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International Journal of Molecular... Nov 2023Natural flavone and isoflavone analogs such as 3',4',7-trihydroxyflavone (), 3',4',7-trihydroxyisoflavone (), and calycosin () possess significant neuroprotective...
Natural flavone and isoflavone analogs such as 3',4',7-trihydroxyflavone (), 3',4',7-trihydroxyisoflavone (), and calycosin () possess significant neuroprotective activity in Alzheimer's and Parkinson's disease. This study highlights the in vitro human monoamine oxidase (hMAO) inhibitory potential and functional effect of those natural flavonoids at dopamine and serotonin receptors for their possible role in neuroprotection. In vitro hMAO inhibition and enzyme kinetics studies were performed using a chemiluminescent assay. The functional effect of three natural flavonoids on dopamine and serotonin receptors was tested via cell-based functional assays followed by a molecular docking simulation to predict interactions between a compound and the binding site of the target protein. A forced swimming test was performed in the male C57BL/6 mouse model. Results of in vitro chemiluminescent assays and enzyme kinetics depicted as a competitive inhibitor of hMAO-A with promising potency (IC value: 7.57 ± 0.14 μM) and as a competitive inhibitor of hMAO-B with an IC value of 7.19 ± 0.32 μM. Likewise, GPCR functional assays in transfected cells showed as a good hDR antagonist. In docking analysis, these active flavonoids interacted with a determinant-interacting residue via hydrophilic and hydrophobic interactions, with low docking scores comparable to reference ligands. The post-oral administration of to male C57BL/6 mice did not reduce the immobility time in the forced swimming test. The results of this study suggest that and may serve as effective regulators of the aminergic system via hMAO inhibition and the hDR antagonist effect, respectively, for neuroprotection. The route of administration should be considered.
Topics: Mice; Animals; Humans; Male; Dopamine; Flavonoids; Monoamine Oxidase Inhibitors; Molecular Docking Simulation; Neuroprotection; Mice, Inbred C57BL; Monoamine Oxidase; Receptors, Serotonin; Structure-Activity Relationship; Molecular Structure
PubMed: 37958841
DOI: 10.3390/ijms242115859 -
Journal of Psychiatric Research Jun 2024Variability in hepatic cytochrome P450 (CYP) enzymes such as 2C19 and 2D6 may influence side-effect and efficacy outcomes for antipsychotics. Aripiprazole and... (Review)
Review
Variability in hepatic cytochrome P450 (CYP) enzymes such as 2C19 and 2D6 may influence side-effect and efficacy outcomes for antipsychotics. Aripiprazole and risperidone are two commonly prescribed antipsychotics, metabolized primarily through CYP2D6. Here, we aimed to provide an overview of the effect of CYP2C19 and CYP2D6 on side-effects of aripiprazole and risperidone, and expand on existing literature by critically examining methodological issues associated with pharmacogenetic studies. A PRISMA compliant search of six electronic databases (Pubmed, PsychInfo, Embase, Central, Web of Science, and Google Scholar) identified pharmacogenetic studies on aripiprazole and risperidone. 2007 publications were first identified, of which 34 were included. Quality of literature was estimated using Newcastle-Ottowa Quality Assessment Scale (NOS) and revised Cochrane Risk of Bias tool. The average NOS score was 5.8 (range: 3-8) for risperidone literature and 5 for aripiprazole (range: 4-6). All RCTs on aripiprazole were rated as high risk of bias, and four out of six for risperidone literature. Study populations ranged from healthy volunteers to inpatient individuals in psychiatric units and included adult and pediatric samples. All n = 34 studies examined CYP2D6. Only one study genotyped for CYP2C19 and found a positive association with neurological side-effects of risperidone. Most studies did not report any relationship between CYP2D6 and any side-effect outcome. Heterogeneity between and within studies limited the ability to synthesize data and draw definitive conclusions. Studies lacked statistical power due to small sample size, selective genotyping methods, and study design. Large-scale randomized trials with multiple measurements, providing robust evidence on this topic, are suggested.
Topics: Humans; Aripiprazole; Cytochrome P-450 CYP2D6; Risperidone; Cytochrome P-450 CYP2C19; Antipsychotic Agents
PubMed: 38631139
DOI: 10.1016/j.jpsychires.2024.04.001 -
Critical Care (London, England) Aug 2023Haloperidol is frequently used in critically ill patients with delirium, but evidence for its effects has been sparse and inconclusive. By including recent trials, we... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Haloperidol is frequently used in critically ill patients with delirium, but evidence for its effects has been sparse and inconclusive. By including recent trials, we updated a systematic review assessing effects of haloperidol on mortality and serious adverse events in critically ill patients with delirium.
