Shorter incubation period in symptomatic measles patients who had no history of measles vaccination.

In February 2024, a 22-year-old Japanese resident of Osaka Prefecture was diagnosed with measles in the PCR test. He had flown from Dubai to Osaka Kansai International Airport. We finally detected 13 incident measles cases identified as infected by the index case and collected data on these individuals to evaluate the association between vaccination and incubation period.

Development of a novel class of peroxisome proliferator-activated receptor (PPAR) gamma ligands as an anticancer agent with a unique binding mode based on a non-thiazolidinedione scaffold.

We previously identified dibenzooxepine derivative 1 as a potent PPARγ ligand with a unique binding mode owing to its non-thiazolidinedione scaffold. However, while 1 showed remarkably potent MKN-45 gastric cancer cell aggregation activity, an indicator of cancer differentiation-inducing activity induced by PPARγ activation, we recognized that 1 was metabolically unstable. In the present study, we identified a metabolically soft spot, and successfully discovered 3-fluoro dibenzooxepine derivative 9 with better metabolic stability.

The ASK1-specific inhibitors K811 and K812 prolong survival in a mouse model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no cure. To develop effective treatments for this devastating disease, an appropriate strategy for targeting the molecule responsible for the pathogenesis of ALS is needed. We previously reported that mutant SOD1 protein causes motor neuron death through activation of ASK1, a mitogen-activated protein kinase kinase kinase.

Factors affecting the pharmacokinetics and pharmacodynamics of PEGylated liposomal irinotecan (IHL-305) in patients with advanced solid tumors.

IHL-305 is a PEGylated liposomal formulation of irinotecan (CPT-11). The objective of this study was to evaluate the factors associated with interpatient variability in the pharmacokinetics and pharmacodynamics of IHL-305 in patients with advanced solid tumors. IHL-305 was administered intravenously once every 4 weeks as part of a Phase I study.

Quantitative investigation of the brain-to-cerebrospinal fluid unbound drug concentration ratio under steady-state conditions in rats using a pharmacokinetic model and scaling factors for active efflux transporters.

A pharmacokinetic model was constructed to explain the difference in brain- and cerebrospinal fluid (CSF)-to-plasma and brain-to-CSF unbound drug concentration ratios (Kp,uu,brain, Kp,uu,CSF, and Kp,uu,CSF/brain, respectively) of drugs under steady-state conditions in rats. The passive permeability across the blood-brain barrier (BBB), PS1, was predicted by two methods using log(D/molecular weight(0.5)) for PS1(1) or the partition coefficient in octanol/water at pH 7.

Population pharmacokinetics of PEGylated liposomal CPT-11 (IHL-305) in patients with advanced solid tumors.

Purpose: To investigate pharmacokinetics (PK) of encapsulated CPT-11, released CPT-11 and the active metabolite SN-38 following administration of IHL-305 and to identify factors that may influence IHL-305 PK.

Methods: Plasma samples from 39 patients with solid tumors were collected in a phase I study. IHL-305 was administered as a 1 h IV infusion with doses ranging from 3.

Potentials and limitations of nonclinical safety assessment for predicting clinical adverse drug reactions: correlation analysis of 142 approved drugs in Japan.

The objective of this study was to elucidate the range of abilities of nonclinical safety assessment for predicting adverse drug reactions (ADRs) in humans. The dataset included 1256 ADRs with an incidence rate of 5% or more collected from 142 drugs approved in Japan from 2001 to 2010 (excluding anticancer agents and vaccines). Gastrointestinal, neurological and hepatobiliary ADRs were relatively common, followed by hematological, cutaneous, systemic and cardiovascular ADRs in the dataset.

Phase I and pharmacokinetic study of IHL-305 (PEGylated liposomal irinotecan) in patients with advanced solid tumors.

Purpose: IHL-305 is a novel PEGylated liposome containing irinotecan. This study examined the safety profile and pharmacokinetics of IHL-305 and established the maximum tolerated dose and recommended phase II dose (RP2D).

