Search

Avacopan (TAVNEOS™) is a complement 5a receptor (C5aR) antagonist developed by ChemoCentryx for the treatment of autoimmune diseases including anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis. The therapeutic effects of avacopan are attributed to the inhibition of C5aR activity on neutrophils, however, the exact mechanism of therapeutic efficacy in patients with ANCA-associated vasculitis has not been established. In September 2021, avacopan received its first approval in Japan for the treatment of microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA), the two most common forms of ANCA-associated vasculitis, where it is being commercialized by Kissei Pharmaceutical through a partnership with Vifor Pharma. In October 2021, avacopan was approved in the USA as an adjunctive treatment in adults for severe active ANCA-associated vasculitis (specifically MPA and GPA) in combination with standard therapy including glucocorticoids (avacopan does not eliminate glucocorticoid use). Avacopan has received a positive opinion in the EU, and is also undergoing regulatory review in Switzerland and Canada. Avacopan is being investigated for the treatment of complement component 3 glomerulopathy, hidradenitis suppurativa, lupus nephritis and IgA nephropathy. This article summarizes the milestones in the development of avacopan leading to these first approvals in Japan and the USA. [ABSTRACT FROM AUTHOR]

Background and Purpose: High-fat diet (HFD)-induced obesity is accompanied by metabolic and neurochemical changes that have been associated with depression. Recent studies indicate that palmitoylethanolamide (PEA) exerts metabolic effects and holds neuroprotective potential. However, studies on HFD exposure in mice which investigate the effects of PEA on monoamine system and synaptic plasticity are limited.Experimental Approach: In C57Bl/6J male mice, obesity was established by HFD feeding for 12 weeks. Then, mice were treated with ultra-micronized PEA (30 mg·kg-1 daily p.o.) or vehicle for 7 weeks along with HFD. Mice receiving chow diet and vehicle served as controls. Thereafter, depressive-, anhedonic-like behaviour and cognitive performance were measured. Monoamine analyses were performed on brain areas (nucleus accumbens, Nac; prefrontal cortex, PFC; hippocampus), and markers of synaptic plasticity and neurogenesis were evaluated in hippocampus.Key Results: PEA limited depressive- and anhedonic-like behaviour, and cognitive deficits induced by HFD. PEA induced an increase in 5-HT levels in PFC, and a reduction of dopamine and 5-HT turnover in Nac and PFC, respectively. Moreover, PEA increased dopamine levels in the hippocampus and PFC. At a molecular level, PEA restored brain-derived neurotrophic factor signalling pathway in hippocampus and PFC, indicating an improvement of synaptic plasticity. In particular, PEA counteracted the reduction of glutamatergic synaptic density induced by HFD in the stratum radiatum of the CA1 of the hippocampus, where it also exhibited neurogenesis-promoting abilities.Conclusion and Implications: PEA may represent an adjuvant therapy to limit depressive-like behaviours and memory deficit, affecting monoamine homeostasis, synaptic plasticity and neurogenesis.Linked Articles: This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.4/issuetoc. [ABSTRACT FROM AUTHOR]

