bluuebunny/crossref_metadata_2025 huggingface dataset:
BETAINE MITIGATES REINSTATEMENT OF METHAMPHETAMINE- INDUCED CONDITIONED PLACE PREFERENCE IN RATS: INVOLVEMENT OF CAMKK2/AMPK SIGNALING
Authors: Chen *Hwei-Hsien , Lee Mei-Yi , Chen Ching-Yi , Hung Yung-Ting
Published: February 2025

Background

Methamphetamine (MA) use represents a significant worldwide public health concern. Currently, no pharmacological therapy has established efficacy for treating MA use disorder. Betaine has been found to reduce MA-induced behavioral sensitization. In addition, betaine activates adenosine monophosphate (AMP)-activated protein kinase (AMPK) which has been associated with reinstatement of cocaine seeking.

Aims & Objectives

This study aimed to examine the effects of betaine on conditioning and reinstatement of MA-conditioned place preference (CPP). Additionally, it sought to explore the involvement of AMPK and its upstream activator, calcium/calmodulin-dependent protein kinase (CAMKK2), in the reducing effect of betaine on the reinstatement of MA CPP.

Method

Male Sprague-Dawley rats underwent a three-compartment CPP paradigm. Betaine or saline was administered 30 minutes prior to each MA (2 mg/kg) conditioning session or 30 minutes before MA (1 mg/kg) priming-induced reinstatement. To determine the roles of AMPK and CAMKK2 in betaine's reducing effect on the reinstatement of MA CPP, rats received bilateral intra-NAc core infusions of the AMPK inhibitor dorsomorphin or STO-609, a selective inhibitor of CAMKK2, followed by betaine (100 μ g/μ l) before MA priming-induced reinstatement.

Results

Betaine did not affect conditioning, but significantly reduced reinstatement of MA CPP at 100 mg/kg. Furthermore, acute intra-NAc core infusions of betaine effectively ameliorated the reinstatement of MA CPP, and this effect was abolished by co-treatment with dorsomorphin or STO- 609.

Discussion & Conclusions

These findings suggest that betaine may be a novel therapeutic agent for the treatment of MA use disorder, and activation of the CAMKK2-AMPK pathway might be one of the mechanisms underlying the MA relapse-preventing effect of betaine.
MICRORNA EXPRESSION IN PATIENTS WITH METHAMPHETAMINE USE DISORDER: A PILOT STUDY
Authors: Ratta-Apha *Woraphat , Bunmak Nutthaya , Saengsawang Witchuda , Chairoungdua Arthit , Zaw Thet Tun , Ranuwattananon Apichart , Kalayasiri Rasmon
Published: February 2025

Background

MiRNAs have the potential to use as diagnostic biomarkers for neuropsychiatric disorders However, the possibility of using the miRNAs as a biomarker for diagnosis and prognosis of substance use disorders has extensively investigated.

Aims & Objectives

In this study, we aimed to investigate miRNAs expression in the serum of patients with methamphetamine use disorder admitted at an addiction center compared with the control.

Method

We extracted the circulating miRNAs from the serum of 19 methamphetamine users and 19 controls. The expression of 800 human miRNAs from the extracted samples were quantified with NanoString analysis and differential expression analysis of miRNAs between methamphetamine users and control subjects were determined. The candidate miRNAs validated by qPCR and pathway analysis predicted target genes from miRNAs candidates were analyzed.

Results

We selected five differentially expressed miRNAs between drug users and control, i.e., has-miR- 92a-3p, has-miR-451a, has-miR-30e-5p, has-miR-630, has-miR-495-3p. We found that these selected differentially expressed miRNAs are enriched in various pathways including amphetamine addiction pathway, cholinergic synapse pathway in KEGG pathway.

Conclusion

The results from this study would provide information about potential miRNAs that could be further investigate for potential diagnostic or prognostic markers for the methamphetamine use disorder.
CHARACTERISTICS OF ANTIDEPRESSANT CLASSES FOR TREATMENT- RESISTANT DEPRESSION AS DEFINED BY THE NUMBER OF VALID PHARMACOTHERAPIES
Authors: Mori *Keisuke , Kodaka Fumitoshi , Ishii Junpei , Sakai Yoshiyuki , Kobayashi Tamayo , Saeki Chihiro , Kameyama Hiroshi , Shigeta Masahiro
Published: February 2025

Background

Treatment-resistant depression (TRD) is conventionally defined as depression that does not remit with two or more adequate doses of antidepressants of adequate duration (Thase, 1997). Although we have suggested that 3 or more valid pharmacotherapies may include TRD with a high probability, little is known about the characteristics of antidepressants preferred for TRD.

Aims & Objectives

The purpose of this study was to characterize antidepressant classes for TRD by comparing prescriptions for TRD and non-treatment-resistant depression (non-TRD), classified by the number of valid pharmacotherapies. The study was approved by the Ethics Committee of the Jikei University School of Medicine.

Method

A longitudinal prescription data set of 494 patients who visited the Department of Psychiatry, The Jikei University Hospital between January 1, 2018 and December 31, 2021 was analyzed. The patients diagnosed with ICD-10 codes F32 (depressive episode) and F33 (recurrent depressive disorder) and treated with antidepressants for 30 days or more were extracted.Patients treated with 3 or more valid pharmacotherapies were included in the TRD group (58 patients) and those treated with 2 or less pharmacotherapies were included in the non-TRD group (436 patients).The presence or absence of antidepressant prescriptions for each group at the last visit during the period was compared using the chi-square test for each class. The significance level was set at 5%.

