The in vitro pharmacology and non-clinical cardiovascular safety studies of a novel 5-HT receptor agonist, DSP-6952.

The pharmacological activity of DSP-6952, a novel compound was investigated, compared to that of clinically efficacious gastrointestinal (GI) prokinetic 5-hydroxytryptamine (5-HT) receptor agonists. DSP-6952 had a strong affinity of Ki = 51.9 nM for 5-HT receptor, and produced contraction in the isolated guinea pig colon with EC of 271.

CSAHi study-2: Validation of multi-electrode array systems (MEA60/2100) for prediction of drug-induced proarrhythmia using human iPS cell-derived cardiomyocytes: Assessment of reference compounds and comparison with non-clinical studies and clinical information.

With the aim of reconsidering ICH S7B and E14 guidelines, a new in vitro assay system has been subjected to worldwide validation to establish a better prediction platform for potential drug-induced QT prolongation and the consequent TdP in clinical practice. In Japan, CSAHi HEART team has been working on hiPS-CMs in the MEA (hiPS-CMs/MEA) under a standardized protocol and found no inter-facility or lot-to-lot variability for proarrhythmic risk assessment of 7 reference compounds. In this study, we evaluated the responses of hiPS-CMs/MEA to another 31 reference compounds associated with cardiac toxicities, and gene expression to further clarify the electrophysiological characteristics over the course of culture period.

Comprehensive in vitro cardiac safety assessment using human stem cell technology: Overview of CSAHi HEART initiative.

Recent increasing evidence suggests that the currently-used platforms in vitro I and APD, and/or in vivo QT assays are not fully predictive for TdP, and do not address potential arrhythmia (VT and/or VF) induced by diverse mechanisms of action. In addition, other cardiac safety liabilities such as functional dysfunction of excitation-contraction coupling (contractility) and structural damage (morphological damage to cardiomyocytes) are also major causes of drug attrition, but current in vitro assays do not cover all these liabilities. We organized the Consortium for Safety Assessment using Human iPS cells (CSAHi; http://csahi.

CSAHi study: Validation of multi-electrode array systems (MEA60/2100) for prediction of drug-induced proarrhythmia using human iPS cell-derived cardiomyocytes -assessment of inter-facility and cells lot-to-lot-variability.

In vitro screening of hERG channels are recommended under ICH S7B guidelines to predict drug-induced QT prolongation and Torsade de Pointes (TdP), whereas proarrhythmia is known to be evoked by blockage of other ion channels involved in cardiac contraction and compensation mechanisms. A consortium for drug safety assessment using human iPS cells-derived cardiomyocytes (hiPS-CMs), CSAHi, has been organized to establish a novel in vitro test system that would enable better prediction of drug-induced proarrhythmia and QT prolongation. Here we report the inter-facility and cells lot-to-lot variability evaluated with FPDc (corrected field potential duration), FPDc10 (10% FPDc change concentration), beat rate and incidence of arrhythmia-like waveform or arrest on hiPS-CMs in a multi-electrode array system.

Availability of human induced pluripotent stem cell-derived cardiomyocytes in assessment of drug potential for QT prolongation.

Field potential duration (FPD) in human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs), which can express QT interval in an electrocardiogram, is reported to be a useful tool to predict K(+) channel and Ca(2+) channel blocker effects on QT interval. However, there is no report showing that this technique can be used to predict multichannel blocker potential for QT prolongation. The aim of this study is to show that FPD from MEA (Multielectrode array) of hiPS-CMs can detect QT prolongation induced by multichannel blockers.

Translational research into species differences of endocrine toxicity via steroidogenesis inhibition by SMP-028--for human safety in clinical study.

SMP-028 is a drug candidate developed for the treatment of asthma. In a 13-week repeated dose toxicity study of SMP-028 in rats and monkeys, differences of endocrine toxicological events between rats and monkeys were observed. In rats, these toxicological events mainly consisted of pathological changes in the adrenal, testis, ovary, and the other endocrine-related organs.

Effect of SMP-028 on steroidogenesis in rats; mechanism of toxicological events on endocrine organs of rats.

