Search

Copyright of Canadian Journal of Anaesthesia / Journal Canadien d'Anesthésie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Understanding the relationship between the concentration of a drug and its therapeutic efficacy or side effects is crucial in drug development, especially to understand therapeutic efficacy in central nervous system drug, quantifying drug-induced site-specific changes in the levels of endogenous metabolites, such as neurotransmitters. In recent times, evaluation of quantitative distribution of drugs and endogenous metabolites using matrix-assisted laser desorption/ionization (MALDI)-mass spectrometry imaging (MSI) has attracted much attention in drug discovery research. However, MALDI-MSI quantification (quantitative mass spectrometry imaging, QMSI) is an emerging technique, and needs to be further developed for practicable and convenient use in drug discovery research. In this study, we developed a reliable QMSI method for quantification of clozapine (antipsychotic drug) and dopamine and its metabolites in the rat brain using MALDI-MSI. An improved mimetic tissue model using powdered frozen tissue for QMSI was established as an alternative method, enabling the accurate quantification of clozapine levels in the rat brain. Furthermore, we used the improved method to evaluate drug-induced fluctuations in the concentrations of dopamine and its metabolites. This method can quantitatively evaluate drug localization in the brain and drug-induced changes in the concentration of endogenous metabolites, demonstrating the usefulness of QMSI., (© 2024. The Author(s).)

Objective: Deep learning (DL) has shown promising results for improving mammographic breast cancer diagnosis. However, the impact of artificial intelligence (AI) on the breast cancer screening process has not yet been fully elucidated in terms of potential workload reduction. We aim to assess if AI-based triaging of breast cancer screening mammograms could reduce the radiologist's workload with non-inferior sensitivity., Methods: PubMed, EMBASE, Cochrane Central, and Web of Science databases were systematically searched for studies that evaluated AI algorithms on computer-aided triage of breast cancer screening mammograms. We extracted data from homogenous studies and performed a proportion meta-analysis with a random-effects model to examine the radiologist's workload reduction (proportion of low-risk mammograms that could be theoretically ruled out from human's assessment) and the software's sensitivity to breast cancer detection., Results: Thirteen studies were selected for full review, and three studies that used the same commercially available DL algorithm were included in the meta-analysis. In the 156,852 examinations included, the threshold of 7 was identified as optimal. With these parameters, radiologist workload decreased by 68.3% (95%CI 0.655-0.711, I ² = 98.76%, p  < 0.001), while achieving a sensitivity of 93.1% (95%CI 0.882-0.979, I ² = 83.86%, p  = 0.002) and a specificity of 68.7% (95% CI 0.684-0.723, I ² = 97.5%, p  < 0.01)., Conclusions: The deployment of DL computer-aided triage of breast cancer screening mammograms reduces the radiology workload while maintaining high sensitivity. Although the implementation of AI remains complex and heterogeneous, it is a promising tool to optimize healthcare resources., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: To prevent rehospitalization for heart failure (HF), patients need to be able to perceive physical changes that occur at the onset of HF exacerbation and seek early help., Objective: The aim of this study was to evaluate the effect of a self-monitoring intervention on patients' perceptions of physical sensations during daily activities in the context of HF via a randomized controlled trial., Methods: Participants (N = 70) were randomly assigned to the intervention (received daily activity record-based self-monitoring intervention support; group A) or control (only explained the measured results from the records; group B) group. Group A reflected on and described the physical sensations in their daily activities within 1 month after discharge. Outcome measures were assessed at 1 month after the intervention using the European Heart Failure Self-care Behavior Scale, Evaluation Scale for Self-Monitoring by patients with Heart Failure, clinical events, physical activity, and sleep., Results: There was no significant difference in the change in the "asking for help" subscale score of the European Heart Failure Self-care Behavior Scale between the groups (+0.7 vs +0.4 points, P = .716). Group A had improved score on the self-monitoring subscale related to "concern about how movements affect body" from baseline (from 12.7 to 14.0 points, P = .026). There was no significant effect of self-monitoring intervention support on the first rehospitalization related to HF and all-cause death (log-rank χ 2 = 0.432, P = .511). A significant difference in moderate-intensity physical activity between the groups was observed (+4.6 vs -0.5 minutes, P = .029)., Conclusions: A focused strategy that enables patients to perceive their physical sensations and promotes early help-seeking behavior is needed., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Heart Failure (HF) is a common chronic disease that has a high readmission rate and is associated with worsening symptoms and major financial impacts. Disease management implemented during or after an HF hospitalization has been shown to reduce hospitalization and mortality rates. Particularly for outpatients, it is necessary to provide self-care interventions. Structured nurse-led support such as timely follow-ups, including phone calls, is beneficial for improving self-care assessments. Evidence for nurse-led support has been investigated but is less than conclusive. The aim of this study is to compare the effectiveness of a nurse-led structured intervention for outpatients with chronic HF against the usual medical care in terms of self-care behaviors and occurrence of symptom exacerbation or rehospitalization., Methods and Analysis: This is a cluster-randomized controlled trial. A total of 40 facilities with certified HF nurses will be allocated to two-arm clusters at a 1:1 ratio, randomly to the intervention or usual care arms. A total of 210 participants will be assigned from the hospital. Participants will be adults aged 18 years or older diagnosed with chronic HF who are classified as Stage C according to the ACCF/AHA Heart Failure staging system. In the intervention group, patients will receive structured nursing support. This begins with weekly support, including phone calls, for the first month, then transitions to monthly support thereafter. The aim is to ensure the stability of their living conditions, promote medication adherence, and encourage self-management. In the control group, patients will receive the usual care. Primary outcomes will assess the improvement or continuation of self-care behavior as measured by changes in EHFScBS (European Heart Failure Self-Care Behavior Scale) scores. Secondary outcomes include occurrence of readmission within 30 days, 3 months, 6 months, and 1 year after discharge, duration of home care until readmission, and blood levels of BNP and NT-proBNP.