METHODS
This is an updated systematic review with meta-analysis and trial sequential analysis of randomised clinical trials investigating haloperidol versus placebo or any comparator in critically ill patients with delirium. We adhered to the Cochrane handbook, the PRISMA guidelines and the grading of recommendations assessment, development and evaluation statements. The primary outcomes were all-cause mortality and proportion of patients with one or more serious adverse events or reactions (SAEs/SARs). Secondary outcomes were days alive without delirium or coma, delirium severity, cognitive function and health-related quality of life.
RESULTS
We included 11 RCTs with 15 comparisons (n = 2200); five were placebo-controlled. The relative risk for mortality with haloperidol versus placebo was 0.89; 96.7% CI 0.77 to 1.03; I = 0% (moderate-certainty evidence) and for proportion of patients experiencing SAEs/SARs 0.94; 96.7% CI 0.81 to 1.10; I = 18% (low-certainty evidence). We found no difference in days alive without delirium or coma (moderate-certainty evidence). We found sparse data for other secondary outcomes and other comparators than placebo.
CONCLUSIONS
Haloperidol may reduce mortality and likely result in little to no change in the occurrence of SAEs/SARs compared with placebo in critically ill patients with delirium. However, the results were not statistically significant and more trial data are needed to provide higher certainty for the effects of haloperidol in these patients.
TRIAL REGISTRATION
CRD42017081133, date of registration 28 November 2017.
Topics: Humans; Haloperidol; Coma; Critical Illness; Quality of Life; Delirium; Randomized Controlled Trials as Topic
PubMed: 37633991
DOI: 10.1186/s13054-023-04621-4 -
Neuropsychopharmacology Reports Mar 2024Cognitive impairment are among the core features of schizophrenia, experienced by up to 75% of patients. Available treatment options for schizophrenia including dopamine... (Review)
Review
BACKGROUND
Cognitive impairment are among the core features of schizophrenia, experienced by up to 75% of patients. Available treatment options for schizophrenia including dopamine antagonists and traditional antipsychotic medications have not been shown to confer significant benefits on cognitive deficits. Contrary to the focus on management of positive symptoms in schizophrenia, cognitive abilities are main predictor of independent living skills, functional abilities, employment, engagement in relapse prevention, and patients' subjective sense of well-being and quality of life. This review aims to provide a summary of recent literature on pharmacological options for the treatment of cognitive deficits in schizophrenia.
METHODS
We conducted a literature search of studies from 2011 to 2021 across four electronic databases including PubMed, PsycInfo, MEDLINE, and Embase. Human studies using a pharmacological treatment for cognitive impairment in schizophrenia were included.
RESULTS
Fifty-eight eligible publications, representing 11 pharmacological classes, were included in this review. Major limitations involved small sample size, methodological limitations as well as heterogeneity of participants and outcome measures.
CONCLUSIONS
Overall evidence remains inconclusive for any pharmacological classes studied for the treatment of cognitive deficits in schizophrenia. Methodological limitations in a majority of the studies rendered their findings preliminary. We further discuss possible explanations for these findings that could guide future research.
Topics: Humans; Schizophrenia; Quality of Life; Cognitive Dysfunction; Cognition Disorders; Cognition
PubMed: 37794723
DOI: 10.1002/npr2.12382 -
CNS Neuroscience & Therapeutics Nov 2023General anesthesia has long been used in clinical practice, but its precise pharmacological effects on neural circuits are not fully understood. Recent investigations...
BACKGROUND
General anesthesia has long been used in clinical practice, but its precise pharmacological effects on neural circuits are not fully understood. Recent investigations suggest that the sleep-wake system may play a role in the reversible loss of consciousness induced by general anesthetics. Studies in mice have shown that microinjection of dopamine receptor 1 (D1R) agonists into the nucleus accumbens (NAc) promotes recovery from isoflurane anesthesia, while microinjection of D1R antagonists has the opposite effect. Furthermore, during the induction and maintenance of sevoflurane anesthesia, there is a significant decrease in extracellular dopamine levels in the NAc, which subsequently increases during the recovery period. These findings suggest the involvement of the NAc in the regulation of general anesthesia. However, the specific role of D1R-expressing neurons in the NAc during general anesthesia and the downstream effect pathways are still not well understood.