Results

The TRD group had significantly higher prescription rates for tricyclic antidepressants and serotonin- noradrenaline reuptake inhibitors (p=3.73×10-5 and 3.22×10-5, respectively), while the non-TRD group had significantly higher prescription rates for selective serotonin reuptake inhibitors (p=1.28×10-2). Prescription rates for noradrenergic and specific serotonergic antidepressants and tetracyclic antidepressants were not significantly different between the two groups (p= 6.14×10-1 and 1.61×10-1, respectively).

Discussion & Conclusion

It was suggested that in the real-world setting, psychiatrists choose antidepressant classes based on tolerability.

References

1. Thase, M. E. and Rush A. J. (1997), “When at first you don't succeed: sequential strategies for antidepressant nonresponders”, J Clin Psychiatry 58: 23–29.
ROLE OF MICROSOMAL PROSTAGLANDIN E SYNTHASE-1 IN MOUSE MODELS OF STRESS
Authors: Ikeda-Matsuo *Yuri , Takagi Hina , Kawabata Yuta , Iwato Saki , Doumae Asumi , Akira Shizuo , Uematsu Satoshi , Takahashi Tatsuo
Published: February 2025

Although there are many antidepressants available, most of which are drugs based on the monoamine hypothesis, and about one third of patients experience treatment-resistant depression. Thus, new therapeutic targets for antidepressants need to be discovered. We have previously reported that microsomal prostaglandin E synthase-1 (mPGES-1), a terminal inducible enzyme for PGE2 synthesis, induced at lesion sites in animal models and patients with Parkinson's disease and cerebral infarction contributes to the brain inflammation and deterioration of the pathology through PGE2 production1,2). Recently, brain inflammation has been reported to be involved in not only stroke or neurodegenerative diseases, but also psychiatric disorders. In this study, to elucidate the contribution of mPGES-1 to stress-induced brain inflammation and functions, we used two mouse models of stress, acute restraint stress (RS: 6 h) and social defeat stress (SDS). mPGES-1 mRNA was significantly increased after RS. Induction of mPGES-1 protein was observed in neurons in the frontal cortex (FC). PGE2 in FC was also significantly upregulated in wild-type (WT) mice, but not in mPGES-1 knockout (ES1KO) mice. The inflammatory responses, such as increases in GFAP and TNF-α, observed after RS in ES1KO were significantly less than those in WT. In sucrose preference test (SPT), the ratio of sucrose intake after RS in WT was significantly less than that in ES1KO. In SDS model, upregulation of mPGES-1 mRNA was also observed in FC, amygdala and ventral tegmental area at Day1 and 4. Induction of mPGES-1 protein was observed in neurons in the FC at Day4. PGE2 in FC was significantly upregulated at Day4 in WT mice, but not in ES1KO mice. The inflammatory responses, such as increases in Iba-1, GFAP and IL-1β, observed at Day10 of SDS in ES1KO were significantly less than those in WT. The ratio of sucrose intake at Day8 of SDS in WT was significantly less than that in ES1KO. Taken together, these results suggest that mPGES- 1 is induced by both RS and SDS stress in FC neurons, and then contributes to brain inflammation and anhedonia through PGE2 production. Thus, mPGSE-1 may be a promising novel therapeutic target for treatment of depression.

References

1)Ikeda-Matsuo Y, et al., Proc Natl Acad Sci U S A. 2006; 103(31): 11790-11795.

2)Ikeda-Matsuo Y, et al., Neurobiol Dis. 2019;124: 81-92.
DRUG-RESPONSE RELATIONSHIP OF ESCITALOPRAM IN OBSESSIVE COMPULSIVE DISORDER BASED ON TREATMENT OUTCOME: A PHARMACOKINETIC-PHARMACODYNAMIC MODELING APPROACH
Authors: Kim *Seoyoung , Kim Bo-Hyung , Kim Euitae , Kwon Jun Soo
Published: February 2025

Background

While selective serotonin reuptake inhibitors (SSRIs) are the established first-line treatment for obsessive compulsive disorder (OCD), substantial number of patients show unsatisfactory response. Effectiveness of high dose SSRIs has been reported, but evidences from randomized clinical trial is still limited. In the meantime, population pharmacokinetic-pharmacodynamic (PK-PD) model approach and model-based simulation might be useful in establishing time course of the dose-response relationship, whichthen can be utilized to predict treatment response.

Aim and Objectives

This study aimed to evaluate the time course of the relationship between plasma escitalopram concentration and treatment response measured by the Yale-Brown Obsessive Compulsive Scale (YBOCS) score by a simulation based on population PK-PD model.

Methods

The steady-state plasma escitalopram concentrations and YBOCS scores from 91 patients who were enrolled in the prior escitalopram clinical trial were used in this analysis. Subjects were randomly assigned to two groups with different maintenance dose of escitalopram, 20 or 40mg. The serial plasma escitalopram concentrations from 12 healthy volunteers were also used for the development of escitalopram PK model. The changes in YBOCS score after escitalopram treatment were described sequentially by a PD model using the predicted concentrations from the patient PK model. All the PK-PD models were developed using NONMEM®

Results

The escitalopram PK data from the patients and healthy volunteers were modeled using two- compartment model with a first-order absorption (Ka). The clearance of escitalopram for patients was estimated to be 43% lower than healthy subjects. The relationship between exposure to escitalopram and YBOCS score was described by an inhibitory Emax model with effect compartment model. Simulated relationship between escitalopram concentrations in effect compartment and YBOCS score of treatment responders and non-responders showed difference in dose-response relationship.