Patients And Methods: In a standard 3 + 3 design, IHL-305 was administered IV on day 1 of a 28-day treatment schedule.

Discovery of novel 5,5-diarylpentadienamides as orally available transient receptor potential vanilloid 1 (TRPV1) antagonists.

We have developed a novel and potent chemical series of 5,5-diphenylpentadienamides for targeting TRPV1 in vitro and in vivo. In this investigation, we examined a variety of replacements for the 5-position of dienamides with the goal of addressing issues related to pharmacokinetics. Our data suggest that substitution with alkoxy groups on the phenyl ring at the 5-position increases their ability to penetrate the blood-brain barrier.

Species differences in the pharmacokinetics of KW-7158 [(2S)-(+)-3,3,3-Trifluoro-2-hydroxy-2-methyl-N-(5,5,10-trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propanamide]: formation of hydrolyzed metabolite in human and animals.

Species differences in the pharmacokinetics of KW-7158 [(2S)-(+)-3,3,3-Trifluoro-2-hydroxy-2-methyl-N-(5,5,10-trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propanamide] were studied in in vivo and in vitro experiments. The exposure ratio of hydrolyzed metabolite (M2, primary metabolite in human plasma)/KW-7158 was higher than the ratio of thiophen-to-furan converted metabolite (M1)/KW-7158 in human subjects after oral administration, but the mouse, rat and dog studies gave opposite results. M2 was produced in the highest amount by the 9000g supernatant of small intestine, followed by that of liver and kidney in human subjects.

Antitumor activity of IHL-305, a novel pegylated liposome containing irinotecan, in human xenograft models.

The antitumor effect of IHL-305, a novel pegylated liposome containing irinotecan, was investigated in human xenograft models. After subcutaneous transplantation of several human cancer cell lines (colorectal, non-small cell lung, small cell lung, prostate, ovarian and gastric cancer cells) to nude mice, IHL-305 or CPT-11 was administered intravenously 3 times at 4-day intervals. In all xenograft models tested, IHL-305 showed superior antitumor activity to that of CPT‑11 and a comparable tumor-growth-inhibitory effect at one-eighth or less of the dose of CPT-11, even against HT-29 colorectal and NCI-H460 non-small cell lung cancer cell lines, which show intrinsic resistance to CPT-11.

Quantitative evaluation of the impact of active efflux by p-glycoprotein and breast cancer resistance protein at the blood-brain barrier on the predictability of the unbound concentrations of drugs in the brain using cerebrospinal fluid concentration as a surrogate.

This study investigated the impact of the active efflux mediated by P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) at the blood-brain barrier (BBB) on the predictability of the unbound brain concentration (C(u,brain)) by the concentration in the cerebrospinal fluid (CSF) (C(u,CSF)) in rats. C(u,brain) is obtained as the product of the total brain concentration and unbound fraction in the brain (f(u,brain)) determined in vitro in brain slices. Twenty-five compounds, including P-gp and/or Bcrp substrates, were given a constant intravenous infusion, and their plasma, brain, and CSF concentrations were determined.

Novel acrylonitrile derivatives, YHO-13177 and YHO-13351, reverse BCRP/ABCG2-mediated drug resistance in vitro and in vivo.

Breast cancer resistance protein (BCRP/ABCG2) confers resistance to anticancer drugs such as 7-ethyl-10-hydroxycamptothecin (SN-38, an active metabolite of irinotecan), mitoxantrone, and topotecan. In this study, we examined the reversing effects of YHO-13177, a novel acrylonitrile derivative, and its water-soluble diethylaminoacetate prodrug YHO-13351 on the BCRP-mediated drug resistance. YHO-13177 potentiated the cytotoxicity of SN-38, mitoxantrone, and topotecan in both BCRP-transduced human colon cancer HCT116 (HCT116/BCRP) cells and SN-38-resistant human lung cancer A549 (A549/SN4) cells that express BCRP, but had little effect in the parental cells.

Kinetic analysis of the cooperation of P-glycoprotein (P-gp/Abcb1) and breast cancer resistance protein (Bcrp/Abcg2) in limiting the brain and testis penetration of erlotinib, flavopiridol, and mitoxantrone.

