Designation Products: Boron Neutron Capture Therapy for Head and Neck Carcinoma.

The Japanese Ministry of Health, Labour and Welfare approved a drug called borofalan (10 B), a treatment system, and a dose calculation program for boron neutron capture therapy (BNCT) in March 2020. The application pertaining to the products submitted to the Pharmaceuticals and Medical Devices Agency was supported by a Japanese, open-label, uncontrolled trial (Study 002) in patients with unresectable, locally recurrent head and neck squamous cell carcinoma after chemoradiotherapy or radiotherapy, or in those with unresectable locally advanced or locally recurrent (LA/LR) head and neck nonsquamous cell carcinoma. The drug was administered as a single intravenous dose using infusion rates of 200 mg/kg per hour for the first 2 hours after the start of administration and 100 mg/kg per hour during irradiation. Neutron irradiation was performed using the devices at a single dose of 12 Gy-equivalent for oral, pharyngeal, or laryngeal mucosa for up to 60 minutes from 2 hours after the start of drug administration. The primary endpoint was the overall response rate (ORR). The results of Study 002 showed that the ORR based on an assessment of the Independent Central Review Committee per RECIST version 1.1 was 71.4% (90% confidence interval [CI], 51.3%-86.8%). The lower limit of the 90% CI exceeded the prespecified threshold for ORR. When BNCT is applied to patients with unresectable LA/LR head and neck cancer, precautions should be taken, and patients should be monitored for possible onset of dysphagia, brain abscess, skin disorder, crystal urine, cataract, and/or carotid hemorrhage. IMPLICATIONS FOR PRACTICE: Borofalan (10 B), a treatment system and a dose calculation program for boron neutron capture therapy (BNCT), demonstrated significant efficacy in an open-label, uncontrolled trial in which overall response rate was the primary endpoint for patients with unresectable locally advanced or locally recurrent head and neck cancer. Although no information about survival benefits was obtained, BNCT will become an effective treatment option that is expected to manage local lesions that are intractable with any standard therapy. In addition, BNCT is expected to maintain quality of life of the intended patient population, on account of its high tumor selectivity and low invasiveness.

TGF-ß-induced intracellular PAI-1 is responsible for retaining hematopoietic stem cells in the niche.

Hematopoietic stem and progenitor cells (HSPCs) reside in the supportive stromal niche in bone marrow (BM); when needed, however, they are rapidly mobilized into the circulation, suggesting that HSPCs are intrinsically highly motile but usually stay in the niche. We questioned what determines the motility of HSPCs. Here, we show that transforming growth factor (TGF)-ß-induced intracellular plasminogen activator inhibitor (PAI)-1 activation is responsible for keeping HSPCs in the BM niche. We found that the expression of PAI-1, a downstream target of TGF-ß signaling, was selectively augmented in niche-residing HSPCs. Functional inhibition of the TGF-ß-PAI-1 signal increased MT1-MMP-dependent cellular motility, causing a detachment of HSPCs from the TGF-ß-expressing niche cells, such as megakaryocytes. Furthermore, consistently high motility in PAI-1-deficient HSPCs was demonstrated by both a transwell migration assay and reciprocal transplantation experiments, indicating that intracellular, not extracellular, PAI-1 suppresses the motility of HSPCs, thereby causing them to stay in the niche. Mechanistically, intracellular PAI-1 inhibited the proteolytic activity of proprotein convertase Furin, diminishing MT1-MMP activity. This reduced expression of MT1-MMP in turn affected the expression levels of several adhesion/deadhesion molecules for determination of HSPC localization, such as CD44, VLA-4, and CXCR4, which then promoted the retention of HSPCs in the niche. Our findings open up a new field for the study of intracellular proteolysis as a regulatory mechanism of stem cell fate, which has the potential to improve clinical HSPC mobilization and transplantation protocols.

Identification of novel plasminogen activator inhibitor-1 inhibitors with improved oral bioavailability: Structure optimization of N-acylanthranilic acid derivatives.

