Basic & Clinical Pharmacology & Toxicology最新文献

Long-term sample stability of five atypical antipsychoticdrugs risperidone, paliperidone, clozapine, quetiapine and olanzapine and the antidepressant drug mirtazapine in serum was studied by use of a newly developed and validated analytical method based on solid-phase extraction and liquid chromatography–tandem mass spectrometry. Ascorbic acid was used as an antioxidative agent to stabilize olanzapine during storage and sample preparation.

We assessed analyte stability on long-term storage in serum samples at 25°C, 5°C, −20°C and −80°C, and during five freeze–thaw cycles. Analytes were stable for 23 days at room temperature except for olanzapine and mirtazapine (17 days). All analytes were stable for at least 30 days at 5°C. All analytes were stable for 270 days at −20°C, except for paliperidone and mirtazapine with 60 days and 180 days, respectively. All analytes were stable for 270 days at −80°C. Furthermore, all analytes were stable for five freeze–thaw cycles.

We recommend storage at −80°C when samples drawn for analysis of antipsychotic drugs are stored for more than 60 days, whereas a temperature of −20°C is sufficient for storage less than 60 days.

This study aimed to assess the effectiveness and safety of botulinum toxin (BTX) injections for managing motor disorders in patients with Parkinson's disease (PD). An electronic search was conducted based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data from available randomized controlled trials (RCTs) assessing BTX injections for motor disorders in PD patients were extracted for meta-analysis. Ultimately, 215 patients from eight RCTs were enrolled. Pooled analyses indicated that BTX was more effective than placebo in improving tremor (standardized mean difference [SMD] = 0.96, 95% CI [0.34, 1.58], p < 0.01), whereas no notable differences were observed between BTX and placebo regarding freezing of gait (SMD = 0.66, 95% CI [−0.26, 1.58], p = 0.162), United Parkinson's Disease Rate Scale (UPDRS) III score (SMD = −0.20, 95% CI [−1.17, 0.76], p = 0.68) and clinical global impression (CGI) score (SMD = 0.84, 95% CI [−0.74, 2.42], p = 0.298). Adverse events related to BTX injections were comparable to placebo (OR = 1.74, 95% CI [0.59, 5.14], p = 0.32). The current evidence suggests that BTX is effective and safe in treating PD tremor but fails to provide therapeutic benefits for freezing of gait and motor functional scores in PD patients. Furthermore, the limited number of included studies and heterogeneity in BTX intervention protocols suggest more research is needed, with additional standardized RCTs, to better understand and optimize BTX injections for motor disorders in PD.

Arvidsson, M, Franck, J, Ackehed, G, et al. Plasma concentrations of methylphenidate enantiomers in adults with ADHD and substance use disorder, with focus on high doses and relationship to carboxylesterase activity. Basic Clin Pharmacol Toxicol 2022; 130(4): 492–500, DOI: 10.1111/bcpt.13707.

Figure 3 caption should be:

FIGURE 3 d-RA/d-MPH metabolic ratio (MR) in subjects with multiple samples (n = 12) and those with only one visit (1A, n = 9). Subjects with an MR variability exceeding 3 between the lowest and highest MR are shown with dotted lines.

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Dapagliflozin (DPG) is a sodium-glucose cotransporter-2 (SGLT2) inhibitor that has been suggested to possess anti-inflammatory properties in diabetes. The aim of this study is to evaluate the role of DPG administration in preventing lipopolysaccharide (LPS)-induced damage in the female genital system. Thirty-two female Wistar Albino rats were randomly allocated into four groups: control group, LPS group, LPS + DPG group and DPG group. At the end of the experimental phase, ovary, fallopian tube and uterus tissues were collected for histopathological, immunohistochemical, genetic and biochemical analyses. The findings showed that LPS caused histopathological changes characterized by marked hyperaemia, mild to moderate haemorrhage, oedema and neutrophil leucocyte infiltrations and degenerative and necrotic changes in the female genital tract. In addition, it decreased total antioxidant status (TAS), increased total oxidant status (TOS) and oxidative stress index (OSI) levels. LPS also increased the expressions of Cas-3, G-CSF and IL-1β in the ovary, fallopian tubes and uterus immunohistochemically. While Claudin-1 expression decreased, NLRP3 and AQP4 gene expressions increased due to LPS. However, DPG treatment prevented all these changes. The results of this study indicate that, DPG can be used to prevent LPS-induced lesions in the female reproductive system.

Several medications are commonly administered to older Japanese patients. Since some of them have not been included in previously developed scales to estimate the anticholinergic burden, we have developed a new muscarinic receptor binding-based anticholinergic burden scale. This study aimed to investigate the functional inhibitory effects of 60 medications, classified as anticholinergic burden scales 3 and 2 by the anticholinergic burden scale, on muscarinic receptor-mediated contractions in the bladder and ileum.

The relaxation response induced by these drugs on isolated rat bladders and ileum smooth muscles constricted by carbachol was assessed using the organ bath method. All drugs inhibited smooth muscle contractile responses induced by the muscarinic receptor activation in a concentration-dependent manner in the rat bladder and ileum. Notably, variations were observed in the relaxation responses of the drugs, and the function EC₅₀ values were positively correlated with the binding IC₅₀ values in the bladder and ileum.

