-
Pharmaceutics Feb 2023Therapeutic drug monitoring is a tool for optimising the pharmacological treatment of diseases where the therapeutic effect is difficult to measure or monitor....
Therapeutic drug monitoring is a tool for optimising the pharmacological treatment of diseases where the therapeutic effect is difficult to measure or monitor. Therapeutic reference ranges and dose-effect relation are the main requirements for this drug titration tool. Defining and updating therapeutic reference ranges are difficult, and there is no standardised method for the calculation and clinical qualification of these. The study presents a basic model for validating and selecting routine laboratory data. The programmed algorithm was applied on data sets of antidepressants and antipsychotics from three public hospitals in Denmark. Therapeutic analytical ranges were compared with the published therapeutic reference ranges by the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) and in additional literature. For most of the drugs, the calculated therapeutic analytical ranges showed good concordance between the laboratories and to published therapeutic reference ranges. The exceptions were flupentixol, haloperidol, paroxetine, perphenazine, and venlafaxine + o-desmethyl-venlafaxine (total plasma concentration), where the range was considerably higher for the laboratory data, while the calculated range of desipramine, sertraline, ziprasidone, and zuclopenthixol was considerably lower. In most cases, we identified additional literature supporting our data, highlighting the need of a critical re-examination of current therapeutic reference ranges in Denmark. An automated approach can aid in the evaluation of current and future therapeutic reference ranges by providing additional information based on big data from multiple laboratories.
PubMed: 36839995
DOI: 10.3390/pharmaceutics15020673 -
British Journal of Anaesthesia Jul 2023
Topics: Humans; Postoperative Nausea and Vomiting; Vomiting; Antiemetics; Dexamethasone; Quinuclidines
PubMed: 36737386
DOI: 10.1016/j.bja.2023.01.005 -
Environmental Pollution (Barking, Essex... Mar 2023Despite increasing reports of pharmaceuticals in surface waters, aquatic hazard information remains limited for many contaminants, particularly for sublethal, chronic... (Review)
Review
Despite increasing reports of pharmaceuticals in surface waters, aquatic hazard information remains limited for many contaminants, particularly for sublethal, chronic responses plausibly linked to molecular initiation events that are largely conserved across vertebrates. Here, we critically examined available refereed information on the occurrence of 67 antipsychotics in wastewater effluent and surface waters. Because the majority of sewage remains untreated around the world, we also examined occurrence in sewage influents. When sufficient information was available, we developed probabilistic environmental exposure distributions (EEDs) for each compound in each matrix by geographic region. We then performed probabilistic environmental hazard assessments (PEHAs) using therapeutic hazard values (THVs) of each compound, due to limited sublethal aquatic toxicology information for this class of pharmaceuticals. From these PEHAs, we determined predicted exceedances of the respective THVs for each chemical among matrices and regions, noting that THV values of antipsychotic contaminants are typically lower than other classes of human pharmaceuticals. Diverse exceedances were observed, and these aquatic hazards varied by compound, matrix and geographic region. In wastewater effluent discharges and surface waters, sulpiride was the most detected antipsychotic; however, percent exceedances of the THV were minimal (0.6%) for this medication. In contrast, we observed elevated aquatic hazards for chlorpromazine (30.5%), aripiprazole (37.5%), and perphenazine (68.7%) in effluent discharges, and for chlorprothixene (35.4%) and flupentixol (98.8%) in surface waters. Elevated aquatic hazards for relatively understudied antipsychotics were identified, which highlight important data gaps for future environmental chemistry and toxicology research.
Topics: Animals; Humans; Sewage; Antipsychotic Agents; Wastewater; Environmental Exposure; Pharmaceutical Preparations; Water Pollutants, Chemical; Environmental Monitoring
PubMed: 36646406
DOI: 10.1016/j.envpol.2023.121042 -
The Role of Total White Blood Cell Count in Antipsychotic Treatment for Patients with Schizophrenia.Current Neuropharmacology 2024Total white blood cell count (TWBCc), an index of chronic and low-grade inflammation, is associated with clinical symptoms and metabolic alterations in patients with... (Randomized Controlled Trial)
Randomized Controlled Trial Clinical Trial
BACKGROUND
Total white blood cell count (TWBCc), an index of chronic and low-grade inflammation, is associated with clinical symptoms and metabolic alterations in patients with schizophrenia. The effect of antipsychotics on TWBCc, predictive values of TWBCc for drug response, and role of metabolic alterations require further study.
METHODS
Patients with schizophrenia were randomized to monotherapy with risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, perphenazine or haloperidol in a 6-week pharmacological trial. We repeatedly measured clinical symptoms, TWBCc, and metabolic measures (body mass index, blood pressure, waist circumference, fasting blood lipids and glucose). We used mixed-effect linear regression models to test whether TWBCc can predict drug response. Mediation analysis to investigate metabolic alteration effects on drug response.