A synergistic effect of P-glycoprotein (P-gp)/Abcb1a and breast cancer resistance protein (Bcrp)/Abcg2 was reported to limit the brain penetration of their common substrates. This study investigated this based on pharmacokinetics using Mdr1a/1b(-/-), Bcrp(-/-), and Mdr1a/1b(-/-)/Bcrp(-/-) mice. Comparison of the brain- and testis-to-plasma ratios (C(brain)/C(plasma) and C(testis)/C(plasma), respectively) of the reference compounds quinidine and dantrolene for P-gp and Bcrp, respectively, indicates that impairment of either P-gp and Bcrp did not cause any change in the efflux activities of Bcrp or P-gp, respectively, at both the blood-brain barrier (BBB) and blood-testis barrier (BTB).

Identification of proteins phosphorylated directly by the Us3 protein kinase encoded by herpes simplex virus 1.

We have developed a system to analyze the specific protein kinase activity of herpes simplex virus 1 Us3 in vitro and shown that Us3 directly phosphorylates viral proteins UL34, ICP22, and Us9 and the cellular protein Bad, previously reported to be putative substrates. Using this system, we determined the phosphorylation sites of UL34 and identified UL31 as a previously unreported, novel substrate of Us3. This system will be useful for further identification of Us3 substrates and their phosphorylation sites, clarification of the role of Us3 in viral replication, and identification of additional Us3 function(s).

Effective accumulation of poly(vinylpyrrolidone-co-vinyl laurate) into the spleen.

To optimize polymer-conjugated drugs as a polymeric drug delivery system, it is essential to design polymeric carriers with tissue-specific targeting capacity. Previously, we showed that polyvinylpyrrolidone (PVP) was the most suitable polymeric carrier for prolonging the blood-residency of drugs, and was one of the best parent polymers to design the polymeric carriers with targeting capacity. In this study, we synthesized some hydrophobic PVP derivatives, poly(vinylpyrrolidone-co-styrene) [poly(VP-co-S)] and poly(vinylpyrrolidone-co-vinyl laurate) [poly(VP-co-VL)], and assessed their biopharmaceutical properties after intravenous administration in mice.

Construction of recombinant herpes simplex virus type I expressing green fluorescent protein without loss of any viral genes.

For use in various applications in research on herpes simplex virus type 1, we attempted to generate recombinant HSV-1 expressing green fluorescent protein (GFP) without any loss of viral genes. Our results were as follows. (i) A recombinant HSV-1 (YK333), in which a GFP expression cassette driven by the Egr-1 promoter was inserted into the intergenic region between UL3 and UL4, was constructed.

Design of a pH-sensitive polymeric carrier for drug release and its application in cancer therapy.

Purpose: In this study, to optimize the polymeric drug delivery system for cancer chemotherapy, we developed a new pH-sensitive polymeric carrier, poly(vinylpyrrolidone-co-dimethylmaleic anhydride) [PVD], that could gradually release native form of drugs with full activity, from the conjugates in response to changes in pH. We examined the usefulness of PVD as a polymeric drug carrier.

Experimental Design: PVD was radically synthesized with vinylpyrrolidone and 2,3-dimethylmaleic anhydride, which is known to be a pH-reversible amino-protecting reagent.

The targeting of anionized polyvinylpyrrolidone to the renal system.

We reported that the co-polymer composed of vinylpyrrolidone and maleic acid selectively distributed into the kidneys after i.v. injection.

The use of PVP as a polymeric carrier to improve the plasma half-life of drugs.

To achieve an optimum drug delivery such as targeting or controlled release utilizing bioconjugation with polymeric modifier, the conjugate between drugs and polymeric modifiers must be designed to show desirable pharmacokinetic characteristics in vivo. In this study, we assessed the biopharmaceutical properties of various nonionic water-soluble polymers as polymeric drug carriers. Polyvinylpyrrolidone (PVP) showed the longest mean resident time (MRT) after i.