Patients with heart failure have difficulty recognizing and identifying changes in bodily sensations, despite the importance of symptom monitoring. The way patients with heart failure experience their bodies from exacerbation to recovery is poorly understood. We aimed to describe the lived bodily experience of heart failure from exacerbation to recovery. Participatory observations and interviews were conducted in seven patients admitted to the intensive care unit with worsening heart failure. Benner's interpretive phenomenology was used for analysis. Four major themes were identified: a non-functional body becomes the central concern and an object; being conscious of bodily changes before hospitalization when asked; the central concern shifted to daily life and the body becomes the background; and having a feeling of death in the body that no longer functions or a weakened body after recovery. This study found that patients with heart failure were conscious and concerned about their bodies changing as they underwent rapid changes during exacerbations and recovery. In addition, immediately after their bodies recovered and until they were discharged from the hospital, they looked toward their daily lives through their bodily experiences during heart failure exacerbation. The lived bodily experience of heart failure, which is less conscious in daily life, is made conscious through storytelling in the period immediately following recovery from an acute exacerbation and can be the basis for subsequent self-care exploration.

Alterations in the experience-dependent and autonomous elaboration of neural circuits are assumed to underlie autism spectrum disorder (ASD), though it is unclear what synaptic traits are responsible. Here, utilizing a valproic acid-induced ASD marmoset model, which shares common molecular features with idiopathic ASD, we investigate changes in the structural dynamics of tuft dendrites of upper-layer pyramidal neurons and adjacent axons in the dorsomedial prefrontal cortex through two-photon microscopy. In model marmosets, dendritic spine turnover is upregulated, and spines are generated in clusters and survived more often than in control marmosets. Presynaptic boutons in local axons, but not in commissural long-range axons, demonstrate hyperdynamic turnover in model marmosets, suggesting alterations in projection-specific plasticity. Intriguingly, nasal oxytocin administration attenuates clustered spine emergence in model marmosets. Enhanced clustered spine generation, possibly unique to certain presynaptic partners, may be associated with ASD and be a potential therapeutic target., (© 2024. The Author(s).)

Ivabradine, a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel inhibitor, has been reported to induce photosensitivity-related visual disturbances such as phosphene in humans. Ivabradine-induced visual disturbances are caused by inhibition of HCN channels in the retina, and the mechanisms have been verified using HCN channel knockout mice and electroretinography (ERG). However, in rats, classical ERG using single flash light stimulus with standard analyses of waveform amplitude and latency has not revealed abnormal retinal function after administration of ivabradine. To verify whether retinal dysfunction after ivabradine administration was detectable in rats, we performed ERG using multistep flash light stimulation at the time when plasma concentration of ivabradine was high. Furthermore, the mechanism of the change in the waveform that appeared after the b-wave was investigated. Ivabradine and cilobradine, a selective HCN channel inhibitor, were administered subcutaneously to rats at 4-40 mg/kg as a single dose, and flash or long-duration ERG recordings at each light stimulus luminance were conducted 1.5 h after administration. Plasma and retinal concentrations of both compounds were measured immediately after the ERG recordings. In the flash ERG, prolongation of a- and/or b-wave latencies were detected at each light stimulus, and dose-dependent waveform changes after the b-wave were recorded at the specific light stimulus luminance for both compounds. These ERG changes increased in response to increasing plasma and retinal concentrations for both ivabradine and cilobradine. In the long-duration light stimulus ERG, a change in the waveform of the b-wave trough and attenuation of the c-wave were recorded, suggesting that the feedback control in the photoreceptor cells may be inhibited. This study revealed that the retinal dysfunction by HCN channel inhibitors in rats can be detected by multistep light stimulus ERG. Additionally, we identified that the inhibition of feedback current and the sustained responses in the photoreceptor cells cause the retinal dysfunction of HCN channel inhibitors in rats., Competing Interests: Declaration of competing interest Naohisa Umeya, Yuki Yoshizawa, Kosuke Fukuda, Keigo Ikeda, Mami Kamada, Hiroshi Inada, Toru Usui and Izuru Miyawaki are employees of Sumitomo Pharma Co., Ltd., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Tipepidine, an antitussive drug, has been reported to have central pharmacological effects and can be expected to be safely repositioned as treatment for psychiatric disorders. Since tipepidine requires three doses per day, development of a once-daily medication would be highly beneficial. Previously, we reported that combination use with quinidine, a CYP2D6 inhibitor, prolongs the half-life of tipepidine in chimeric mice with humanised liver.In this study, to predict this combination effect in humans, a physiologically based pharmacokinetic (PBPK) model was developed, and quantitative simulation was conducted. The simulation results indicated that concomitant administration of tipepidine with quinidine increased the predicted C max , AUC , and t 1/2 of tipepidine in the Japanese population by 3.4-, 6.6-, and 2.4-fold, respectively.Furthermore, to compare with another approach that aims to prolong the half-life, the PK profile of tipepidine administered in hypothetical extended-release form was simulated. Extended-release form was predicted to be more influenced by CYP2D6 genotype than combination with quinidine, and the predicted plasma exposure was markedly increased in poor metabolizers, potentially leading to adverse effects.In conclusion, quantitative simulation using the PBPK model suggests the feasibility of the safe repositioning of tipepidine as a once-daily medication in combination with quinidine.