RESULTS
At baseline, TWBCc was higher among patients previously medicated. After treatment with risperidone, olanzapine, quetiapine, perphenazine, and haloperidol, TWBCc decreased significantly ( < 0.05). Lower baseline TWBCc predicted greater reductions in Positive and Negative Syndrome Scale (PANSS) total and negative scores over time ( < 0.05). We found significant mediation of TWBCc for effects of waist circumference, fasting low-density lipoprotein cholesterol, and glucose on reductions in PANSS total scores and PANSS negative subscale scores ( < 0.05).
CONCLUSION
TWBCc is affected by certain antipsychotics among patients with schizophrenia, with decreases observed following short-term, but increases following long-term treatment. TWBCc is predictive of drug response, with lower TWBCc predicting better responses to antipsychotics. It also mediates the effects of certain metabolic measures on improvement of negative symptoms. This indicates that the metabolic state may affect clinical manifestations through inflammation.
Topics: Humans; Antipsychotic Agents; Schizophrenia; Olanzapine; Risperidone; Quetiapine Fumarate; Haloperidol; Perphenazine; Benzodiazepines; Glucose; Inflammation
PubMed: 36600620
DOI: 10.2174/1570159X21666230104090046 -
ACS Chemical Neuroscience Jan 2023Alzheimer's disease is imposing a growing social and economic burden worldwide, and effective therapies are urgently required. One possible approach to modulation of the...
Alzheimer's disease is imposing a growing social and economic burden worldwide, and effective therapies are urgently required. One possible approach to modulation of the disease outcome is to use small molecules to limit the conversion of monomeric amyloid (Aβ42) to cytotoxic amyloid oligomers and fibrils. We have synthesized modulators of amyloid assembly that are unlike others studied to date: these compounds act primarily by sequestering the Aβ42 monomer. We provide kinetic and nuclear magnetic resonance data showing that these perphenazine conjugates divert the Aβ42 monomer into amorphous aggregates that are not cytotoxic. Rapid monomer sequestration by the compounds reduces fibril assembly, even in the presence of pre-formed fibrillar seeds. The compounds are therefore also able to disrupt monomer-dependent secondary nucleation, the autocatalytic process that generates the majority of toxic oligomers. The inhibitors have a modular design that is easily varied, aiding future exploration and use of these tools to probe the impact of distinct Aβ42 species populated during amyloid assembly.
Topics: Humans; Perphenazine; Amyloid beta-Peptides; Amyloid; Alzheimer Disease; Amyloidogenic Proteins; Peptide Fragments
PubMed: 36542544
DOI: 10.1021/acschemneuro.2c00498 -
Current Computer-aided Drug Design 2023Parkinson's disease (PD) and Alzheimer's disease (AD) are the most common forms of neurodegenerative disorders. The aim of the current work is to study the potential of...
OBJECTIVE
Parkinson's disease (PD) and Alzheimer's disease (AD) are the most common forms of neurodegenerative disorders. The aim of the current work is to study the potential of some new indanone derivatives for the treatment of these neurological disorders.
METHODS
A new series of 4-(2-oxo-2-aminoethoxy)-2-benzylidene substituted indanone derivatives have been synthesized and studied for anti-Parkinsonian and anti-Alzheimer's effects. Substitution of different aminoalkyl functionalities at the para position of 2-benzylidene moiety of indanone ring resulted in the formation of potent anti-parkinsonian and anti-Alzheimer's agents (5-10). The neuroprotective effects of newly synthesized compounds were evaluated using perphenazine (PPZ)-induced catatonia in rats and LPS-induced cognitive deficits in mice models. Further, in silico molecular modelling studies of the new indanone derivatives were performed by docking against the 3D structures of various neuroinflammatory mediators, such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and monoamine oxidase-B (MAO-B), to gain the mechanistic insights of their anti-Alzheimer's and antiparkinsonian effects.
RESULTS
The newly synthesized indanone analogues 5-10 were found effective against PPZinduced motor dysfunction and LPS-induced memory impairment in animal models. Among all the synthesized analogues, morpholine-substituted indanone 9 displayed maximum anti-parkinsonian activity, even better than the standard drug L-DOPA, while pyrrolidine and piperidine substituted analogues 5 and 6 were found to be the most potent anti-Alzheimer's agents.
CONCLUSION
The new 2-arylidene-1-indanone analogues show good potential as promising leads for designing compounds against Parkinson's and Alzheimer's diseases.