Novel plasminogen activator inhibitor-1 (PAI-1) inhibitors with highly improved oral bioavailability were discovered by structure-activity relationship studies on N-acyl-5-chloroanthranilic acid derivatives. Because lipophilic N-acyl groups seemed to be important for the anthranilic acid derivatives to strongly inhibit PAI-1, synthesis of compounds in which 5-chloroanthranilic acid was bound to a variety of highly lipophilic moieties with appropriate linkers was investigated. As the result it appeared that some of the derivatives possessing aryl- or heteroaryl-substituted phenyl groups in the acyl chain had potent in vitro PAI-1 inhibitory activity. Oral absorbability of typical compounds was also evaluated in rats, and compounds 40, 55, 60 and 76 which have diverse chemical structure with each other were selected for further pharmacological evaluation.

[What are Considerations for Clinical Investigation of New Drugs and Treatment Techniques for Major Depressive Disorders?].

Major depressive disorder treatments remain unsatisfactory, and the development of novel antidepressants is continuing. Therefore, not only the establishment of therapeutic strategies to accumulate evidence on existing therapies, but also the development of novel therapies is required in order to improve the medical standards. In principle, parallel, double-blind, randomized, placebo-controlled trials are necessary to assess new compounds for the treatment of major depressive disorders from a scientific perspective. To provide unambiguous evidence of antidepressant activity, well-controlled studies with adequate designs must show efficacy with a statistically significant effect on a clinically meaningful endpoint. For this purpose, it is important to examine all aspects of factors that adversely affect the efficacy and safety assessment in the planning stage of clinical trials and reduce these factors. There are several specific characteristics of clinical trials for neuropsychiatric disorders. Some typical features are as follows: 1) a high and variable response, 2) impact on the effect of the baseline severity of disorders, 3) high dropout rates, 4) biases related to subjective measures of clinical symptoms. In this paper, considerations for the planning and performing of clinical trials for major depressive disorders will be discussed based on these features.

[What are the Specific Characteristics of Clinical Trials for Neuropsychiatric Disorders?].

To increase medical standards, not only the establishment of therapeutic strategies to accumulate evidence for existing therapies but also the development of new therapies are required. In recent years, as a number of new drugs have been approved, treatment options for neuropsychiatric disorders have expanded. It is significant for clinicians to interpret the evidence adequately in order to select the optimal therapeutic method. This paper aims to describe the important points in interpreting the results of clinical trials, which involve direct evidence for efficacy and safety. There are several specific characteristics of clinical trials for neuropsychiatric disorders. As typical features, the following can be mentioned: 1) a high and variable response in placebo groups, 2) impact on the effect size of the baseline severity of disorders, 3) high dropout rates, and 4) biases related to subjective measures of clinical symptoms. In this paper, the key points to be evaluated in the results of clinical trials for neuropsychiatric disorders are discussed based on these features.

Guideline for evaluating the effects of psychotropic drugs on motor vehicle driving performance in Japan: A tiered approach for the assessment of clinically meaningful driving impairment.

In December 2022, the Ministry of Health, Labour and Welfare (MHLW) of Japan issued and implemented the guideline for evaluating the effects of psychotropic drugs on motor vehicle driving performance. This guideline recommends the use of a tiered approach to assess clinically meaningful driving impairment. It is noted that adverse events cannot be solely explained by pharmacokinetics, as the onset and duration of these events vary. Among these adverse events, those affecting alertness, such as drowsiness caused by psychotropic drugs on driving performance, are more frequently observed during initial treatment stages and dose escalation. Hence, when evaluating the effects of psychotropic drugs on driving performance, it becomes crucial to assess the persistence of clinically meaningful impairment. Therefore, the MHLW guideline, developed by the authors, emphasizes the need to assess the temporal profile of adverse events affecting driving in all clinical trials. Additionally, the guideline states that when conducting driving studies, the timing of multiple dosing should consider not only the pharmacokinetics of the investigational drug but also its tolerance.

The new guideline for evaluating effects of psychotropic drugs on the performance to drive a motor vehicle in Japan: Comparison with US FDA guideline.