Discussion and Conclusions

The developed PK-PD model adequately describes the dose-response relationship of escitalopram and the improvement in YBOCS score in OCD adequately. The model-based simulation shows that the drug trial of adequate dose for sufficient duration and monitoring the plasma drug level is important when determining treatment response to escitalopram. The difference in dose-response relationship of escitalopram in patients with OCD according to treatment responsiveness imply the possibility of different neurobiologic mechanism underlying OCD patients who are not responding to the SSRI treatment.
HUMAN MICROBIOTA FROM DRUG-NAIVE PATIENTS WITH OBSESSIVE- COMPULSIVE DISORDER DRIVES BEHAVIORAL SYMPTOMS AND NEUROINFLAMMATION VIA SUCCINIC ACID IN MICE
Authors: Shi *Dong-Dong , Zhang Ying-Dan , Wang Zhen
Published: February 2025

Background

Emerging evidence suggests that the gut microbiota is closely related to psychiatric disorders. However, little is known about the role of the gut microbiota in the development of obsessive- compulsive disorder (OCD).

Aims & Objectives

Here, to investigate the contribution of gut microbiota to the pathogenesis of OCD, we transplanted fecal microbiota from first-episode, drug-naive OCD patients or demographically matched healthy individuals into antibiotic-treated specific pathogen-free (SPF) mice.

Method & Results

Our study showed that colonization with OCD microbiota is sufficient to induce core behavioral deficits, including abnormal anxiety-like and compulsive-like behaviors. The fecal microbiota was analyzed using 16S rRNA full-length sequencing, and the results demonstrated a clear separation of the fecal microbiota of mice colonized with OCD and control microbiota. Notably, microbiota from OCD- colonized mice resulted in injured neuronal morphology and function in the mPFC, with inflammation in the mPFC and colon. Unbiased metabolomic analyses of the serum and mPFC region revealed the accumulation of succinic acid (SA) in OCD-colonized mice. SA impeded neuronal activity and induced an inflammatory response in both the colon and mPFC, impacting intestinal permeability and brain function, which act as vital signal mediators in gut microbiota– brain– immune crosstalk. Manipulations of dimethyl malonate (DM) have been reported to exert neuroprotective effects by suppressing the oxidation of accumulated succinic acid, attenuating the downstream inflammatory response and neuronal damage, and can help to partly improve abnormal behavior and reduce neuroinflammation and intestinal inflammation in OCD-colonized mice.

Discussion & Conclusion

We propose that the gut microbiota likely regulates brain function and behaviors in mice via succinic acid signaling, which contributes to the pathophysiology of OCD through gut-brain crosstalk and may provide new insights into the treatment of this disorder.
DORSAL CA3 NEURAL ACTIVITY MEDIATES WITNESSING STRESS- INDUCED RECOGNITION MEMORY DEFICITS IN ADOLESCENT MALE MICE
Authors: Liu *Xiao , Li Ji-Tao , Si Tian-Mei
Published: February 2025

Background

Witnessing traumatic events is a common adverse life experience in children or adolescents and is associated with several adverse effects. The role of hippocampus in adolescent witnessing stress needs to be uncovered.

Aims & Objectives

To establish the CWSD model in adolescent male mice and reveal the involvement of hippocampus in CWSD-induced cognitive and emotional problems.

Method

Cognitive and anxiety-like behaviors were assessed in adolescent male mice exposed to chronic witnessing social defeat (CWSD) stress. Immediate early gene c-fos immunostaining was used to examine the neuronal functional activity of hippocampus. Chemogenetic and pharmacological experiments were performed to investigate the causal involvement of dorsal and ventral CA3 neurons in CWSD-induced behavioral deficits.

Results

CWSD impaired cognitive function and increased anxiety levels in adolescent male mice and the behavioral deficits persisted into adulthood. Stressed mice had more dCA3 neurons activated during the spatial object recognition test and fewer vCA3 neurons activated during the light- dark box task. Chemogenetic activation and inhibition of dCA3 neuron activity specifically mimicked and reversed CWSD-induced recognition memory deficits, not anxiety-like behaviors. In comparison, both inhibiting and activating vCA3 neurons increased anxiety-like behaviors in adolescent mice. Chronic administration of vortioxetine (a novel multimodal antidepressant) successfully restored the overactivation of dCA3 neurons and impaired recognition memory in CWSD mice.

Discussion & Conclusion

These results suggest that dorsal CA3 neural activity mediates CWSD-induced recognition memory deficits in adolescent male mice, which shed light on the pathophysiology of adolescent CWSD-induced adverse effects and provide preclinical evidence for early treatment of stress-induced cognitive deficits.
FACTORS ASSOCIATED WITH THE INITIATION OF LAXATIVE USE IN THE SAME PATIENTS WITH SCHIZOPHRENIA OVER A 20-YEAR PERIOD: RETROSPECTIVE COHORT STUDY
Authors: Kawamata *Yasushi , Sugawara Norio , Sasaki Taro , Yokoyama Saaya , Okayasu Hiroaki , Shinozaki Masataka , Takeuchi Yoshitaka , Sato Aoi , Ishikawa Takaaki , Komahashi-Sasaki Hazuki , Miyazaki Kensuke , Fukasawa Takashi , Furukori Hanako , Yasui-Furukori Norio
Published: February 2025

Background

Constipation is a common adverse effect of antipsychotics, but little investigation has been conducted. We aimed to address the factors associated with the initiation of laxative use in the same patients with schizophrenia over a 20-year period.

Methods

We enrolled patients with schizophrenia attending each hospital (n=14) from April 1, 2021, and retrospectively examined all prescriptions as of April 1, 2016, 2011, 2006, and 2001, every 5 years starting in 2021, for this population. 716 participants with complete data were included in the analysis. The Cochran Q test followed by Bonferroni correction and the Cochran– Armitage trend test were used to determine the differences and trends of the frequency of each laxative. Multivariate logistic regression analysis was performed to assess the factors on the initiation of laxative use over a 20-year period.