An adverse effect of drug candidates, seizure is a serious issue in drug development. Improving evaluation systems for seizure liability is crucial for selecting good candidates. Firstly, in vitro electrophysiological measurement by a multielectrode array system in rat hippocampal brain slices was employed to confirm an increase in electrically evoked population spike (PS) area, the occurrence of multiple population spikes (MPSs), and thereby the seizure liability of five positive control chemicals: picrotoxin, 4-aminopyridine, pentylenetetrazole, penicillin G, and chlorpromazine. Aspirin, a negative control, did not affect PS area or generate MPSs. Furthermore, baclofen, an anticonvulsant drug, decreased PS area and inhibited the increase in PS area or occurrence of MPSs induced by picrotoxin. A comparative study of seizure liability among carbapenem antibiotics revealed that tienam > carbenin > omegacin and finibax. Despite leading to a strong decrease in PS area, physostigmine, cisplatin, and paroxetine still produced MPSs. Therefore, the increase in PS area or the occurrence of the MPS are considered significant evaluation parameters for seizure liability. In contrast, the in vitro electrophysiological measurement could not detect the seizure liability of diphenhydramine or fluvoxamine. A follow-up study of in vivo mouse behavioral change induced by intracerebroventricular administration of these drugs clearly detected convulsions. The in vitro electrophysiological study using hippocampal brain slices combined with in vivo behavior observation study of drug candidates administered by intracerebroventricular injection can implement to assess the seizure liability of even small amounts, especially in the early stages of drug development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Drug-induced steatohepatitis is considered more serious than drug-induced hepatic steatosis, so that differentiating between the two is crucial in drug development. In addition, early detection of drug-induced steatohepatitis is considered important since recovery is possible with drug withdrawal. However, no method has been established to differentiate between the two. In the development of drug-induced steatohepatitis, reactive oxygen species (ROS) is excessively generated in the liver. It has been reported that ROS can be monitored with electron spin resonance (ESR) and dynamic nuclear polarization-magnetic resonance imaging (DNP-MRI) by using nitroxyl radicals, which are known to participate in various in vivo redox reactions. The decay/reduction rate, which is an index for monitoring nitroxyl radicals, has been reported to be increased in tissues with excessive ROS levels other than liver, but decreased in methionine choline deficient (MCD) diet-induced steatohepatitis with excess ROS. Therefore, looking to differentiate between drug-induced hepatic steatosis and steatohepatitis, we examined whether the reduction rate decreases in steatohepatitis other than the MCD-diet induced disease and whether the decrease could be detected by MRI. We used STAM™ mice in which hepatic steatosis and steatohepatitis developed sequentially under diabetic conditions. 3-carbamoyl-PROXYL (CmP), one of the nitroxyl radicals, was injected intravenously during the MRI procedure and the reduction rate was calculated. The reduction rate was significantly higher in early steatohepatitis than in hepatic steatosis and the control. Excess ROS in early steatohepatitis was detected by an immunohistochemical marker for ROS. Therefore, it was indicated that the increase or decrease in the reduction rate in steatohepatitis differs depending on the model, and early steatohepatitis could be noninvasively differentiated from hepatic steatosis using CmP in MRI. Since the change in direction of the reduction rate in steatohepatitis in clinical studies could be predicted by confirming the reduction rate in preclinical studies, the present method, which can be used consistently in clinical and preclinical studies, warrants consideration as a candidate monitoring method for differentiating between early drug-induced steatohepatitis and hepatic steatosis in drug development., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier B.V.)