The results of this study provide functional pharmacological evidence for the muscarinic receptor binding-based anticholinergic burden scale. Implementation of this scale may help reduce the risk of constipation and urinary retention, which are common side effects associated with anticholinergic drugs.

The midbrain dorsomedial periaqueductal grey column (dmPAG) is involved in the regulation of cardiovascular responses. Due to the presence of Gamma-Aminobutyric acid (GABA) receptors in the dmPAG, this study aimed to investigate the role of GABA_A receptors in the dmPAG on cardiovascular parameters and its possible peripheral mechanisms. The left femoral artery was cannulated, and systolic arterial pressure (SAP), mean arterial pressure (MAP) and heart rate (HR) were recorded using a Power lab system. Microinjection of saline, muscimol and bicuculline (BIC) was done using a stereotaxic device. Also, the peripheral mechanisms dependent on GABA_A receptors in the dmPAG were evaluated by intravenous (i.v.) injection of hexamethonium (Hexa) and atropine (Atr) 5 min before the BIC. Results showed that BIC significantly increased ∆SAP, ∆MAP and ∆HR than the control group, but muscimol had no significant effect. Injection of Hex significantly attenuates the effect of BIC on ∆SAP and ∆MAP. Atr (i.v) significantly increased the ∆HR, and when injected before BIC microinjection, it did not affect the cardiovascular responses induced by BIC. These findings show that GABA_A receptors of the dmPAG have inhibitory effects on the cardiovascular system, which are mostly mediated by the sympathetic system.

Over the past decade, increasing off-label use of quetiapine has been reported worldwide from various sources. We wanted to investigate how this is reflected in therapeutic drug monitoring (TDM) data. Requisitions for serum concentration measurements of quetiapine from a TDM service in Central Norway during 2001–2019 were obtained and analysed for age, gender, trends in quetiapine doses, serum concentrations and indicators of diagnoses. There were 19 759 requisitions from 7459 individuals. Daily doses of quetiapine decreased by 24 mg per year (95% CI: −25.61 to −21.48, p < 0.001, N = 4505). A corresponding decrease in quetiapine serum concentrations was not seen. The proportion of requisitions with diagnoses indicating reimbursable use was 13% for the whole study period. Mean daily doses were slightly higher in the reimbursable group, but declined over time in these samples, as well. To our understanding, these results signal a trend towards lower prescribed doses of quetiapine, possibly reflecting drug repurposing and/or off-label use. The discrepancy in the decrease of doses versus serum concentrations may reflect the intake of higher doses than prescribed and/or inappropriate TDM sampling. Our findings show that TDM data have limitations when it comes to making inferences about the use of quetiapine based on serum concentrations and clinical information on the requisitions.

Alzheimer's disease (AD) is a devastating disorder with a multifaceted aetiology characterized by dementia, which later progresses to cognitive impairment. Significant efforts have been made to develop pharmacological interventions that slow down the pathogenesis of AD. However, conventional drugs have failed to satisfactorily treat AD and are more focussed towards symptomatic management. Thus, there is a gap in the literature regarding novel targets and modulators targeting them for the effective treatment of AD. Recent studies have demonstrated that modulation of transient receptor potential (TRP) channels has the potential to halt AD pathogenesis at an early stage and rescue hippocampal neurons from death. Amongst several members, TRP channels like TRPA1, TRPC6, TRPM2 and TRPV2 have shown promising results in the attenuation of neurobehavioural cognitive deficits as well as signalling pathways governing such cognitive decline. Furthermore, as these channels govern the ionic balance in the cell, their beneficial effects have also been known to maintain the homeostasis of Ca²⁺, which is the major culprit eliciting the vicious cycle of excitotoxicity, mitochondrial dysfunction, ROS generation and neurodegeneration. Despite such tremendous potential of TRP channel modulators, their clinical investigation remains elusive. Therefore, in the present review, we have discussed such agents in the light of TRP channels as molecular targets for the amelioration of AD both at the preclinical and clinical levels.

This population pharmacokinetics (PopPK) analysis of eptinezumab used data from a paediatric study and a prior adult PopPK model to compare eptinezumab pharmacokinetics between adult and paediatric populations to determine dose recommendations for the phase 3 paediatric studies in migraine. The data consisted of 16 adolescents and 12 children with migraine, with corresponding demographics and 278 plasma concentrations in total. PopPK analysis was performed through nonlinear mixed effect modelling and with prior knowledge taken from a previous PopPK model in adults. A two-compartment model—adjusted for body weight impact on clearances and volumes of distributions and scaled to the power of 0.75 and 1.0, respectively—was found to adequately describe the paediatric pharmacokinetic data. The simulated population showed overlap in area under the plasma concentration–time curve and maximum plasma concentration between the paediatric and adult populations, with paediatric exposures within 10%–15% above adult levels on average. To provide comparable exposure to the approved adult doses, weight-based dosing adjustments are recommended for paediatric patients weighing ≤40 kg, while no adjustments are needed for patients weighing >40 kg. These results support the dosing strategy being used in the ongoing efficacy and safety studies with eptinezumab in children and adolescents with migraine.