Results

Of the patients, 25.1% were treated with laxatives in 2001, and 34.1% were treated in 2021. The numbers of patients treated with any laxatives significantly differed over the 20-year period, with a significant increasing trend. In all laxatives, the numbers of patients treated magnesium oxide, lubiprostone and elobixibat were differed with a significant increasing trend. Female sex, age, the total DZP equivalent dose, and the doses of levomepromazine maleate, olanzapine, quetiapine, zotepine, lithium, and carbamazepine in 2021 were significant factors associated with the initiation of laxative use over the 20-year period.

Conclusions

Careful monitoring is needed for patients treated with levomepromazine maleate, olanzapine, quetiapine and zotepine. Optimizing prescriptions according to treatment guidelines could reduce antipsychotic-induced constipation.

References

Kawamata Y, Sugawara N, Sasaki T, Yokoyama S, Okayasu H, Shinozaki M, Takeuchi Y, Sato A, Ishikawa T, Komahashi-Sasaki H, Miyazaki K, Fukasawa T, Furukori H, Yasui-Furukori N. Factors associated with the initiation of laxative use in the same patients with schizophrenia over a 20-year period: Retrospective cohort study. Neuropsychopharmacol Rep. 2023 Sep 12. doi: 10.1002/npr2.12378. Epub ahead of print. PMID: 37698084.
IDENTIFYING THE UNIQUE GENETIC ARCHITECTURE OF SCHIZOPHRENIA DISTINGUISHED FROM BIPOLAR DISORDER USING GENOMIC STRUCTURAL EQUATION MODELING
Authors: Jang *Yoonjeong , Park Sanghyeon , Won Hong-Hee , Myung Woojae
Published: February 2025

Background

Schizophrenia (SCZ) and bipolar disorder (BIP) exhibit considerable overlap in symptomatology and genetic components. The pharmacological treatments and clinical differential diagnosis between these disorders present significant challenges due to their shared characteristics. Unraveling the specific genetic architecture of SCZ, independent of BIP, could significantly advance the identification of therapeutic targets and the development of biomarkers for SCZ.

Methods

This study aimed to explore the unique genetic architecture of SCZ. We employed Genomic Structural Equation Modeling (Genomic SEM) on genome-wide association study (GWAS) data for SCZ and BIP. It integrates the results of schizophrenia GWAS analysis and bipolar disorder GWAS analysis to construct a genetic structure, including factors, as a multivariate model, enabling the validation of associated genetic variants for each factor. GWAS-by-Subtraction is a technique used with the Genomic SEM method to elucidate the specific genetic composition of a particular trait by removing the genetic influence of other traits. Our approach focused on identifying the unique genetic pathways of SCZ by subtracting the genetic variance attributable to BIP.

Results

From the initial 205 SCZ-associated single nucleotide polymorphisms (SNPs) identified in GWAS, conditioning on BIP resulted in the attenuation of 13 signals, leaving 192 SCZ-specific signals (p <5 x 10- 8, r2 = 0.2). Notably, the SNP-based heritability for SCZ GWAS was 40% (s.e. = 1.8%), but it was estimated to be 9% (s.e. = 0.4%) when SCZ conditioned on BIP.

Conclusion

These findings enhance our understanding of the pathophysiology of SCZ and indicate distinct genetic underpinnings that differentiate it from BIP. This study paves the way for more targeted SCZ treatments and the development of specific biomarkers, contributing to precision medicine in psychiatric disorders.
GENDER DIFFERENCES IN THE OCCURRENCE OF NEUROPSYCHIATRIC DISORDERS INDUCED BY DIPEPTIDYL PEPTIDASE-4 INHIBITORS
Authors: Shishido *Masataka , Noguchi Yoshihiro , Yosimura Tomoaki
Published: February 2025

Background

Neuropsychiatric comorbidities in diabetic patients are becoming an increasingly significant concern. Although gender differences have been identified in the development of neuropsychiatric disorders, the association between gender differences and neuropsychiatric disorders induced by dipeptidyl peptidase- 4 (DPP-4) inhibitors, the most commonly used drugs in the treatment of type 2 diabetes in Japan, has not been fully elucidated.

Aims and Objectives

In this study, the association between gender differences and neuropsychiatric disorders induced by DPP-4 inhibitors using the US Food and Drug Administration Adverse Event Reporting System (FAERS) was explored.

Methods

In this study, we analyzed 10,676,525 cases registered in the FAERS during the third quarter of FY2021. The targeted neuropsychiatric disorders were defined as psychiatric disorders within the System Organ Class of the Medical Dictionary for Regulatory Activities. To assess the association between gender differences and neuropsychiatric disorders caused by DPP-4 inhibitors, signal scores were used (the frequentist statistical index: relative reporting odds ratio; rROR, and the Bayesian statistical index: information component delta; ICΔ) in the disproportionality analysis. We applied previously reported signal detection criteria, which included having a minimum of 3 reports, a lower limit of the 95 % confidence interval for rROR (rROR025) >1, and a lower limit of the 95 % credible interval for ICΔ (ICΔ 025) >0.

Results

Two signals associated with males were detected. In contrast, nine signals linked to females, including confusion (rROR025: 1.16, ICΔ025: 0.24), aphasia (rROR025: 1.93, ICΔ025: 1.09), and personality disorder (rROR025: 8.34, ICΔ025: 3.74), were identified.

Discussion and Conclusion

This study elucidated gender differences in DPP-4 inhibitor-induced neuropsychiatric disorders through pharmacoepidemiological analysis based on the FAERS. Notably, gender differences were identified in DPP-4 inhibitor-induced neuropsychiatric disorders, particularly warranting special attention in females. Consequently, it is crucial to assess the mental status of female patients with diabetes during treatment with a DPP-4 inhibitor.
CB2 RECEPTOR IS ONE OF THE REGULATORY FACTORS OF THE AGE- RELATED CHANGES IN IMMUNE MECHANISM
Authors: Hosoki *Haruka , Asahi Toru , Nozaki Chihiro
Published: February 2025

Background

Aging is one of the important factor which regulates immunity. It is established in adolescence, whereas immunosenescence occurs in the old age. It is necessary to examine the changes in immune mechanisms during each period to consider what effects the immunity-decline in old age. Cannabinoid type 2 (CB2) receptor is known to be expressed throughout immune-related cells, and it has been reported to act as an inhibitory regulator of immune response. However, contribution of CB2 receptors to immunosenescence still remains unknown.