In December 2022, the new guideline for evaluating the effect of psychotropic drugs on the performance to drive a motor vehicle was issued by the Ministry of Health, Labour and Welfare (MHLW) and implemented in Japan. Of the safety information, information on the influence of medications on driving performance is particularly important because it can be relevant to the social functioning of patients. In principle, the package inserts of medications are designed based on evidence and provide precautions regarding the operation of heavy machinery such as automobiles in Japan, the United States, and Europe. The effects of medications on driving performance are generally evaluated in a tiered approach involving nonclinical and clinical studies. Because of the wide variety of functional domains involved in automobile driving, the selection of evaluation methods for a given medication depends on their characteristics, which is a complicated method. Therefore, to evaluate the effects of psychotropic drugs on driving performance efficiently and appropriately, we developed the MHLW guideline that specifically defines the evaluation methods used in pharmacological studies, the neuropsychological tests used in pharmacodynamic studies, and the situations in which driving studies are necessary. Regarding the planning of appropriate drug development strategies, we review the background of the MHLW guideline and its differences from the US Food and Drug Administration (FDA) guideline.

A pharmacovigilance approach for assessing the occurrence of suicide-related events induced by antiepileptic drugs using the Japanese adverse drug event report database.

Increased suicidality after antiepileptic drug (AED) treatment remains controversial. This study aimed to investigate the occurrence of suicide-related events (SREs) in Japan. SREs signals with AEDs used orally were evaluated by calculating reporting odds ratios (RORs) and information components (ICs) using the Japanese Adverse Drug Event Report (JADER) database from April 2004 to December 2021. Additionally, factors affecting the occurrence of SREs and time-to-onset from the initial AED treatment were analyzed. Of 22 AEDs, 12 (perampanel hydrate, nitrazepam, levetiracetam, clonazepam, clobazam, sodium valproate, phenobarbital, lamotrigine, lacosamide, gabapentin, zonisamide, and carbamazepine) showed signals of SREs. Patients in their 20 and 30 s, female sex, and concomitant use of multiple AEDs affected the occurrence of SREs. In six AEDs, the median time-to-onset of SREs in patients taking all AEDs was <100 days. The pharmacovigilance approach revealed that several AEDs displayed suicidality signals. Female patients, those in their 20 and 30 s, undergoing combination therapy with ≥2 AEDs, and patients early (<100 days from the initial treatment) in the course of AED therapy should be cautioned about SREs.

Case Report: Auditory Hallucination Induced by Amitriptyline for the Treatment of Atypical Odontalgia.

Auditory hallucination is usually associated with psychiatric diseases and organic brain illness. It was rarely found as adverse events of antidepressants. Amitriptyline is considered as one of the first line medications for the psychopharmacotherapy of chronic pain including atypical odontalgia (AO) which shows chronic tooth pain without corresponding abnormalities. Anticholinergic adverse events induced by amitriptyline are usually bearable and not critical since the prescription dose is very low for the patients with AO. This is a first case report about the AO patients who showed auditory hallucination by the low dose of amitriptyline. A 43-years-old female, housewife, complained chronic toothache following dental procedures and was diagnosed as AO. Amitriptyline was initially prescribed 25 mg and gradually increased up to 60 mg with the improvement of AO symptoms in 7 months. Although the temporary recurrence was observed following to the retreatment of prosthodontic dental procedures, it improved in a few weeks. Therefore, the dose of amitriptyline was decreased, and the continuation dose was set 30 mg. In 24 months, the AO symptoms were very much improved; however, she reported that she had been heard the voices at midnight for a year. The voices were neighborhoods' and talking about the noise troubles she had claimed before. She had not realized that the voices were auditory hallucination since they were heard only at midnight infrequent and not bothering her daily life. At the time she reported auditory hallucination, she worried whether organic brain diseases are hiding because the frequency of voices was increased and sometimes occurred in daytime. The adverse event of amitriptyline was suspected since she had never had psychotic symptoms before. Amitriptyline was decreased and continued with the dose of 25 mg. Magnetic resonance imaging and psychiatric consultation revealed no abnormality of brain and in psychiatric aspects. After final prosthodontic treatment, the amitriptyline was discontinued in 30 months. Two months after the discontinuation, auditory hallucination was almost disappeared with no recurrence of AO. The present case report suggests that amitriptyline has possibility to induce auditory hallucination even in conventional dose throughout the treatment of chronic pain including AO.