METHODS
In order to analyze the impact of sevoflurane anesthesia on NAc neurons and the NAc -VP pathway, this study employed calcium fiber photometry to investigate alterations in the fluorescence intensity of calcium signals in dopamine D1-receptor-expressing neurons located in the nucleus accumbens (NAc neurons) and the NAc -VP pathway during sevoflurane anesthesia. Subsequently, optogenetic techniques were utilized to activate or inhibit NAc neurons and their synaptic terminals in the ventral pallidum (VP), aiming to elucidate the role of NAc neurons and the NAc -VP pathway in sevoflurane anesthesia. These experiments were supplemented with electroencephalogram (EEG) recordings and behavioral tests. Lastly, a genetically-encoded fluorescent sensor was employed to observe changes in extracellular GABA neurotransmitters in the VP during sevoflurane anesthesia.
RESULTS
Our findings revealed that sevoflurane administration led to the inhibition of NAc neuron population activity, as well as their connections within the ventral pallidum (VP). We also observed a reversible reduction in extracellular GABA levels in the VP during both the induction and emergence phases of sevoflurane anesthesia. Additionally, the optogenetic activation of NAc neurons and their synaptic terminals in the VP resulted in a promotion of wakefulness during sevoflurane anesthesia, accompanied by a decrease in EEG slow wave activity and burst suppression rate. Conversely, the optogenetic inhibition of the NAc -VP pathway exerted opposite effects.
CONCLUSION
The NAc -VP pathway serves as a crucial downstream pathway of NAc neurons, playing a significant role in regulating arousal during sevoflurane anesthesia. Importantly, this pathway appears to be associated with the release of GABA neurotransmitters from VP cells.
Topics: Mice; Animals; Nucleus Accumbens; Dopamine; Sevoflurane; Basal Forebrain; Calcium; Receptors, Dopamine D1; Dopaminergic Neurons; Anesthesia; Neurotransmitter Agents; gamma-Aminobutyric Acid
PubMed: 37208941
DOI: 10.1111/cns.14267 -
Journal of the American Academy of... Mar 2024To summarize the available evidence on metabolic parameters indicating metabolic adverse effects and risk of metabolic syndrome in children and adolescents treated with...
OBJECTIVE
To summarize the available evidence on metabolic parameters indicating metabolic adverse effects and risk of metabolic syndrome in children and adolescents treated with antipsychotics, following a pre-specified protocol (PROSPERO ID 252336).
METHOD
We searched PubMed, Embase and PsycINFO until May 14, 2021, to identify systematic reviews (SR), meta-analyses (MA) and network meta-analyses (NMA) examining symptoms associated to metabolic syndrome in patients <18 years of age who required treatment with oral antipsychotic drugs. Evidence from quantitative analyses for all outcomes related to anthropometric, glyco-metabolic, and blood pressure parameters (measured from baseline to intervention-end and/or follow-up, in subjects exposed to antipsychotics and placebo) was reported on the basis of their metrics (median difference [medianD], mean difference [MD], standardized mean difference [SMD], odds ratio [OR], risk ratio ([RR]). A qualitative synthesis was also made. A formal quality assessment of the included studies was carried out by using the AMSTAR 2. We also provided a hierarchical stratification of the evidence from meta-analyses based on the class of evidence.
RESULTS
A total of 23 articles (13 MA, 4 NMA and 6 SR) were included for review. As compared with placebo, an increase in triglyceride levels was associated with olanzapine (medianD [95% CI]: 37 [12.27, 61.74] mg/dL; MD [95% CI]: 38.57 [21.44, 55.77] mg/dL) and quetiapine (medianD [95% CI]: 21.58 [95% CI]: 4.27, 38.31 mg/dL; MD [95% CI]: 34.87 [20.08, 49.67] mg/dL; SMD [95% CI]: 0.37 [0.06, 0.068]), whereas decreased triglyceride levels were found for lurasidone. Increased total cholesterol level was associated with asenapine (medianD [95% CI]: 9.1 [1.73, 16.44] mg/dL), quetiapine (medianD [95% CI]: 15.60 [7.30, 24.05] mg/dL; olanzapine (MD [95% CI] from 3.67 [1.43, 5.92] mg/dL to 20.47 [13.97, 26.94] mg/dL]; and lurasidone (medianD [95% CI]: 8.94 [1.27, 16.90] mg/dL). Change in glucose levels did not differ among antipsychotics or placebo. Lurasidone, molindone, and ziprasidone were the best tolerated in terms of weight gain. According to the AMSTAR 2 scoring system, 13 (56.5%) reviews were rated as very low quality. According to classes of evidence, most MA were level 4, especially because of their limited total sample size.
CONCLUSION
By collating meta-analyses assessing biochemical markers of metabolic syndrome in antipsychotic-treated children, we conclude that olanzapine should not be the antipsychotic of choice in patients at risk for hypertriglyceridemia or hypercholesterolemia. Aripiprazole and lurasidone appear to be better tolerated in terms of metabolic adverse events. Insufficient meta-analytic data are available to provide a precise risk estimate of metabolic syndrome, and, overall, the quality of evidence is low.