Purpose of Review: Remote monitoring (RM) is the standard of care for patients with cardiac implantable electronic devices (CIEDs), particularly pacemakers. However, the long-term outcomes of RM versus conventional monitoring (CM) of pacemakers and its effectiveness in reducing in-office (IO) visits for device reprogramming require elucidation. This systematic review and meta-analysis aimed to compare the RM and CM of pacemakers over a long-term follow-up., Recent Findings: We systematically searched the PubMed/MEDLINE, Embase, Cochrane, and ClinicalTrials.gov databases for randomized controlled trials (RCTs) comparing RM and CM of pacemakers with at least 12 months of follow-up. Binary endpoints were pooled with risk ratios (RRs), whereas continuous outcomes were computed using mean differences (MDs) or standardized MDs (SMDs). Heterogeneity was assessed using I 2 statistics. Among the eight included RCTs, 2159 (48.9%) of 4063 patients underwent RM. Follow-up periods ranged from 12 to 24 months. There were no significant between-group differences in all-cause mortality (RR = 1.19; 95% confidence interval [CI], 0.90-1.57; p = 0.22; I 2  = 0%), stroke (RR = 0.90; 95% CI, 0.43-1.91; p = 0.79; I 2  = 23%), hospitalizations for cardiovascular and/or device-related adverse events (RR = 0.95; 95% CI, 0.75-1.21; p = 0.70; I 2  = 0%), and quality of life (SMD = - 0.06; 95% CI, - 0.22 to 0.10; p = 0.473; I 2  = 0%). RM was associated with fewer IO visits/patient/year (MD = 0.98; 95% CI, - 1.64 to - 0.33; p = 0.08; I 2  = 98%) and higher rates of atrial tachyarrhythmia (ATA) detection (RR = 1.22; 95% CI, 1.01-1.48; p = 0.04; I 2  = 0%) than was CM. This meta-analysis suggests that RM of pacemakers leads to higher rates of ATA detection and fewer IO visits/patient/year, without compromising patient safety., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The number of patients on ventilators is rapidly increasing owing to the coronavirus pandemic. The previously developed Questionnaire for the Reflective Practice of Nursing Involving Invasive Mechanical Ventilation (Q-RPN-IMV) for the care of patients on ventilators includes nurses' thought processes as items. This study aims to develop a short form of the Q-RPN-IMV for immediate use in practice and to test its reliability and validity. A convenience sample of 629 participants was used to explore the factor structure using factor analysis. The test-retest reliability was assessed using the intraclass correlation coefficient (ICC). The study was a cross-sectional design instrument development study and was reported according to GRRAS guidelines. Q-RPN-IMV short form was divided into ventilator management and patient management. The ventilator management comprised 31 items organized into six factors. Cronbach's alpha ranged from 0.82 to 0.91, and the ICC ranged from 0.82 to 0.89. The patient management comprised 27 items organized into five factors. Cronbach's alpha ranged from 0.75 to 0.97, and ICC ranged from 0.75 to 0.97. The Q-RPN-IMV short form is a reliable and validated instrument for assessing care for patients on ventilators. This study was not registered.

Background: Electrocardiographic (ECG) criteria to detect left ventricular hypertrophy (LVH) in patients with left bundle branch block (LBBB) remain under debate. We conducted a systematic review and meta-analysis to evaluate the diagnostic accuracy of different ECG criteria for diagnosing LVH in patients with LBBB., Methods: We searched PubMed, Embase, Cochrane, and LILACS for articles evaluating the diagnostic accuracy of ECG criteria for LVH in patients with LBBB published between 1984 and 2023. Echocardiogram, magnetic resonance imaging, or autopsy were used as the reference standard for diagnosis of LVH. Risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. The co-primary outcomes were sensitivity, specificity, the diagnostic odds ratio, and likelihood ratios, estimated using a bivariate generalized linear mixed model for each ECG criterion. The prespecified protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO)., Results: We included 12 studies with a total of 1023 patients. We analyzed 10 criteria for LVH on ECG, including the Sokolow-Lyon criterion, the Cornell criterion, the RaVL (R wave in aVL) criterion, the Gubner-Ungerleider criterion, and the Dálfo criterion, among others. The Dalfó criterion was used for 487 patients and had the highest pooled sensitivity of 86% (95% confidence interval [CI] 57%-97%). All the other criteria had poor sensitivities. The Gubner-Ungerleider criterion and the RV5 or RV6 > 25 mm criterion had the highest specificities, with the former being used for 805 patients, obtaining a specificity of 99% (95% CI 80%-100%) and the latter being used for 355 patients, obtaining a specificity of 99% (95% CI 94%-100%)., Conclusions: In patients with LBBB, the use of ECG criteria had poor performance for ruling out LVH, mostly due to low sensitivities. None of the criteria analyzed demonstrated a balanced tradeoff between sensitivity and specificity, suggesting that ECG should not be used routinely to screen for LVH., (© 2023 The Authors.)