SMP-028 is a new compound for treatment of asthma. Oral administration of SMP-028 to rats was associated with toxicological events in endocrine organs. These events mainly consisted of pathological changes in the adrenal gland, testis, prostate, seminal vesicle, ovaries, and uterus.

Protective effects of dietary 1,5-anhydro-D-glucitol as a blood glucose regulator in diabetes and metabolic syndrome.

1,5-Anhydro-D-glucitol (1,5-AG) is fairly widespread in food products. It is also one of the major polyols in the human body, and its concentration is homeostatically regulated. We report here on the beneficial effects of 1,5-AG in preventing hyperglycemia and its role in improving metabolic syndrome.

The effects of clobazam treatment in rats on the expression of genes and proteins encoding glucronosyltransferase 1A/2B (UGT1A/2B) and multidrug resistance-associated protein-2 (MRP2), and development of thyroid follicular cell hypertrophy.

Clobazam (CLB) is known to increase hepatobiliary thyroxine (T4) clearance in Sprague-Dawley (SD) rats, which results in hypothyroidism followed by thyroid follicular cell hypertrophy. However, the mechanism of the acceleration of T4-clearance has not been fully investigated. In the present study, we tried to clarify the roles of hepatic UDP-glucronosyltransferase (UGT) isoenzymes (UGT1A and UGT2B) and efflux transporter (multidrug resistance-associated protein-2; MRP2) in the CLB-induced acceleration of T4-clearance using two mutant rat strains, UGT1A-deficient mutant (Gunn) and MRP2-deficient mutant (EHBR) rats, especially focusing on thyroid morphology, levels of circulating hormones (T4 and triiodothyronine (T3)) and thyroid-stimulating hormone (TSH), and mRNA or protein expressions of UGTs (Ugt1a1, Ugt1a6, and Ugt2b1/2) and MRP2 (Mrp).

Evaluation of ovarian toxicity of sodium valproate (VPA) using cultured rat ovarian follicles.

Sodium valproate (VPA) is a major antiepileptic drug that is widely used for the treatment of epilepsy as well as other neuropsychiatric diseases. The present study was conducted to evaluate the ovarian toxicity of VPA using cultured rat ovarian follicles. Secondary follicles were isolated from the ovaries of 14-day-old female rats and cultured for 48 hr with VPA (0, 0.

Evaluation of ovarian toxicity of mono-(2-ethylhexyl) phthalate (MEHP) using cultured rat ovarian follicles.

Mono-(2-ethylhexyl) phthalate (MEHP) is the most toxic metabolite of di-(2-ethylhexyl) phthalate (DEHP). It has been reported that DEHP causes abnormal reproductive development in women, and suppresses estradiol synthesis and ovulation in female rats with diminished size of preovulatory follicles. The present study was conducted to evaluate the ovarian toxicity of MEHP using cultured rat ovarian follicles.

Cerebral reactive oxygen species assessed by electron spin resonance spectroscopy in the initial stage of ischemia-reperfusion are not associated with hypothermic neuroprotection.

Using an in vivo L-band electron spin resonance (ESR) system, we determined changes in reactive oxygen species (ROS) levels during the early stage (within 60 minutes) of global cerebral ischemia-reperfusion (IR) under normothermic and hypothermic conditions in rats. To confirm the neuroprotective role of hypothermia in this IR model, we immunohistochemically evaluated the levels of active caspase-3 in the hippocampal CA1 sector. ROS levels increased within the first 15 minutes following IR under both normothermic and hypothermic conditions; however, the ROS levels did not differ significantly between normothermic and hypothermic conditions.

Use of moderate sedation for a patient with Down syndrome, intellectual disability, and Eisenmenger syndrome: a case report.

For patients who have Eisenmenger syndrome (ES), perioperative risks are high even for noncardiac surgery, such as dental extractions. We report on the case history of a 38-year-old male patient with Down syndrome (DS), intellectual disability (ID), and ES. The patient was scheduled for extraction of the right maxillary second molar tooth.

GC-MS-based metabolomics reveals mechanism of action for hydrazine induced hepatotoxicity in rats.