STUDY REGISTRATION INFORMATION
Association between the use of antipsychotic drugs and alterations of the parameters defining the Metabolic Syndrome (MetS) in children and adolescents: an umbrella review; https://www.crd.york.ac.uk/prospero/; CRD42021252336.
Topics: Child; Humans; Adolescent; Antipsychotic Agents; Olanzapine; Quetiapine Fumarate; Lurasidone Hydrochloride; Metabolic Syndrome; Schizophrenia; Triglycerides
PubMed: 37391174
DOI: 10.1016/j.jaac.2023.04.018 -
Molecules (Basel, Switzerland) Dec 2023Neurological-related disorders are diseases that affect the body's neurons or peripheral nerve tissue, such as Parkinson's disease (PD) and Alzheimer's disease (AD). The... (Review)
Review
Neurological-related disorders are diseases that affect the body's neurons or peripheral nerve tissue, such as Parkinson's disease (PD) and Alzheimer's disease (AD). The development of neurological disorders can cause serious harm to the quality of life and functioning of the patient. The use of traditional therapeutic agents such as dopamine-promoting drugs, anticholinergic drugs, cholinesterase inhibitors, and NMDA receptor antagonists is often accompanied by a series of side effects such as drug resistance, cardiac arrhythmia, liver function abnormalities, and blurred vision. Therefore, there is an urgent need to find a therapeutic drug with a high safety profile and few side effects. Herbal medicines are rich in active ingredients that are natural macromolecules. Ginsenoside is the main active ingredient of ginseng, which has a variety of pharmacological effects and is considered to have potential value in the treatment of human diseases. Modern pharmacological studies have shown that ginsenosides Rg2 and Rh1 have strong pharmacological activities in the nervous system, with protective effects on nerve cells, improved resistance to neuronal injury, modulation of neural activity, resistance to cerebral ischemia/reperfusion injury, improvement of brain damage after eclampsia hemorrhage, improvement of memory and cognitive deficits, treatment of AD and vascular dementia, alleviation of anxiety, pain, and inhibition of ionic-like behavior. In this article, we searched the pharmacological research literature of Rg2 and Rh1 in the field of neurological diseases, summarized the latest research progress of the two ginsenosides, and reviewed the pharmacological effects and mechanisms of Rg2 and Rh1, which provided a new way of thinking for the research of the active ingredients in ginseng anti-neurological diseases and the development of new drugs.
Topics: Humans; Ginsenosides; Quality of Life; Nervous System; Panax
PubMed: 38067664
DOI: 10.3390/molecules28237935 -
The Journal of Clinical Psychiatry Sep 2023Aripiprazole 2-month ready-to-use 960 mg (Ari 2MRTU 960) is a new long-acting injectable antipsychotic formulation for administration every 2 months. A randomized,... (Randomized Controlled Trial)
Randomized Controlled Trial
Safety and Efficacy of Aripiprazole 2-Month Ready-to-Use 960 mg: Secondary Analysis of Outcomes in Adult Patients With Schizophrenia in a Randomized, Open-label, Parallel-Arm, Pivotal Study.
Aripiprazole 2-month ready-to-use 960 mg (Ari 2MRTU 960) is a new long-acting injectable antipsychotic formulation for administration every 2 months. A randomized, open-label, 32-week trial evaluated the safety, tolerability, and pharmacokinetics of Ari 2MRTU 960 in clinically stable adults with schizophrenia or bipolar I disorder (per criteria). This secondary analysis evaluated the safety and efficacy of Ari 2MRTU 960 in the subpopulation of patients with schizophrenia. Patients were randomized to receive Ari 2MRTU 960 every 56 ± 2 days (4 injections scheduled) or aripiprazole once-monthly 400 mg (AOM 400) every 28 ± 2 days (8 injections scheduled). Data were collected during August 2019-July 2020 across 16 US sites. Primary endpoints included safety and tolerability, evaluated throughout. Secondary endpoints for efficacy in patients with schizophrenia included change from baseline at week 32 in Positive and Negative Syndrome Scale, Clinical Global Impression - Severity, and Subjective Well-being under Neuroleptic Treatment - Short Form scores, along with Clinical Global Impression - Improvement at week 32. Patients with schizophrenia were randomized to Ari 2MRTU 960 (n = 92) or AOM 400 (n = 93). The incidence of treatment-emergent adverse events (TEAEs) was similar between Ari 2MRTU 960 (66.3%) and AOM 400 (63.4%). The most frequently reported TEAE was increased weight (Ari 2MRTU 960: 21.7%; AOM 400: 18.3%). Patients in both treatment groups remained clinically stable throughout, with minimal change from baseline observed in efficacy parameters at week 32. Ari 2MRTU 960 was well tolerated in clinically stable patients with schizophrenia, with efficacy similar to AOM 400. ClinicalTrials.gov identifier: NCT04030143.