Aims & Objectives

This study focus on clarifying what CB2 signaling will do in context of systemic immune regulation from the perspective of age, by comprehensive analysis of immune cell behavior under presence or absence of CB2 activity.

Methods

We chose LPS-induced systemic inflammatory model to evoke immune activation. LPS (10 mg/kg) was given by i.p. to CB2-KO and WT controls of 5 different ages: 2 month-old to 6 month-old, one month apart. Spleen has been harvested from these mice 2 hours after the administration, and immunophenotyping by flow cytometry has been conducted. As a result, T/NKT and NK cell populations particularly increased in LPS-treated CB2-KO, whereas B cells and CD11chigh cell populations significantly decreased in same animals. Interestingly, such population change has only been seen in particular ages, which are between 2 and 4 months (Fig 1). This particular age range in mouse is equivalent to the 10s to 20s in human.

Discussion & Conclusion

Altogether, we found that CB2 signaling may affect LPS-mediated immune cell population change, particularly in specific age range that is young to mature adult. These results further suggest that CB2 signaling could be one of the key modulator of the immune system transition among age. Identification of the possibly-affected immune cells will be required, to confirm the detailed mechanism between CB2 activation and cell population fluctuations under aging.
IN VITRO METABOLISM OF THE STRUCTURALLY SIMILAR FENTANYL ANALOGS, 3-PHENYLPROPANOYLFENTANYL AND BENZOYLFENTANYL
Authors: Abe *Konosuke , Itoh Kosuke , Iwai Kosei , Shimada Momoka , Soda Midori , Oida Yasuhisa , Kitaichi Kiyoyuki
Published: February 2025

Background

Opioid addiction and toxicity due to overdose by fentanyl analogs (FAs) are a serious problem worldwide. Predicting the pharmacological effect of FAs is very difficult because many new FAs with slight structural alterations frequently appear in the market. The investigation of in vitro metabolism of FAs is an easy and quick method to predict their pharmacological effects.

Aims and Objectives

In this study, we examined the in vitro metabolism of structurally similar FAs with N-acyl group modification, N-phenyl-N-[1-(2-phenylethyl)-4-piperidyl]-3-phenylpropanamide (3- phenylpropanoylfentanyl, 3-PPF) and N-phenyl-N-[1-(2-phenylethyl)-4-piperidyl]benzamide (benzoylfentanyl, BZF), using human liver microsomes (HLMs).

Methods

3-PPF and BZF were incubated with HLMs for 2 and 3 h, respectively (Kadomura et al. 2021). Samples were collected at the designated time points. These FAs and their metabolites were detected by LC-MS/MS and LC-MS IT-TOF.

Results

The metabolic half-life of 3-PPF was less than 10 min, whereas that of BZF was more than 80 min. Time-course metabolic profiles of these FAs demonstrated that 3-PPF was rapidly metabolized to 3- PPF monohydroxylate, whereas BZF was gradually metabolized into several metabolites. A detailed analysis using LC-MS IT-TOF showed that 3-PPF was primarily monohydroxylated at the N-acyl group. Oxidative N-dealkylated metabolites of 3-PPF and BZF, nor-3-PPF and nor-BZF, were predominantly observed at the end of the experiment, rather than other metabolites.

Discussion and Conclusion

The relatively longer metabolism of BZF suggests that it may exhibit more significant pharmacological effects than 3-PPF. The rapid metabolism of 3-PPF suggests that FAs with a longer N-acyl group are susceptible to rapid hydroxylation at the N-acyl group. Although various studies have already demonstrated that nor-FAs are inactive metabolites, the detection of nor-3-PPF and nor- BZF may be a useful surrogate for drug intake.

References

Kadomura N, Ito T, Kawashima H, Matsuhisa T, Kinoshita T, Soda M, Kohyama E, Iwaki T, Nagai H & Kitaichi K (2021) In vitro metabolic profiles of adamantylpositional isomers of synthetic cannabinoids. Forensic Toxicology vol no. 39, pp 26-44.
COMORBIDITY OF MENTAL ILLNESS, NON-COMMUNICABLE DISEASES AND POLYPHARMACY IN HOME MEDICAL CARE USING MEDICAL BIG DATA
Authors: Arai *Shun , Iida Makoto , Yoshinaga Yasunori , Sakagami Ryuji , Shoji Yoshihisa , Morikawa Nagisa , Nohara Yume , Nohara Shoichiro , Fukumoto Yoshihiro , Ishii Kazuo
Published: February 2025

Background

According to the progress of super-aging society in Japan, the number of patients with non- communicable diseases (NCDs) and the number of people requiring medical care and nursing care is rapidly increasing. The number of receiving home medical care (HMC) is also rapidly increasing. In HMC, most of patients are elderly people and a lot of patients with NCDs, such as diabetes mellitus, hypertension, cardiovascular disease, and cerebrovascular disorders, and mental illnesses, such as dementia and depression, are containing. At the same time, polypharmacy such as psychotropic drugs was often recognized.

Aims & Objectives

In this study, using NDB (National Database of Health Insurance Claims and Specific Health Checkups of Japan) established by the Ministry of Health, Labour and Welfare, comorbidity of mental Illness, NCDs and polypharmacy in HMC were analyzed.