No method of monitoring drug-induced hepatic steatosis has been established, which is a concern in drug development. Hepatic steatosis is divided into diffuse and non-diffuse forms according to the pattern of fat deposition. Diffuse hepatic steatosis was reported as evaluable by 1 H-magnetic resonance spectroscopy ( 1 H-MRS), which is used as an adjunct to the MRI examination. Blood biomarkers for hepatic steatosis have been also actively investigated. However, there are few reports to conduct 1 H-MRS or blood test in human or animal non-diffuse hepatic steatosis with reference to histopathology. Therefore, to investigate whether non-diffuse hepatic steatosis can be monitored by 1 H-MRS and/or blood samples, we compared histopathology to 1 H-MRS and blood biochemistry in a non-diffuse hepatic steatosis rat model. Non-diffuse hepatic steatosis was induced by feeding rats the methionine choline deficient diet (MCDD) for 15 days. The evaluation sites of 1 H-MRS and histopathological examination were three hepatic lobes in each animal. The hepatic fat fraction (HFF) and the hepatic fat area ratio (HFAR) were calculated from 1 H-MRS spectra and digital histopathological images, respectively. Blood biochemistry analyses included triglycerides, total cholesterol, alanine aminotransferase, and aspartate aminotransferase. A strong correlation was found between HFFs and HFARs in each hepatic lobe (r = 0.78, p < 0.0001) in rats fed the MCDD. On the other hand, no correlation was found between blood biochemistry values and HFARs. This study showed that 1 H-MRS parameters correlated with histopathological changes but blood biochemistry parameters didn't, so that it is suggested that 1 H-MRS has the potential to be a monitoring method for non-diffuse hepatic steatosis in rats fed the MCDD. Given that 1 H-MRS is commonly used in preclinical and clinical studies, 1 H-MRS should be considered a candidate method for monitoring drug-induced hepatic steatosis., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Recently, it has been reported that tipepidine has various central pharmacological effects and can be expected to be safely repositioned as a treatment for psychiatric disorders. Since tipepidine has a very short half-life and requires three doses per day, the development of a once-daily medication would be highly beneficial to improve adherence and quality of life in patients with chronic psychiatric disorders. The aim of this study was to identify the enzymes involved in tipepidine metabolism and to verify that combination use with an enzyme inhibitor prolongs the half-life of tipepidine.Metabolism studies using recombinant human cytochrome P450 (P450, CYP) isoforms and inhibition studies using various selective P450 inhibitors and human liver microsomes revealed that CYP2D6 is the main enzyme catalysing tipepidine metabolism, with a metabolic contribution ratio of 85.4%.Furthermore, a pharmacokinetic study using chimeric mice with humanised liver showed that oral coadministration of a CYP2D6 inhibitor, quinidine, increased the C max , AUC 0-t , and t 1/2 of tipepidine by 1.5-, 3.2-, and 3.0-fold, respectively.These results indicated that coadministration of a CYP2D6 inhibitor is effective in increasing plasma exposure and prolonging the half-life of tipepidine and is useful for repositioning tipepidine as a treatment for psychiatric disorders.