Introduction: In Japan, hepatitis C virus (HCV) genotype (GT) 2 accounts for approximately 32% of HCV infections. Limited treatment options exist in Japan for HCV GT2-infected patients. GIFT-II was a phase 3, randomized, open-label study evaluating the efficacy and safety of 16- and 12-week regimens of co-formulated ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) plus ribavirin (RBV) in Japanese adults with HCV GT2 infection.Methods: Patients were randomized in a 1:1 ratio to once-daily, co-formulated OBV/PTV/r (25/150/100 mg) with weight-based RBV for 16 or 12 weeks. The primary efficacy endpoint was the sustained virologic response at 12 weeks post-treatment (SVR12) rate in the primary efficacy population of non-cirrhotic treatment-naive patients.Results: A total of 171 patients were randomized to OBV/PTV/r + RBV. In the primary efficacy population, SVR12 rates were 91.5% (43/47; 95% confidence interval 83.5-99.5%) and 75.0% (36/48; 95% confidence interval 62.8-87.2%) in the 16-week arm and 12-week arm, respectively. No patient in the 16-week arm relapsed by post-treatment week 12. Among non-cirrhotic treatment-experienced patients, the overall SVR rate in the 16-week arm was 75.8% (25/33) and was highest [93.8% (15/16)] among those who had relapsed after previous interferon-based therapy. SVR12 rates were consistently higher in patients with HCV GT2a infection versus HCV GT2b infection [16-week treatment arm: 93.9% (31/33) versus 85.7% (12/14) and 93.8% (15/16) versus 56.3% (9/16) among non-cirrhotic treatment-naive and treatment-experienced patients, respectively]. No patient discontinued treatment because of an adverse event. The most common adverse events were anemia, increased blood bilirubin, and nasopharyngitis.Conclusions: OBV/PTV/r + RBV for 16 weeks resulted in high SVR12 rates in non-cirrhotic Japanese patients infected with HCV GT2 who were treatment-naive or who had relapsed after an interferon-based therapy. Higher SVR12 rates were observed among patients with HCV GT2a infection versus those with GT2b infection. This regimen demonstrated a favorable safety profile.Trial Registration: ClinicalTrials.gov identifier, NCT02023112.Funding: AbbVie. [ABSTRACT FROM AUTHOR]

Background and Objective: Hepatitis C virus (HCV) infection is of considerable clinical concern in Japan. We modeled the population pharmacokinetics of an oral interferon-free, direct-acting antiviral agent (DAA) regimen (i.e., the 2D regimen) recently approved for the treatment of chronic HCV genotype 1 infection as a new option for affected Japanese patients.Methods: Using data from a phase III clinical trial (GIFT-I) that enrolled Japanese patients with HCV genotype 1b infection, population pharmacokinetic models were developed for the drugs that comprise the 2D regimen: paritaprevir, ombitasvir, and ritonavir. Demographic and clinical covariates with potential to influence 2D pharmacokinetics were evaluated for their effects on drug exposures. Proposed models were assessed using goodness-of-fit plots, visual predictive checks, and bootstrap evaluations.Results: One-compartment models with first-order absorption and elimination adequately described the population pharmacokinetics of paritaprevir, ombitasvir, and ritonavir. On average, patients with cirrhosis had approximately 95-145 % higher, 19-24 % lower, and 58-68 % higher exposures of paritaprevir, ombitasvir, and ritonavir, respectively. Female patients had 58-81 % higher ombitasvir exposures, whereas patients with mild renal impairment (creatinine clearance 75 mL/min) had 9-14 % higher ombitasvir exposures than did patients with normal renal function (creatinine clearance 105 mL/min). The DAA exposure values were comparable between responders and non-responders.Conclusion: Population pharmacokinetic modeling did not reveal any patient-related or clinical parameters that would require dose adjustment of the 2D regimen when used for the treatment of HCV genotype 1b infection in Japanese patients. [ABSTRACT FROM AUTHOR]

Introduction: The all-oral 2 direct-acting antiviral (DAA) regimen of ombitasvir/paritaprevir/ritonavir 25/150/100 mg once a day has been evaluated in hepatitis C virus subgenotype 1b-infected Japanese adults in the GIFT-I study. The aim of this analysis was to evaluate potential relationships between DAA exposures and laboratory abnormalities/adverse events of peripheral edema in patients in GIFT-I.Methods: The GIFT-I study consisted of a randomized, double-blind, placebo-controlled substudy in patients without cirrhosis and an open-label substudy in patients with compensated cirrhosis. Patients received ombitasvir/paritaprevir/ritonavir for 12 weeks. Exposure-response relationships between individual components of the ombitasvir/paritaprevir/ritonavir regimen and clinical parameters of interest were explored using pharmacokinetic and clinical data from patients in the study. Graphical analyses were performed. For events that occurred in at least 10 patients (total bilirubin elevation ≥grade 2 and peripheral edema ≥grade 1), multivariate logistic regression analyses were used to identify significant relationships between predictor variables (drug exposures) and response variables (probability of adverse events or laboratory abnormalities), with consideration for the effect of potential covariates and baseline status of response variables.Results: Data from 321 noncirrhotic and 42 compensated cirrhotic patients were analyzed. There were 14 events of peripheral edema (10 at grade 1 and 4 at grade 2) in patients who received concomitant administration of calcium channel blockers and ombitasvir/paritaprevir/ritonavir. There was no apparent relationship between the incidences of peripheral edema and exposures of paritaprevir, ombitasvir, or ritonavir. There was a shallow relationship between total bilirubin elevation and exposures of paritaprevir which is an inhibitor of bilirubin transporter organic anion-transporting polypeptide 1B. Based on graphical analyses, exposures of paritaprevir, ombitasvir, or ritonavir were weakly associated with hemoglobin decrease, but not associated with post baseline alanine aminotransferase or aspartate aminotransferase elevations.Conclusions: In Japanese patients, there were no associations or only shallow relationships between DAA exposures and peripheral edema or laboratory abnormalities. Consequently, therapeutic drug monitoring is not expected to be beneficial in managing patients on the 2-DAA regimen.Trial Registration: ClinicalTrials.gov identifier, NCT02023099.Funding: AbbVie Inc. [ABSTRACT FROM AUTHOR]