[Development of a Guideline on Clinical investigation of Medicinal Product in the Treatment of Depression in Japan].

Drug development is one of the methods for qualitative improvement of medical treatment. The Ministry of Health, Labour and Welfare in Japan (MHLW) published "A Guideline on Clinical Investigation of Medicinal Product in the Treatment of Depression" in November 2010. The guideline was developed by a Japanese expert working group in psychiatry and regulatory science. The purpose of the guideline is to describe accepted principles and practices in the conduct of both individual clinical trials and development strategy for new medicinal products intended to be used for treating depression and to facilitate efficient drug development. This document describes the major issues discussed during the guideline development. This work was supported by Grants-in-Aid from the Research Committee of "A Guideline on Clinical Investigation of Medicinal Product in the Treatment of Depression", MHLW.

Associations of coprescribed medications for chronic comorbid conditions in very old adults with clinical dementia: a retrospective cohort study using insurance claims data.

OBJECTIVE: To assess the association of coprescribed medications for chronic comorbid conditions with clinical dementia in older adults, as indicated by the initiation of a new prescription of antidementia medication (NPADM). DESIGN: Retrospective enumeration cohort study. SETTING: A Japanese city in Tokyo Metropolitan Area. PARTICIPANTS: A total of 42 024 adults aged ≥77 years residing in Kashiwa City, a suburban city of Tokyo Metropolitan Area, who did not have any prscription of antidementia medication from 1 April to 30 June 2012. MAIN OUTCOME MEASURE: The primary outcome was NPADM during follow-up period until 31 March 2015 (35 months). Subjects were categorised into four age groups: group 1 (77-81 years), group 2 (82-86 years), group 3 (87-91 years) and group 4 (≥92 years). In addition to age and sex, 14 sets of medications prescribed during the initial background period (from 1 April 2012 and 31 June 2012) were used as covariates in a Cox proportional hazard model. RESULTS: In a follow-up period of 1 345 457 person-months (mean=32.0±7.5 months, median 35 months), NPADM occurred in 2365 subjects. NPADM incidence at 12 months was 1.9%±0.1% (group 1: 0.9%±0.1%, group 2: 2.1%±0.1%, group 3: 3.2%±0.2% and group 4: 3.6%±0.3%; p<0.0001). In addition to older age and female sex, use of the following medications was significantly associated with NPADM: statins (HR: 0.82, 95% CI 0.73 to 0.92; p=0.001), antihypertensives (HR: 0.80, 95% CI 0.71 to 0.85; p<0.0001), non-steroidal bronchodilators (HR: 0.72, 95% CI 0.58 to 0.88; p=0.002), antidepressants (HR: 1.79, 95% CI 1.47 to 2.18; p<0.0001), poststroke medications (HR: 1.45, 95% CI 1.16 to 1.82; p=0.002), insulin (HR: 1.34, 95% CI 1.01 to 1.78; p=0.046) and antineoplastics (HR: 1.12, 95% CI 1.01 to 1.24; p=0.035). CONCLUSIONS: This retrospective cohort study identified the associations of coprescribed medications for chronic comorbid conditions with NPADM in older adults. These findings would be helpful in understanding the current clinical practice for dementia in real-world setting and potentially contribute to healthcare policymaking. TRIAL REGISTRATION NUMBER: UMIN000039040.

Abnormal microstructures of the basal ganglia in schizophrenia revealed by diffusion tensor imaging.

There has been a hypothesis that deficits in the basal ganglia-thalamic system may play an important role in the dysfunctional goal-directed behaviour in schizophrenia. By using diffusion tensor imaging, we measured fractional anisotropy (FA) values in the basal ganglia-thalamic system in 42 schizophrenics and 42 matched controls to investigate microstructural tissue alterations in the basal ganglia-thalamic system in schizophrenia. Schizophrenics had significantly lower FA values in the bilateral globus pallidus and left thalamus compared to controls, suggesting that schizophrenics might have microstructural abnormalities in globus pallidus and thalamus. These data support the notion that myelination abnormalities in basal ganglia-thalamic system are related to the pathophysiology of schizophrenia.