There are no specific and sensitive biomarkers for arteritis, and the occurrence of arteritis in nonclinical toxicological studies of a candidate drug makes development of the drug very difficult. However, we showed in a previous study that the high signal intensity region around the artery on magnetic resonance imaging (MRI) could be a candidate biomarker for detection of arteritis. The present study was conducted to clarify the details of midodrine hydrochloride (MH)-induced arteritis lesions and whether arteritis induced by a mechanism other than the vasodilatory effect, which was evaluated in a previous study, could be detected by MRI. MH is a selective peripherally acting alpha-1 adrenergic receptor agonist, known to induce arteritis due to its vasoconstrictor action, but there is not enough information about MH-induced arteritis. Based on the data obtained under multiple dosing conditions, MH was administered subcutaneously to each rat once daily for 2 days at a dose level of 40 mg/kg/day for MRI assessment. The mesenteric arteries were examined using in vivo MRI at 1 day or 7 days after administration of the final dose and examined histopathologically. On the day after the final dose, high signal intensity region around the artery was observed in animals with minimal perivascular lesions confirmed by histopathology and not observed in an animal without histological changes. On the 7th day after the final dose, no abnormality was observed in histopathological examinations and no high signal intensity regions were observed by MRI in any animal. In conclusion, although further investigation is needed to confirm that high signal intensity is a reliable biomarker for humans, it is suggested that high signal intensity around the artery could be a versatile candidate biomarker with high specificity and sensitivity., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Background: The prevention of recurrent readmission among heart failure (HF) patients requires support for appropriate self-care behaviors to prevent exacerbation of HF and self-monitoring to allow for patients' early perception of physical changes during exacerbations. Such support may enable patients to seek early consultation. This study developed a self-monitoring intervention that aimed at increasing the perception of patient-unique physical sensations caused by HF, based on daily activity records of patients., Method: A parallel two-arm randomized controlled trial is being conducted with 68 HF patients early after their discharge. Participants in both groups wear a wristwatch activity tracker from time-of-discharge. Participants in the self-monitoring intervention group receive support to reflect on their actual daily activities and the associated physical sensations they experienced, based on their daily activity records. The primary outcome is participants' "Asking for Help" dimension of self-care behavior, measured using the European Heart Failure Self-Care Behavior Scale at one month follow-up after intervention., Conclusion: This study is the first trial to use an activity tracker as a tool for symptom perception among HF patients. The problem of delayed consultations during exacerbations may be resolved by assisting patients in improving their perception of their unique physical sensations associated with specific daily activities, based on their daily activity records. If the effect is clarified, it could lead to the construction of new nursing interventions for continuous disease management that aim towards re-hospitalization prevention., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Purpose: We studied the conditions under which c-waves of the electroretinogram (ERG), that represent retinal pigment epithelium (RPE) function, were detectable using an alternating current (AC) amplifier and whether the c-wave recorded using an AC amplifier was useful for evaluating RPE function., Methods: We recorded ERG responses in rats to 5 s stimuli under the conditions in which the low-cut frequency and the stimulus luminance were varied. In addition, changes in ERGs were studied after intravenous injection of sodium iodate (SI) to induce RPE degeneration., Results: The c-wave was detected clearly when the frequency of the low-cut filter was set at 0.01 Hz and light stimulus luminances were ≥ - 1.0 log cd/m 2 . The c-wave was attenuated earlier than other waves (e.g., a-wave and b-wave) after SI administration., Conclusions: The c-wave was easily detectable using an AC amplifier with the low-cut filter set at 0.01 Hz. Using the AC amplifier may allow easier c-wave recording, compared with the conventional use of a direct current (DC) amplifier, and could be useful for evaluating RPE function., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Although clozapine-induced granulocytopenia (CIG) is less severe than clozapine-induced agranulocytosis (CIA), and some patients with CIG may not go on to develop serious complications, clozapine is discontinued in cases of both CIA and CIG. Understanding the pathogenic mechanisms of CIA/CIG could provide better management of clozapine therapy. Recently, as a mechanistic insight into adaptive immune systems, European groups reported clozapine-specific proliferative responses and clozapine-specific T cells using blood taken from patients with CIA and/or CIG., Aims: The aims of our study are to support this mechanistic evidence and to investigate the difference in the lymphocyte response to clozapine between patients with CIG and those with CIA., Methods: Lymphocyte stimulation tests (LSTs) were conducted using CD25-positive cell-depleted peripheral blood-derived mononuclear cells (PBMCs) isolated from blood of four Japanese patients with CIA, four patients with CIG, and nine clozapine-tolerant subjects., Results: Three of four patients with CIA and one of four patients with CIG showed proliferative responses to clozapine with a stimulation index of greater than 2. In contrast, none of the nine clozapine-tolerant subjects showed any response to clozapine. Olanzapine did not stimulate PBMCs of patients with CIA, patients with CIG, or clozapine-tolerant subjects., Conclusions: Clozapine- and CIA-specific lymphocyte reactions in a Japanese population provided supportive evidence that the pathogenesis of CIA is based on adaptive immune reactions. In addition, patients with CIG who show a positive response to an LST may at the very least not be chosen for clozapine-rechallenge and further prospective studies are desirable to verify this hypothesis.

A method capable of identifying drug-induced arteritis is highly desirable because no specific and sensitive biomarkers have yet been defined. Although magnetic resonance imaging (MRI) may be used to find a biomarker candidate for drug-induced arteritis, there are no reports on the evaluation of drug-induced arteritis by MRI. The present study was conducted to clarify whether Fenoldopam mesylate (FM)-induced arteritis in rats can be detected by MRI. FM, a dopamine (D1 receptor) agonist, is known to induce arteritis in rats. FM was administered subcutaneously to each rat once daily for 2 days at a dose of 100 mg/kg/day. These arteries were examined with ex vivo high-resolution MRI or postmortem MRI after euthanasia. These arteries were also examined using in vivo MRI on the day after final dosing or 3 days after administration of the final dose. These arteries were examined histopathologically in all experiments. The ex vivo MRI showed low-intensity areas and a high signal intensity region around the artery, and these findings were considered to be erythrocytes infiltrating the arterial wall and perivascular edema, respectively. In the in vivo study, the MRI of the FM-administered group showed a high signal intensity region around the artery. The perivascular edema observed histopathologically was recognized as a high signal intensity region around the artery on the image of MRI. In conclusion, detection of the high signal intensity region around the artery by MRI is considered to be a useful method for identifying arteritis. Although further investigation is needed to be a reliable biomarker, it is suggested that it could be a biomarker candidate., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors. Published by Elsevier B.V.)