Method

This study was conducted using the NDB Sampling Dataset in NDB provided by the Ministry of Health, Labor and Welfare. Medical Non-Hospitalization Receipts and Prescription Receipts were linked by patient ID. Based on the Injury/Disease Code and Drug Code, the disease prevalence and drug prescription status of patients receiving HMC were summarized. Patients receiving HMC were counted as patients containing the phrase "home medical care (zaitaku)" in Prescription Codes.

Results

When investigating the status of polypharmacy in patients receiving HMC, polypharmacy was observed almost 90% of patients, most of whose possessing NCDs and mental illness. The peak of patients receiving HMC with polypharmacy was around 85 years of age. In the Injury/Disease Codes, among patients receiving HMC, many of patients with mental illnesses were found to suffer from diseases that showed neurocognitive disorders, such as unspecified dementia, delirium, and Parkinson's disease. Polypharmacies were recognized to include psychotropic drugs and drugs related to NCDs such as diabetes mellitus and hypertension. These results were visualized using various methods such as word clouds and co-occurrence networks to understand the overall trends of comorbidities.

Discussion & Conclusion

Analysis of NDB reveals that in HMC, there are many elderly patients, many patients with comorbidities with mental illnesses and NCDs, and polypharmacy of psychotropic drugs and drugs related to NCDs such as diabetes mellitus and hypertension is significant. These findings suggest the need to reduce the adverse events of polypharmacy by optimizing drug prescriptions.
PREVALENCE OF MANAGED AND UNMANAGED METABOLIC SYNDROME COMPONENTS AMONG ADULT PATIENTS ADMITTED IN THE PSYCHIATRIC WARD OF THE PHILIPPINE GENERAL HOSPITAL FROM 2018-2020: A RETROSPECTIVE CROSS-SECTIONAL STUDY
Authors: Cammayo *Tyrone Paul Baylon
Published: February 2025

The risk of psychiatric patients developing metabolic syndrome greatly increases with the psychiatric diagnoses and use of certain psychotropic medications; hence, psychiatrists must be alert in addressing the syndrome.

The primary objective of this study is to describe how the adult psychiatric patients with metabolic syndrome components admitted at Ward 7 of PGH Department of Psychiatry and Behavior Medicine are managed while they were admitted. A retrospective cross-sectional study was employed. Ninety patient charts were reviewed from the admitted patients in 2018-2020. The demographic profile, anthropometric measurements, highest BP, FBS, and lipid profile results were obtained. Charts were reviewed for any interventions done regarding observed metabolic syndrome components.

There were 7 (7.78%) patients with increased FBG or known diabetic. Anti-diabetic prescription was given to 71.42% of these patients. There were 16 (17.78%) patients found to have increased blood pressure or had previous anti-hypertensive medication. Anti-hypertensive medication was given to 56.25%. There were 55 (61.11%) patients who had increased triglycerides, decreased HDL-C, or had anti- dyslipidemic medications. Only 7 (12.73%) of these patients were given anti-dyslipidemic medication while diet modification was advised in 13 (23.64%) patients. Of the total patients, only seven (7.78%) were referred to other services for management of their co-morbidities.

This study shows that while MS components were detected during admission, disparity between the number of managed and unmanaged patients were observed.
Simulated exposures of oritavancin in in vitro pharmacodynamic models select for methicillin-resistant Staphylococcus aureus with reduced susceptibility to oritavancin but minimal cross-resistance or seesaw effect with other antimicrobials
Authors: Werth Brian J , Zhang Rutan , Barreras Beltran Ismael A , Penewit Kelsi , Waalkes Adam , Holmes Elizabeth A , Salipante Stephen J , Xu Libin
Published: February 2025

Background

Dalbavancin exposures select for VAN and daptomycin cross-resistance in Staphylococcus aureus often by walK-related mutations. Oritavancin is another long-acting lipoglycopeptide, but its proclivity to select for cross-resistance is unknown. The objective of this study was to determine if post-distributional pharmacokinetic oritavancin exposures select for meaningful susceptibility changes in S. aureus.

Methods

We simulated average post-distributional, free-drug exposures of oritavancin 1200 mg IV once (fCmax 11.2 µg/mL; β-elimination t1/2 13.4 h; γ-elimination t1/2 245 h) in an in vitro pharmacodynamic model for 28 days against five S. aureus including four MRSA. Samples were taken daily for colony enumeration and resistance screening. Susceptibility testing was repeated on isolates from resistance screening plates against oritavancin, vancomycin, daptomycin, dalbavancin and 6 beta-lactams with varying penicillin-binding protein affinities.

Results

Tested oritavancin exposures were bactericidal against 5/5 strains for 2–17 days before regrowth of less-susceptible subpopulations occurred. Isolates with reduced susceptibility to oritavancin were detected as early as 5 days, but the MIC increased above the susceptibility breakpoint (>0.125 mg/L) in 4/5 strains eventually. Vancomycin and daptomycin MICs increased by 2- to 8-fold but did not exceed the susceptibility breakpoints in most isolates. β-lactam MICs were largely unchanged among the recovered isolates with reduced oritavancin susceptibility. Mutations were diverse but often involved purR with 13 unique variants identified among 4/5 strains.