Personality in schizophrenia assessed with the Temperament and Character Inventory (TCI).

The Temperament and Character Inventory (TCI) is a well-established self-report questionnaire measuring four temperament and three character dimensions. However, surprisingly few studies have used it to examine the personality of patients with schizophrenia, and none in Japan. Moreover, possible gender differences in personality among patients with schizophrenia have not been well documented. We administered the TCI to 86 Japanese patients with schizophrenia and 115 age- and gender-matched healthy controls to characterize personality traits in patients with schizophrenia and to examine their relationships with clinical variables, particularly gender and symptoms. Compared with controls, patients demonstrated significantly lower novelty seeking, reward dependence, self-directedness and cooperativeness, and higher harm avoidance and self-transcendence. Male patients showed even more pronounced personality alteration than female patients when both of them were compared with healthy people. Personality dimensions were moderately correlated with symptom dimensions assessed by the Positive and Negative Syndrome Scale (PANSS). These results, together with prior findings in several other countries, suggest that schizophrenia patients have a unique personality profile which appears to be present across cultures and that the greater alteration of personality in schizophrenia males might be related to their poorer social and community functioning.

Impact of demographic factors on the antidepressant effect: A patient-level data analysis from depression trials submitted to the Pharmaceuticals and Medical Devices Agency in Japan.

A substantial and variable placebo response can cause unreliable findings in clinical trials designed to demonstrate the efficacy of antidepressants, and the high rate of failed trials represents a major obstacle in the development of new drugs for major depressive disorder (MDD). However, the influence of demographic and symptom factors on the antidepressant effect remains to be established. The purpose of this study was to estimate the magnitude of this influence. A patient-level meta-analysis of data from double-blind, randomized, placebo-controlled trials involving the use of antidepressants for adults with MDD was performed. Data from five confirmatory trials evaluating the efficacy of four antidepressants that were submitted to the Pharmaceuticals and Medical Devices Agency (PMDA) to support new drug applications were pooled (n = 1898). The change in the total score of 17-item Hamilton Depression Rating Scale (HDRS17) was the primary outcome of interest in our analysis. The changes in the total HDRS17 score in both the antidepressant medication group (ADM) and the placebo group (PBO) increased in relation to baseline symptom severity. Among older patients and those with a history of prior treatment with antidepressants, the changes in the total HDRS17 score decreased in ADM and remained static in PBO. There were no notable clinical symptoms that influenced the change in the total HDRS17 score. Baseline symptom severity, participant age and a history of previous treatment with antidepressants were suggested as moderators of the antidepressant effect. The drug-placebo difference in the estimated changes as a function of baseline symptom severity varied depending on the regression models used, and further studies are required to investigate appropriate models.

A small-molecule PAI-1 inhibitor prevents bone loss by stimulating bone formation in a murine estrogen deficiency-induced osteoporosis model.

Osteoporosis is a progressive bone disease caused by an imbalance between bone resorption and formation. Recently, plasminogen activator inhibitor-1 (PAI-1) was shown to play an important role in bone metabolism using PAI-1-deficient mice. In this study, we evaluated the therapeutic benefits of novel, orally available small-molecule PAI-1 inhibitor (iPAI-1) in an estrogen deficiency-induced osteoporosis model. Eight-week-old C57BL/6J female mice were divided into three groups: a sham + vehicle (Sham), ovariectomy + vehicle (OVX + v), and OVX + iPAI-1 (OVX + i) group. iPAI-1 was administered orally each day for 6 weeks starting the day after the operation. Six weeks of iPAI-1 treatment prevented OVX-induced trabecular bone loss in both the femoral bone and lumbar spine. Bone formation activity was significantly higher in the OVX + i group than in the OVX + v and Sham groups. Unexpectedly, OVX-induced osteoclastogenesis was partially, but significantly reduced. Fluorescence-activated cell sorting analyses indicated that the number of bone marrow stromal cells was higher in the OVX + i group than that in the OVX + v group. A colony-forming unit-osteoblast assay indicated enhanced mineralized nodule formation activity in bone marrow cells isolated from iPAI-1-treated animals. Bone marrow ablation analysis indicated that the remodeled trabecular bone volume was significantly higher in the iPAI-1-treated group than that in the control group. In conclusion, our results suggest PAI-1 blockade via a small-molecule inhibitor is a new therapeutic approach for the anabolic treatment of postmenopausal osteoporosis.