We showed that an ethanol extract from Zanthoxylum piperitum can shorten the circadian rhythm at the cellular level and that this activity was due to hydroxy-β-sanshool, a secondary metabolite in this plant. An ethanol extract of Z. piperitum was repeatedly fractionated using solid phase extraction and reverse-phase HPLC, then the circadian rhythms of cells to which the fractions were loaded were monitored using real-time reporter gene assays. We purified one HPLC peak and identified it as hydroxy-β-sanshool using liquid chromatography (LC)-precision-mass spectrometry (MS). This compound shortened the period of Bmal1 and Per2 at the cellular level. Incubation cells for 24 h with hydroxy-β-sanshool resulted in upregulated Per2 promoter activity. Hydroxy-β-sanshool also dose-dependently upregulated expression of the clock genes Bmal1 , Per1 , Per2 and Cry1 and the clock-controlled oxidative stress responsive genes Gpx1 and Sod2 .

Abstract: Flubendiamide belongs to the modern insecticides applied in Japanese tea cultivation to control smaller tea tortrix and tea leaf roller. Since fate and behavior in soil have been only monitored sparsely and fragmentarily until today, laboratory tests were performed on sorption, leaching, biotransformation and photo-induced biotransformation of flubendiamide in two different soils. In batch equilibrium tests, Kd and KOC values were 15 and 298Lkg−1 for the Japanese tea field soil as well as 16 and 1610Lkg−1 for the German arable field soil classifying flubendiamide to be moderately mobile and slightly mobile, respectively. The affinity to the tea field soil was additionally confirmed by soil column tests where flubendiamide was predominantly retarded in the topsoil layers resulting in a percolate contamination of only 0.002mgL−1. In the aerobic biotransformation tests, flubendiamide did not substantially disappear within the 122-d incubation period. Due to DT50 >122 d, flubendiamide was assessed very persistent. Supplementary, photo-induced impacts on biotransformation were studied in a special laboratory irradiation system. Despite a 14-d irradiation period, photo-induced biotransformation in the tea field soil was not identifiable, neither by HPLC/DAD nor by LC/MS/MS. 3-d irradiation tests in photosensibilizing acetone, however, showed that the primary photo-transformation product desiodo-flubendiamide was formed. How far this photochemical reaction may also occur in soil of perennial tea plant stands, however, has to be checked in field studies. [Copyright &y& Elsevier]

Abstract: A new cyclic depsipeptide, designated neamphamide B (1), was isolated from a marine sponge of Neamphius sp. collected at Okinawa, Japan in 1993 as an anti-mycobacterial substance against active and dormant bacilli. The planar structure of neamphamide B (1) was determined on the basis of spectroscopic analysis, and stereostructure of amino acid was deduced by chromatographic comparison of the acid hydrolysate of 1 with appropriate amino acid standards after derivatizing with FDAA or GITC. Neamphamide B (1) showed potent anti-mycobacterial activity against Mycobacterium smegmatis under standard aerobic growth conditions as well as dormancy-inducing hypoxic conditions with MIC of 1.56μg/mL. Neamphamide B (1) was also effective to Mycobacterium bovis BCG with MIC in the ranging of 6.25–12.5μg/mL. [Copyright &y& Elsevier]