Conclusions

Oritavancin-selected resistance was primarily associated with purR mutation and less frequently associated with cross-resistance and walK mutation than dalbavancin-selected resistance in similar strains and conditions. The reason for this is unclear but may stem from differences in the mechanism(s) and divergent mutational pathways.
Evaluation of dietary acid-binding capacity level on nursery pig growth performance and fecal dry matter
Authors: Stas Ethan B , Tokach Mike D , Woodworth Jason C , DeRouchey Joel M , Goodband Robert D , Gebhardt Jordan T
Published: February 2025

Two experiments were conducted to evaluate dietary acid-binding capacity-4 (ABC-4) level on weanling pig performance and fecal dry matter (DM). In both experiments, there were 5 pigs per pen and 12 replications per dietary treatment fed in two phases. In Exp. 1, 360 barrows, initially 5.9 kg, were allotted to 1 of 6 treatments. Five treatments were formulated with increasing ABC-4 ranging from 150 (low ABC-4) to 312 meq/kg (high ABC-4) in phase 1 and 200 (low ABC-4) to 343 meq/kg (high ABC-4) in phase 2. The low ABC-4 diet was formulated with specialty soy protein concentrate (SSPC; AX3 Digest, Protekta, Newport Beach, CA) and a combination of dietary acidifiers. Increasing ABC-4 was achieved by progressively replacing SSPC with enzymatically treated soybean meal (ESBM; HP 300, Hamlet Protein, Findlay, OH) on a standardized ileal digestible (SID) Lys basis and decreasing acidifiers. Diets were formulated to contain 100 mg/kg of Zn. For the sixth treatment, pharmacological levels of Zn from ZnO was added to the high ABC-4 diet. From d 0 to 23 and d 0 to 38, increasing ABC-4 increased then decreased (quadratic, P ≤ 0.046) ADG and ADFI. On d 10 and 17, increasing ABC-4 decreased (linear, P ≤ 0.022) fecal DM. From d 0 to 23, pigs fed the diet containing ZnO had increased (P ≤ 0.009) BW, ADG and ADFI compared to the high ABC-4 diet without ZnO. In Exp 2, 300 pigs, initially 6.0 kg, were allotted to 1 of 5 dietary treatments. Diet 1 was a low ABC-4 diet formulated to 200 and 250 meq/kg in phase 1 and 2, respectively. Two intermediate ABC-4 levels were formulated by either replacing SSPC with ESBM on an SID Lys basis (diet 2) or removing acidifiers (diet 3). Diet 4 was a high ABC-4 diet formulated by replacing SSPC and removing acidifiers to increase ABC-4. Diet 5 was diet 4 but with pharmacological levels of Zn from ZnO. Diets 1 through 4 contained 110 mg/kg of Zn. From d 0 to 24 and d 0 to 38, increasing ABC-4 decreased (linear, P ≤ 0.046) G:F. On d 10 and 24, increasing ABC-4 decreased (linear, P ≤ 0.005) fecal DM. From d 0 to 24, pigs fed the diet containing ZnO had increased (P ≤ 0.047) BW, ADG, ADFI, and G:F compared to the high ABC-4 diet without ZnO. In conclusion, an ABC-4 of 200 meq/kg from d 0 to 10 post-weaning and 250 meq/kg from d 10 to 24 post-weaning improves pig growth performance and fecal DM for compared to higher ABC-4 diets. In diets without ZnO, low ABC-4 diet formulation can improve performance and fecal DM of weanling pigs.
Evaluation of Low-Resistivity Reservoirs Based on the New Three-Water Model and Comprehensive Identification of Fluid Properties Using a Committee Machine-A Case Study of the Dongying Formation Member 1 Reservoir in the Gangdong Fault Zone
Authors: Chen Changwei , Pan Baozhi , Lin Xuechun , Zhang Pengji , Zhang Lihua , Ren Shulian , Xie Fei , Li Yan
Published: February 2025

Member 1 of the Dongying Formation in the Gangdong Fault Zone is characterized by shallow-water delta front deposits influenced by faults and sedimentation, which have led to the development of various lithological-structural micro oil reservoirs. The area's high irreducible water saturation and additional clay conductivity have contributed to the formation of low-resistivity reservoirs, complicating the identification of oil and gas layers. This has led to significant discrepancies between well-logging interpretations and actual production outcomes. Based on rock physics experiments and geological characteristics, this study identifies the main controlling factors of low-resistivity reservoirs and proposes specific identification criteria for these reservoirs. For the first time, a new three-water saturation model is applied in the quantitative evaluation of low-resistivity reservoirs in the study area, with processing results that align with production conclusions. By integrating the processing results from the new three-water model with multiple methods, the fluid properties are comprehensively assessed using a committee machine. This study establishes a set of well logging reservoir parameter evaluation methods specifically tailored for low-resistivity reservoirs, enhancing the accuracy of fluid identification and providing valuable insights for further promotion and application.
Diagnosis, clinical characteristics, and treatment of combined hepatocellular-cholangiocarcinoma
Authors: Terashima Takeshi , Harada Kenichi , Yamashita Taro
Published: February 2025

The concept and definition of combined hepatocellular-cholangiocarcinoma (cHCC-CCA), an extremely rare condition accounting for only 1% of all primary liver cancers, has shifted in recent years. The latest World Health Organization Classification (fifth edition) includes two types of cHCC-CCAs, (i) the classical type described in the previous edition, which contains a mixture of distinctly differentiated components of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) and (ii) intermediate cell carcinoma wherein all cells comprising the tumor express both hepatocellular and cholangiocellular features. However, the pathogenesis of cHCC-CCA, including its origins, remains controversial even among experts. Treatment strategies for cHCC-CCA in clinical practice have been determined based on imaging findings, tumor markers, and pathologically predominant tumor components for either HCC or ICC, suggesting that cHCC-CCA has yet to be been established as an independent disease entity. As with HCC and ICC, the treatment strategy for HCC-CCA involves initially considering resectability. Although systemic therapy has been considered for patients unsuitable for local treatment, no prospective clinical trials have evaluated the efficacy and safety of systemic therapy for cHCC-CCA, which could explain the lack of a standard of care. In recent years, however, studies have demonstrated the efficacy of immune checkpoint inhibitors for HCC and ICC, with therapeutic results having been reported for cHCC-CCA. Hence, further accumulation of cases is expected to facilitate the establishment of a consensus on treatment strategies in the near future.
Perturbations in levels of essential metals less severe in Parkinson's disease without dementia than in Parkinson's disease dementia
Authors: Scholefield Melissa , Church Stephanie J , Cooper Garth J S
Published: February 2025

Background

It is currently unknown why some individuals with Parkinson's disease (PD) go on to develop dementia (Parkinson's disease dementia; PDD), whereas others do not. One possibility is differences in susceptibility to metallomic dysregulation. A previous study of the PDD brain identified substantive perturbations in metal levels, including severe multi-regional decreases in Cu. The current work uses the same methods to ascertain whether this metallomic dysfunction is also present in the PD brain.