Failure to confirm an association between the PLXNA2 gene and schizophrenia in a Japanese population.

Plexins are receptors for multiple classes of semaphorins, either alone or in combination with neuropilins. Plexins participate in many cellular events that include axonal repulsion, axonal attraction, cell migration, axon pruning, and synaptic plasticity. PLXNA2 maps to chromosome 1q32. Several linkage studies reported schizophrenia susceptibility loci in the 1q22-42 region. A recent study reported that intronic single nucleotide polymorphisms (SNPs) of PLXNA2 were associated with schizophrenia in a European American population. We attempted to replicate this finding in a Japanese sample of 336 patients with schizophrenia and 304 controls. In addition, we examined 3 non-synonymous SNPs (Arg5Gln, GLn57Arg, and Ala267Thr) in PLXNA2. Genotyping was performed by the TaqMan allelic discrimination assay. There was no significant difference in genotype or allele distribution of either the 4 intronic SNPs or the 3 non-synonymous SNPs between patients and controls. Furthermore, haplotype-based analyses did not provide evidence for an association. These results suggest that PLXNA2 may not play a major role in the development of schizophrenia in our Japanese sample.

The association between the Val158Met polymorphism of the catechol-O-methyl transferase gene and morphological abnormalities of the brain in chronic schizophrenia.

The catechol-O-methyl transferase (COMT) gene is considered to be a promising schizophrenia susceptibility gene. A common functional polymorphism (Val158Met) in the COMT gene affects dopamine regulation in the prefrontal cortex (PFC). Recent studies suggest that this polymorphism contributes to poor prefrontal functions, particularly working memory, in both normal individuals and patients with schizophrenia. However, possible morphological changes underlying such functional impairments remain to be clarified. The aim of this study was to examine whether the Val158Met polymorphism of the COMT gene has an impact on brain morphology in normal individuals and patients with schizophrenia. The Val158Met COMT genotype was obtained for 76 healthy controls and 47 schizophrenics. The diagnostic effects, the effects of COMT genotype and the genotype-diagnosis interaction on brain morphology were evaluated by using a voxel-by-voxel statistical analysis for high-resolution MRI, a tensor-based morphometry. Patients with schizophrenia demonstrated a significant reduction of volumes in the limbic and paralimbic systems, neocortical areas and the subcortical regions. Individuals homozygous for the Val-COMT allele demonstrated significant reduction of volumes in the left anterior cingulate cortex (ACC) and the right middle temporal gyrus (MTG) compared to Met-COMT carriers. Significant genotype-diagnosis interaction effects on brain morphology were noted in the left ACC, the left parahippocampal gyrus and the left amygdala-uncus. No significant genotype effects or genotype-diagnosis interaction effects on morphology in the dorsolateral PFC (DLPFC) were found. In the control group, no significant genotype effects on brain morphology were found. Schizophrenics homozygous for the Val-COMT showed a significant reduction of volumes in the bilateral ACC, left amygdala-uncus, right MTG and left thalamus compared to Met-COMT schizophrenics. Our findings suggest that the Val158Met polymorphism of the COMT gene might contribute to morphological abnormalities in schizophrenia.

Progressive changes of white matter integrity in schizophrenia revealed by diffusion tensor imaging.