Topics: Humans; Adult; Aripiprazole; Schizophrenia; Antipsychotic Agents; Bipolar Disorder; Diagnostic and Statistical Manual of Mental Disorders
PubMed: 37672016
DOI: 10.4088/JCP.23m14873 -
Psychological Medicine Dec 2023Individuals with schizophrenia exposed to second-generation antipsychotics (SGA) have an increased risk for diabetes, with aripiprazole purportedly a safer drug. Less is...
BACKGROUND
Individuals with schizophrenia exposed to second-generation antipsychotics (SGA) have an increased risk for diabetes, with aripiprazole purportedly a safer drug. Less is known about the drugs' mortality risk or whether serious mental illness (SMI) diagnosis or race/ethnicity modify these effects.
METHODS
Authors created a retrospective cohort of non-elderly adults with SMI initiating monotherapy with an SGA (olanzapine, quetiapine, risperidone, and ziprasidone, aripiprazole) or haloperidol during 2008-2013. Three-year diabetes incidence or all-cause death risk differences were estimated between each drug and aripiprazole, the comparator, as well as effects within SMI diagnosis and race/ethnicity. Sensitivity analyses evaluated potential confounding by indication.
RESULTS
38 762 adults, 65% White and 55% with schizophrenia, initiated monotherapy, with haloperidol least (6%) and quetiapine most (26·5%) frequent. Three-year mortality was 5% and diabetes incidence 9.3%. Compared with aripiprazole, haloperidol and olanzapine reduced diabetes risk by 1.9 (95% CI 1.2-2.6) percentage points, or a 18.6 percentage point reduction relative to aripiprazole users' unadjusted risk (10.2%), with risperidone having a smaller advantage. Relative to aripiprazole users' unadjusted risk (3.4%), all antipsychotics increased mortality risk by 1.1-2.2 percentage points, representing 32.4-64.7 percentage point increases. Findings within diagnosis and race/ethnicity were generally consistent with overall findings. Only quetiapine's higher mortality risk held in sensitivity analyses.
CONCLUSIONS
Haloperidol's, olanzapine's, and risperidone's lower diabetes risks relative to aripiprazole were not robust in sensitivity analyses but quetiapine's higher mortality risk proved robust. Findings expand the evidence on antipsychotics' risks, suggesting a need for caution in the use of quetiapine among individuals with SMI.
Topics: Adult; Humans; Middle Aged; Antipsychotic Agents; Olanzapine; Risperidone; Quetiapine Fumarate; Aripiprazole; Haloperidol; Retrospective Studies; Benzodiazepines; Schizophrenia; Diabetes Mellitus
PubMed: 37753625
DOI: 10.1017/S0033291723001502 -
Frontiers in Pharmacology 2024Caffeine and the selective A receptor antagonist SCH58261 both have ergogenic properties, effectively reducing fatigue and enhancing exercise capacity. This study...
Caffeine and the selective A receptor antagonist SCH58261 both have ergogenic properties, effectively reducing fatigue and enhancing exercise capacity. This study investigates in male Swiss mice the interaction between adenosine A receptors and dopamine D receptors controlling central fatigue, with a focus on the striatum where these receptors are most abundant. We employed DPCPX and SCH58261 to antagonize A and A receptors, caffeine as a non-competitive antagonist for both receptors, and haloperidol as a D receptor antagonist; all compounds were tested upon systemic application and caffeine and SCH58261 were also directly applied in the striatum. Behavioral assessments using the open field, grip strength, and treadmill tests allowed estimating the effect of treatments on fatigue. The results suggested a complex interplay between the dopamine and adenosine systems. While systemic DPCPX had little effect on motor performance or fatigue, the application of either caffeine or SCH58261 was ergogenic, and these effects were attenuated by haloperidol. The intra-striatal administration of caffeine or SCH58261 was also ergogenic, but these effects were unaffected by haloperidol. These findings confirm a role of striatal A receptors in the control of central fatigue but suggest that the D receptor-mediated control of the ergogenic effects of caffeine and of A receptor antagonists might occur outside the striatum. This prompts the need of additional efforts to unveil the role of different brain regions in the control of fatigue.
PubMed: 38860172
DOI: 10.3389/fphar.2024.1390187