Breast cancer resistance protein (BCRP) expressed in the blood-brain barrier plays a major role in limiting drug distribution into the central nervous system (CNS). However, functional involvement of BCRP in drug distribution into the brain and cerebrospinal fluid (CSF) remains unclear. The aim of present study was to reveal the role and quantitative impact of BCRP on CNS distribution. The brain-to-plasma unbound concentration ratio (K p,uu,brain ) and CSF-to-plasma unbound concentration ratio (K p,uu,CSF ) values of BCRP-specific substrates were determined in rats. The K p,uu,brain values decreased, as the in vitro BCRP corrected flux ratio (CFR) increased. The K p,uu,CSF values of BCRP-specific substrates were greater than the K p,uu,brain values. Increase in the K p,uu,brain values induced by co-administration of BCRP inhibitor correlated with the in vitro BCRP CFR and were greater than the increase in K p,uu,CSF values induced by BCRP inhibitor except nebicapone. The contribution of BCRP to the brain and CSF distribution of the dual P-glycoprotein/BCRP substrates, imatinib and prazosin, was similar to that of BCRP-specific substrates. Thus, we revealed that the impact of in vivo BCRP on CNS distribution is correlated with in vitro BCRP CFR, and that BCRP limits drug distribution into the brain more strongly than into the CSF., Competing Interests: Declaration of competing interest The authors declare no conflict of interest. Yuki Katagiri, Hiroko Kawaguchi, Koji Umemura, Jun Tadano, Izuru Miyawaki are employees of Sumitomo Dainippon Pharma Co., Ltd., (Copyright © 2021 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Microsampling (MS) has been increasingly used in toxicity studies reducing animal use for toxicokinetic analysis. However, especially for drugs with hematotoxic properties, the potential effects of MS on hematological parameters and subsequent toxicity assessment should be considered, while such properties are frequently unknown at the discovery stage. Here, we conducted a rat 2-week study of hematotoxic compounds and evaluated the effects of MS on toxicity assessment. Six-week-old female SD rats were orally dosed with vehicle, methylene blue trihydrate (MB: 300 mg/kg/day), or azathioprine (AZP: 12 and 24 mg/kg/day) for 2 weeks. Each treatment group was divided into non-MS and MS subgroups, and in the MS subgroups, 50 μL/time point of blood was collected from the jugular vein at 7 time points each on Days 1 and 13 of dosing. The test items included clinical signs, body weight, urinalysis, hematology, blood chemistry, necropsy, organ weight, and histopathology. In the MB non-MS subgroup, there were low values in red blood cell parameters, high values in reticulocytes and bilirubin, and increased extramedullary hematopoiesis, reflecting hemolytic anemia. In the AZP non-MS subgroup, there were low values of red and white blood cell parameters and decreased cellularity in the bone marrow, reflecting myelosuppression. The effects of MB and AZP were similarly observed in the MS subgroups, and the effects of MS on the toxicological endpoints were generally small. Based on these results, the effects of MS on toxicity assessment were considered to be small in rat toxicity studies even for hematotoxic compounds.

Hepatotoxicity is one of the most common toxicities observed in non-clinical safety studies of drug candidates, and it is important to understand the hepatotoxicity mechanism to assess the risk of drug-induced liver injury in humans. In this study, we investigated the mechanism of hepatotoxicity caused by 2-[2-Methyl-1-(oxan-4-yl)-1H-benzimidazol-5-yl]-1,3-benzoxazole (DSP-0640), a drug candidate that showed hepatotoxicity characterized by centrilobular hypertrophy and vacuolation of hepatocytes in a 4-week oral repeated-dose toxicity study in male rats. In the liver of rats treated with DSP-0640, the expression of aryl hydrocarbon receptor (AHR) target genes, including Cyp1a1, was upregulated. In in vitro reporter assays, however, DSP-0640 showed only minimal AHR-activating potency. Therefore, we investigated the possibility that DSP-0640 indirectly activated AHR by inhibiting the CYP1 enzyme-dependent clearance of endogenous AHR agonists. In in vitro assays, DSP-0640 showed inhibitory effects on both rat and human CYP1A1 and enhanced rat and human AHR-mediated reporter gene expression induced by 6-formylindolo[3,2-b]carbazole, a well-known endogenous AHR agonist. The possible involvement of CYP1A1 inhibition in AHR activation was also demonstrated with other hepatotoxic compounds tacrine and albendazole. These results suggest that CYP1A1 inhibition-mediated AHR activation is involved in the hepatotoxicity caused by DSP-0640 and that DSP-0640 might induce hepatotoxicity in humans as well. We propose that CYP1A1 inhibition-mediated AHR activation is a novel mechanism for drug-induced hepatotoxicity.

Background: A substantial number of patients with shock devices (implantable cardioverter defibrillators [ICDs] or ICDs with resynchronization [CRTDs]) experience psychological distress., Objective: We investigated the device nurse telephone intervention's effect on improving the patient's adaptation to shock devices, quality of life (QOL), and anxiety in the remote monitoring era., Methods: The patient's adaptation to the device, health-related QOL, and anxiety were investigated by the modified Implanted Devices Adjustment-Japan score (IDAS), Short Form-36, and State-Trait Anxiety Inventory (STAI) before and 1-year after the device nurse telephone intervention, performed every 3 months. A total of 95 patients (median age 69 years and 25 females) participated. Sixty patients had ICDs and 35 CRTDs. Structural heart disease was observed in 72 patients, and idiopathic ventricular arrhythmias in the others. The mean left ventricular ejection fraction was 46% ± 15%. The median duration since the device implantation was 5.2 years., Results: The total IDAS score significantly improved from 28.42 ± 7.11 at baseline to 26.77 ± 7.68 (p = 0.0076) at 1 year. Both the state and trait anxiety significantly improved (from 38.9 ± 9.6 to 35.3 ± 9.0 [<0.0001] and 38.8 ± 10.3 to 36.2±9.8 [p = 0.0044], respectively). The prevalence of patients with a state and trait anxiety of more than 40 decreased from 44 (46%) and 38 (40%) patients before the study to 27 (28 %) and 32 (34 %) at 1 year. The SF-36 mental component summary score significantly increased (50.8 ± 8.3 at baseline to 53.1 ± 7.7 at 1 year, p = 0.0031)., Conclusions: The device nurse intervention facilitated the patient's adaptation to the shock device, increased the health-related QOL, and reduced the patient's anxiety., (© 2021 Wiley Periodicals LLC.)