Gas chromatography-mass spectrometry (GC-MS) has great advantages for analyzing organic/amino acids, which are often targets in efficacy and/or toxicity studies. Although GC-MS has been used for the detection of many metabolic disorders, applications of GC-MS-based metabolomics in pharmacology/toxicology are relatively underdeveloped. We intended to investigate applicability of a GC-MS-based metabolomics approach for toxicological evaluation, and tried to elucidate the mechanism of hydrazine-induced hepatotoxicity.

The antipsychotics haloperidol and chlorpromazine increase bone metabolism and induce osteopenia in female rats.

The main objective of this study was to evaluate the effects of the antipsychotic drugs haloperidol (HAL) and chlorpromazine (CPZ) on bone mineral density (BMD) in female rats and to examine the relationship between the effects on bone and reproductive organs or hormone concentrations. Female rats were orally administered HAL (2 or 10 mg/kg) or CPZ (25 or 50 mg/kg) once daily (7 days/week) for 6 months resulting in a significant increase in prolactin. Hyperprolactinemia resulted in enlarged corpora lutea in the ovary, because prolactin has a luteotropic activity.

Influences of biofluid sample collection and handling procedures on GC-MS based metabolomic studies.

Sample collection procedures of pharmacology and toxicology studies might have a great impact on interpretation of metabolomic study results. Characterization of range variation among sample collection methods is necessary to prevent misinterpretation, as is use of optimal methods in animal experiments to minimize biological/technical variation. Here, we investigated the influence of urine and plasma sample collection and handling procedures on GC-MS based metabolomic studies as follows: for urine, pooling period and tube conditions during collection; for plasma, sampling sites, anesthesia and anticoagulants.

Comparison of potential risks of lactic acidosis induction by biguanides in rats.

Lactic acidosis has been considered to be a side effect of some biguanides, after phenformin was withdrawn from the market because of its association with lactic acidosis. The potential of lactic acidosis induced by biguanides at human therapeutic exposure levels, however, has not been examined. Then, we compared the risk of lactic acid at doses providing exposure levels comparable to human therapeutic doses.

Hypothermic and normothermic ischemia-reperfusion activate microglia differently in hippocampal formation.

Using immunohistochemical methods, we investigated microglial profiles under normothermic ischemia and hypothermic ischemia using an anti-ionized calcium-binding adapter molecule 1 (Iba-1) antibody. In the early stages of ischemia-reperfusion, Iba-1-immunoreactive microglial cells under normothermic ischemia were characterized by swollen somata with short and thick processes, while fine long-branched processes in greater numbers were seen emanating from microglial somata under hypothermic ischemia. In animals subjected to hypothermic ischemia, immunoreactive microglial areas in the hippocampal CA1 sector were significantly increased after 5 and 8 h of reperfusion when compared with those under normothermic ischemia.

Measurement of cerebral reactive hyperemia at the initial post-ischemia reperfusion stage under normothermia and moderate hypothermia in rats.

Inhibition of the initial events occurring immediately after ischemia-reperfusion seems to be beneficial for reducing the extent of subsequent chronic neuronal cell injury. We investigated the effects of moderate hypothermia (32 degrees C) commencing 30 min before ischemia on reactive hyperemia by measuring cerebral blood flow (CBF) with a laser-Doppler flowmeter at the initial ischemia-reperfusion stage (60 min) following 10 min of global cerebral ischemia in rats. In normothermia, CBF was increased to approximately 240% and decreased thereafter, although it remained at approximately 150% after 60 min of ischemia-reperfusion.

Coherent precession of magnetization in the superfluid 3He A-phase.

We report the first observation of coherent precession of magnetization in superfluid 3He A-like phase (CP-A) in aerogel. The coherent precession in bulk 3He A-phase is unstable due to the positive feedback of spin supercurrent to the gradient of phase of precession. It was predicted that the homogeneous precession will be stable if the orbital momentum of the 3He A-phase can be oriented along the magnetic field.

Usefulness of noninjectable anesthetic gel for intraperiodontal gingival retraction.

This study aimed to determine the efficacy of local anesthesia using Oraqix for gingival retraction in 35 healthy adult patients. The median visual analogue scale value was 20.5 +/- 24.