Topics: Rats; Mice; Animals; Structure-Activity Relationship; Lipopolysaccharides; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Indans; Alzheimer Disease
PubMed: 36453500
DOI: 10.2174/1573409919666221129155110 -
Health Psychology Research 2022Phenothiazines, a diverse class of drugs, can be used to treat multiple mental health and physical conditions. Phenothiazines have been used for decades to treat mental...
Phenothiazines, a diverse class of drugs, can be used to treat multiple mental health and physical conditions. Phenothiazines have been used for decades to treat mental illnesses, including schizophrenia, mania in bipolar disorder, and psychosis. Additionally, these drugs offer relief for physical illnesses, including migraines, hiccups, nausea, and vomiting in both adults and children. Further research is needed to prove the efficacy of phenothiazines in treating physical symptoms. Phenothiazines are dopaminergic antagonists that inhibit D2 receptors with varying potency. High potency phenothiazines such as perphenazine are used to treat various psychiatric conditions such as the positive symptoms of schizophrenia, the symptoms of psychosis, and mania that can occur with bipolar disorder. Low/mid potency phenothiazines such as chlorpromazine antipsychotic drugs that have been used to treat schizophrenia and schizophrenia-like disorders since the 1950s and are utilized in numerous disease states. The present investigation aims to elucidate the effects of phenothiazines in clinical practice.
PubMed: 36425230
DOI: 10.52965/001c.38930 -
Current Neuropharmacology 2023Since the early clinical efficacy of antipsychotics has not yet been well perceived, this study sought to decide whether the efficacy of antipsychotics at week 2 can... (Randomized Controlled Trial)
Randomized Controlled Trial Clinical Trial
BACKGROUND
Since the early clinical efficacy of antipsychotics has not yet been well perceived, this study sought to decide whether the efficacy of antipsychotics at week 2 can predict subsequent responses at week 6 and identify how such predictive capacities vary among different antipsychotics and psychotic symptoms.
METHODS
A total of 3010 patients with schizophrenia enrolled in a randomized controlled trial (RCT) and received a 6-week treatment with one antipsychotic drug randomly chosen from five atypical antipsychotics (risperidone 2-6 mg/d, olanzapine 5-20 mg/d, quetiapine 400-750 mg/d, aripiprazole 10-30 mg/d, and ziprasidone 80-160 mg/d) and two typical antipsychotics (perphenazine 20-60 mg/d and haloperidol 6-20 mg/d). Early efficacy was defined as the reduction rate using the Positive and Negative Syndrome Scale (PANSS) total score at week 2. With cut-offs at 50% reduction, logistic regression, receiver operating characteristic (ROC) and random forests were adopted.
RESULTS
The reduction rate of PANSS total score and improvement of psychotic symptoms at week 2 enabled subsequent responses to 7 antipsychotics to be predicted, in which improvements in delusions, lack of judgment and insight, unusual thought content, and suspiciousness/ persecution were endowed with the greatest weight.
CONCLUSION
It is robust enough to clinically predict treatment responses to antipsychotics at week 6 using the reduction rate of PANSS total score and symptom relief at week 2. Psychiatric clinicians had better determine whether to switch the treatment plan by the first 2 weeks.
Topics: Humans; Antipsychotic Agents; Benzodiazepines; Schizophrenia; Aripiprazole; Olanzapine; Risperidone; Quetiapine Fumarate; Haloperidol; Treatment Outcome
PubMed: 36411567
DOI: 10.2174/1570159X21666221118164612 -
Chemistry (Weinheim An Der Bergstrasse,... Jan 2023The difluoromethyl group plays an important role in modern medicinal and agrochemistry. While several difluoromethylation reagents have been reported, these typically...
The difluoromethyl group plays an important role in modern medicinal and agrochemistry. While several difluoromethylation reagents have been reported, these typically rely on difluoromethyl carbenes or anions, or target specific processes. Here, we describe a conceptually unique and general process for O-H, N-H and C-H difluoromethylation that involves the formation of a transient dithiole followed by facile desulfurative fluorination using silver(I) fluoride. We also introduce the 5,6-dimethoxy-1,3-benzodithiole (DMBDT) function, which undergoes sufficiently rapid desulfurative fluorination to additionally support F-difluoromethylation. This new process is compatible with the wide range of functional groups typically encountered in medicinal chemistry campaigns, and the use of Ag F is demonstrated in the production of F-labeled derivatives of testosterone, perphenazine, and melatonin, 58.0±2.2, 20.4±0.3 and 32.2±3.6 MBq μmol , respectively. We expect that the DMBDT group and this F/ F-difluoromethylation process will inspire and support new efforts in medicinal chemistry, agrochemistry and radiotracer production.
Topics: Halogenation; Indicators and Reagents; Chemistry, Pharmaceutical; Fluorides
PubMed: 36318597
DOI: 10.1002/chem.202202862