Recent magnetic resonance imaging (MRI) studies using diffusion tensor imaging (DTI) have suggested reduced fractional anisotropy (FA) in the white matter (WM) of the brain in patients with schizophrenia. We tried to examine whether such reduction in FA exists and whether such changes in FA progress in an age-dependent manner in a Japanese sample of chronic schizophrenia. FA values were compared between 42 patients with chronic schizophrenia and 42 controls matched for age and gender, by using DTI with voxel-by-voxel and region-of-interest analyses. Correlations of FA values with age and duration of illness were examined. Patients with schizophrenia showed lower FA values, compared to controls, in the widespread WM areas including the uncinate fasciculi and cingulum bundles. A significant group-by-age interaction was found for FA in the WM, i.e., age-related reduction of FA was more pronounced in schizophrenics than in controls. A significant negative correlation between FA and duration of illness was also found in the WM. Our data confirmed decreased FA in schizophrenics, compared to controls in the widespread WM areas. Such decreased FA values in schizophrenia might be attributable, at least in part, to progressive changes after the onset of the illness.

TM5441, a plasminogen activator inhibitor-1 inhibitor, protects against high fat diet-induced non-alcoholic fatty liver disease.

Recent evidences showed that elevation of plasminogen activator inhibitor 1 (PAI-1) was responsible in mediating obesity-induced non-alcoholic fatty liver disease (NAFLD) and metabolic disorders. Here, we investigated the effect of TM5441, an oral PAI-1 inhibitor that lacks of bleeding risk, on high-fat diet (HFD)-induced NAFLD. HFD-fed C57BL/6J mice was daily treated with 20 mg/kg TM5441. To examine the preventive effect, 10-week-treatment was started along with initiation of HFD; alternatively, 4-week-treatment was started in mice with glucose intolerance in the interventional strategy. In vivo study showed that early and delayed treatment decreased hepatic steatosis. Particularly, early treatment prevented the progression of hepatic inflammation and fibrosis in HFD mice. Interestingly, both strategies abrogated hepatic insulin resistance and mitochondrial dysfunction, presented by enhanced p-Akt and p-GSK3ß, reduced p-JNK signaling, along with p-AMPK and PGC-1α activation. Consistently, TM5441 treatment in the presence of either PAI-1 exposure or TNF-α stimulated-PAI-1 activity showed a restoration of mitochondrial biogenesis related genes expression on HepG2 cells. Thus, improvement of insulin sensitivity and mitochondrial function was imperative to partially explain the therapeutic effects of TM5441, a novel agent targeting HFD-induced NAFLD.

Antipsychotic medication and cognitive function in schizophrenia.

Antipsychotic polypharmacy and excessive dosing still prevail worldwide in the treatment of schizophrenia, while their possible association with cognitive function has not well been examined. We examined whether the "non-standard" use of antipsychotics (defined as antipsychotic polypharmacy or dosage >1,000 mg/day of chlorpromazine equivalents) is associated with cognitive function. Furthermore, we compared cognitive function between patients taking only atypical antipsychotics and those taking only conventionals. Neurocognitive functions were assessed in 67 patients with chronic schizophrenia and 92 controls using the Wechsler Memory Scale-Revised (WMS-R), the Wechsler Adult Intelligence Scale-Revised (WAIS-R), the Wisconsin Card Sorting Test (WCST), and the Advanced Trail Making Test (ATMT). Patients showed markedly poorer performance than controls on all these tests. Patients on non-standard antipsychotic medication demonstrated poorer performance than those on standard medication on visual memory, delayed recall, performance IQ, and executive function. Patients taking atypical antipsychotics showed better performance than those taking conventionals on visual memory, delayed recall, and executive function. Clinical characteristics such as duration of medication, number of hospitalizations, and concomitant antiparkinsonian drugs were different between the treatment groups (both dichotomies of standard/non-standard and conventional/atypical). These results provide evidence for an association between antipsychotic medication and cognitive function. This association between antipsychotic medication and cognitive function may be due to differential illness severity (e.g., non-standard treatment for severely ill patients who have severe cognitive impairment). Alternatively, poorer cognitive function may be due in part to polypharmacy or excessive dosing. Further investigations are required to draw any conclusions.