and intolerable symptoms. It is a third-line intervention... (Review)
Review
BACKGROUND
Evidence exists for the use of palliative sedation for people approaching the last days of life with refractory and intolerable symptoms. It is a third-line intervention that deliberately lowers the conscious state to relieve intolerable and refractory symptoms. This level of intervention is not routinely used in primary care, and there is a lack of guidelines for palliative sedation in this context.
OBJECTIVE
This article provides some key information about palliative sedation and global issues faced by all individuals involved. A tertiary centre case study is used to illustrate the key points. Given this form of therapy may be required for palliative patients in the community, another aim of this article is to provide an overview for primary care practitioners to raise their awareness of such therapy and the issues related to it.
DISCUSSION
While palliative sedation has been regarded as 'controversial' in early palliative care literature, there has been an increased effort to formulate standardised guidelines to define and ethically justify this procedure.
Topics: Aged; Analgesics; Conscious Sedation; Dehydration; Dyspnea; Humans; Hydromorphone; Hypnotics and Sedatives; Male; Methotrimeprazine; Midazolam; Multiple Myeloma; Multiple Organ Failure; Pain; Palliative Care; Phenobarbital; Propofol; Psychomotor Agitation; Sepsis; Terminal Care
PubMed: 31774984
DOI: 10.31128/AJGP-05-19-4938 -
BMJ Open Sep 2019Methotrimeprazine is commonly used for the management of nausea but never tested formally against other drugs used in this setting. The aim was to demonstrate superior... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
Methotrimeprazine is commonly used for the management of nausea but never tested formally against other drugs used in this setting. The aim was to demonstrate superior antiemetic efficacy.
DESIGN
Double-blind, randomised, controlled trial of methotrimeprazine versus haloperidol.
SETTING
11 palliative care sites in Australia.
PARTICIPANTS
Participants were >18 years, had cancer, an average nausea score of ≥3/10 and able to tolerate oral medications. Ineligible patients had acute nausea related to treatment, nausea for which a specific antiemetic was indicated, were about to undergo a procedure or had received either of the study drugs or a change in glucocorticoid dose within the previous 48 hours.
INTERVENTIONS
Based on previous studies, haloperidol was used as the control. Participants were randomised to encapsulated methotrimeprazine 6·25 mg or haloperidol 1·5 mg one time or two times per day and assessed every 24 hours for 72 hours.
MAIN OUTCOME MEASURES
A ≥two-point reduction in nausea score at 72 hours from baseline. Secondary outcome measures were as follows: complete response at 72 hours (end nausea score less than 3), response at 24 and 48 hours, vomiting episodes, use of rescue antiemetics, harms and global impression of change.
RESULTS
Response to treatment at 72 hours was 75% (44/59) in the haloperidol (H) arm and 63% (36/57) in the methotrimeprazine (M) arm with no difference between groups (intention-to-treat analysis). Complete response rates were 56% (H) and 51% (M). In the analysis, there was no difference in response rates: (85% (44/52) (H) and 74% (36/49) (M). Complete response rates were 64% (H) and 59% (M). Toxicity worse than baseline was minimal with a trend towards greater sedation in the methotrimeprazine arm.
CONCLUSION
This study did not demonstrate any difference in response rate between methotrimeprazine and haloperidol in the control of nausea.
TRIAL REGISTRATION NUMBER
ACTRN 12615000177550.
Topics: Antiemetics; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Monitoring; Drug Therapy, Combination; Female; Glucocorticoids; Haloperidol; Humans; Male; Methotrimeprazine; Middle Aged; Nausea; Neoplasms; Palliative Care; Treatment Outcome
PubMed: 31515428
DOI: 10.1136/bmjopen-2019-029942