Huntington's disease (HD) is a progressive, neurodegenerative disease characterized by motor, cognitive, and psychiatric symptoms. To investigate the metabolic alterations that occur in HD, here we examined plasma and whole-brain metabolomic profiles of the R6/2 mouse model of HD. Plasma and brain metabolomic analyses were conducted using capillary electrophoresis-mass spectrometry (CE-MS). In addition, liquid chromatography-mass spectrometry (LC-MS) was also applied to plasma metabolomic analyses, to cover the broad range of metabolites with various physical and chemical properties. Various metabolic alterations were identified in R6/2 mice. We report for the first time the perturbation of histidine metabolism in the brain of R6/2 mice, which was signaled by decreases in neuroprotective dipeptides and histamine metabolites, indicative of neurodegeneration and an altered histaminergic system. Other differential metabolites were related to arginine metabolism and cysteine and methionine metabolism, suggesting upregulation of the urea cycle, perturbation of energy homeostasis, and an increase in oxidative stress. In addition, remarkable changes in specific lipid classes are indicative of dysregulation of lipid metabolism. These findings provide a deeper insight into the metabolic alterations that occur in HD and provide a foundation for the future development of HD therapeutics., (© 2021 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Autism spectrum disorder (ASD) is a multifactorial disorder with characteristic synaptic and gene expression changes. Early intervention during childhood is thought to benefit prognosis. Here, we examined the changes in cortical synaptogenesis, synaptic function, and gene expression from birth to the juvenile stage in a marmoset model of ASD induced by valproic acid (VPA) treatment. Early postnatally, synaptogenesis was reduced in this model, while juvenile-age VPA-treated marmosets showed increased synaptogenesis, similar to observations in human tissue. During infancy, synaptic plasticity transiently increased and was associated with altered vocalization. Synaptogenesis-related genes were downregulated early postnatally. At three months of age, the differentially expressed genes were associated with circuit remodeling, similar to the expression changes observed in humans. In summary, we provide a functional and molecular characterization of a non-human primate model of ASD, highlighting its similarity to features observed in human ASD., (© 2021. The Author(s).)

In recent years, the success rate of drug development has declined, and along with it, R&D costs have continued to rise. The rate of discontinuation of drug development due to safety reasons remains unchanged from 20 years ago. Therefore, it is important to check the safety of candidate compounds early in drug discovery in order to improve drug discovery efficiency. Under such circumstances, each company is focusing on establishing a low-cost, high-precision, and high-throughput safety screening system. The zebrafish is expected as a new experimental animal that serves as a bridge between in vitro and in vivo, and the progress of research in the last 15 years has been remarkable. At present, zebrafish are becoming a major experimental animal in Japan. At the same time, the gap between ideal and reality began to be seen, and it was time to once again understand the characteristics of zebrafish and think about its usage. This paper summarizes the points to be noted in the screening using zebrafish and introduces the use for actual safety evaluation.

Traditionally, safety evaluation at the early stage of drug discovery research has been done using in silico , in vitro , and in vivo systems in this order because of limitations on the amount of compounds available and the throughput ability of the assay systems. While these in vitro assays are very effective tools for detecting particular tissue-specific toxicity phenotypes, it is difficult to detect toxicity based on complex mechanisms involving multiple organs and tissues. Therefore, the development of novel high throughput in vivo evaluation systems has been expected for a long time. The zebrafish ( Danio rerio ) is a vertebrate with many attractive characteristics for use in drug discovery, such as a small size, transparency, gene and protein similarity with mammals (80% or more), and ease of genetic modification to establish human disease models. Actually, in recent years, the zebrafish has attracted interest as a novel experimental animal. In this article, the author summarized the features of zebrafish that make it a suitable laboratory animal, and introduced and discussed the applications of zebrafish to preclinical toxicity testing, including evaluations of teratogenicity, hepatotoxicity, and nephrotoxicity based on morphological findings, evaluation of cardiotoxicity using functional endpoints, and assessment of seizure and drug abuse liability., Competing Interests: The author has no conflicts of interest to be disclosed regarding this paper., (©2020 The Japanese Society of Toxicologic Pathology.)