Methods

Tissue from nine PD cases free of cognitive decline and 15 equivalent controls was obtained from seven brain regions. Levels of Na, Mg, K, Ca, Mn, Fe, Cu, Zn, and Se were quantified using inductively coupled plasma mass spectrometry (ICP-MS). Multiple linear regression analysis was used to determine any potential confounder effects. Results were compared with those previously obtained for PDD.

Results

Decreased Cu in the medulla was the only statistically significant case–control difference observed in the PD brain; this contrasts markedly with the widespread metallic dysfunction observed in PDD. PD and PDD cases were well-separated by PCA analysis. In the PD cohort, tau Braak stage correlated with Cu concentrations in several regions, but these correlations were not retained when including PDD cases.

Conclusions

There is a marked difference in the metallomic profiles of PD and PDD, with an almost complete lack of metallic involvement observed in the former. This resistance to metallomic dysfunction may contribute to resilience against cognitive impairment in individuals with PD who do not develop dementia.
Patterns and change rates of glacial lake water levels across High Mountain Asia
Authors: Wang Yingzheng , Zheng Donghai , Zhang Guoqing , Carrivick Jonathan L , Bolch Tobias , Ren Weiwei , Guo Lei , Su Jianbin , Yuan Shiwei , Li Xin
Published: February 2025

Using satellite altimetry data, this work quantifies the inter-annual trends and intra-annual fluctuations in water levels of glacial lakes in High Mountain Asia during 2019-2023.
Doxycycline postexposure prophylaxis for bacterial STIs: Prescribing patterns, use, short-term outcomes among 2083 patients in a Los Angeles Federally Qualified Health Care Program, and implications for widespread use
Authors: Osmundson J , Holloway I W , Gil R M , Jann J T , Hong C , Bolan R K
Published: February 2025

Background

Rates of bacterial sexually transmitted infections (STIs) have risen dramatically over the past decades. Doxycycline postexposure prophylaxis (DP) is a novel intervention to prevent bacterial STIs. Recent randomized controlled clinical trials reported high DP efficacy at preventing syphilis and chlamydia in cisgender men who have sex with men (MSM) and transgender women.

Methods

We abstracted data from the Electronic Health Records of 2083 patients at the Los Angeles LGBT Center (the Center) who were prescribed DP between 2019 and June 2024. Patient information included race, income, gender, sex, DP prescriptions, and STI tests dating back to 1998.

Results

Over half of the patients prescribed DP patients at the Center were white, and 48.1% were between 31 and 40 years old. Most of these patients were not diagnosed with an STI in the previous year but ever having an STI correlated with early DP initiation. We demonstrate high real-world DP effectiveness in preventing infections with syphilis (86.4%) and chlamydia (89.7%), and moderate effectiveness for gonorrhea (54.7%), all remarkably similar to published clinical trials. DP use was highly variable, and DP failure for syphilis or chlamydia occurred only in patients with low DP use. There was similar effectiveness for chlamydia and gonorrhea regardless of anatomical site (rectal or throat swabs or urine sample).

Conclusions

We show that DP is highly effective at STI prevention in a real-world setting and describe patterns of DP prescribing and use, in addition to STI testing, that can directly inform best clinical practice.
An observational cohort study of bronchoalveolar lavage fluid galactomannan and Aspergillus culture positivity in patients requiring mechanical ventilation
Authors: Gao Catherine A , Markov Nikolay S , Pickens Chiagozie , Pawlowski Anna , Kang Mengjia , Walter James M , Singer Benjamin D , Wunderink Richard G
Published: February 2025

Background

Critically ill patients who develop invasive pulmonary aspergillosis have high mortality rates despite antifungal therapy. Diagnosis is difficult in these patients and incidences vary in the literature. Bronchoalveolar lavage (BAL) fluid galactomannan (GM) is a helpful marker, although the optimal cutoff is unclear.

Methods

This was a single-center cohort study of patients requiring mechanical ventilation in the medical ICU from June 2018-March 2023. Demographics, BAL, and outcome data were extracted from the electronic health record and compared between groups of patients who grew Aspergillus from BAL, those who had elevated BAL GM levels (>0.5, >0.8, or >1.0) but did not grow Aspergillus, and those with neither.

Results

Of >1700 BALs from 688 patients, only 18 BALs from 15 patients grew Aspergillus. Patients who grew Aspergillus had more intubated days (29 vs 11, p=0.002), and more ICU days (34 vs 15, p=0.002). BAL GM level was higher from samples that grew Aspergillus than those that did not (median ODI 7.08 vs 0.11, p<0.001).

Conclusions

In this large cohort of critically ill patients, we found a low rate of Aspergillus growth and variable BAL GM elevation. These data suggest that the pre-test probability of IPA should be considered low in a general ICU population undergoing BAL evaluation to define the etiology of pneumonia. Elevated BAL GM may not reliably indicate invasive disease, but lack of culture positivity may also miss true infection. Improved scoring systems are needed to enhance pre-test probability for diagnostic test stewardship purposes, and tests must be interpreted in their own clinical contexts.