Abstract: Lyngbyacyclamides A (1) and B (2), novel cyclic peptides, were isolated from marine cyanobacteria Lyngbya sp. collected in Okinawa, Japan. Their structures were determined by spectroscopic analyses and degradation studies. They moderately inhibited the growth of B16 mouse melanoma cells. [Copyright &y& Elsevier]

Abstract   Purpose This multicenter phase II study examined the impact of pathological effect on survival after preoperative chemotherapy in Japanese women with early stage breast cancer. Patients and methods Prior to surgery, patients received four cycles of FEC (fluorouracil 500 mg/m2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2 q3w) followed by four cycles of docetaxel (75 mg/m2 q3w). Primary endpoint was 3 year disease free survival (DFS) stratified by the absence or presence of Quasi-pCR (QpCR; absence of invasive tumor or only focal residual tumor cells). Secondary endpoints were predictors for QpCR, clinical response, breast conservation rate, and safety. Results Between June 2002 and June 2004, 202 women were enrolled. Among 191 assessable patients, 25% achieved QpCR. With 40 months median follow-up, 3 year DFS was estimated at 91% for all patients. 3 year DFS for patients with QpCR was 98% vs. 89% without QpCR (hazard ratio 0.38 [95% Confidence Interval 0.09–0.84], P = 0.0134). HER2 status and response to FEC were independent predictors of QpCR. The overall clinical response was 75%; 85% of patients achieved breast conservation. Grade 3/4 neutropenia was the most common adverse event, observed in 44% and 35% of patients during FEC and docetaxel, respectively. Treatment related side effects were manageable; there were no treatment related fatalities. Conclusion FEC followed by docetaxel is an active and manageable preoperative regimen for women with early stage breast cancer. QpCR following preoperative chemotherapy predicts favorable DFS. HER2 overexpression and clinical response to FEC predict QpCR. [ABSTRACT FROM AUTHOR]

Among the many different structurally distinct classes of β-lactams, the carbapenem class is regarded as that which is most potent and which has the widest spectrum of antimicrobial activity. Rapidly bactericidal, and demonstrating time-dependent killing, carbapenemes have a spectrum of antimicrobial activity that includes Gram-positive and Gram-negative aerobic and anaerobic pathogens. Their in-vitro activity includes extended-spectrum β-lactamase (ESBL)-producing pathogens and carbapenems are currently considered to be the treatment of choice for serious infections due to ESBL-producing organisms. However, isolates acquiring resistance under treatment have been reported. Imipenem, meropenem and ertapenem are licensed in the European Community and panipenem and biapenem are also available in Japan and South Korea. Other carbapenemes are under development. [ABSTRACT FROM AUTHOR]

About 10 years have passed since a previous survey on the treatment of West syndrome in Japan. To elucidate current practice, a questionnaire was sent to 113 institutes. It included (1) the drugs used for the treatment, (2) their dosage, and (3) the dosage and the schedule of adrenocorticotropic hormone therapy. Response rate was 5 1.3%. Adrenocorticotropic hormone, valproic acid, vitamin B6, and zonisamide were frequently used. Vitamin B6 was used most frequently as the first-choice drug followed by valproic acid, zonisamide, and adrenocorticotropic hormone. The most frequently used dose of synthetic adrenocorticotropic hormone-Z was 0.0125 mg/kg/d. Adrenocorticotropic hormone was administered every clay for 2 weeks and then tapered off in more than 80% of the institutes. Although therapeutic strategy and drug usage have not changed largely during these 10 years, 2 alterations were observed: an increased use of zonisamide and a shortened duration of adrenocorticotropic hormone therapy. [ABSTRACT FROM AUTHOR]

Introduction: Several clinical studies have reported the efficacy of favipiravir in reducing viral load and shortening the duration of symptoms. However, the viability of SARS-CoV-2 in the context of favipiravir therapy and the potential for resistance development is unclear., Methods: We sequenced SARS-CoV-2 in nasopharyngeal specimens collected from patients who participated in a randomized clinical trial of favipiravir at hospitals across Japan between March and May 2020. Paired genomes were sequenced from those who remained RT-PCR-positive 5-8 days into favipiravir therapy. Daily nasopharyngeal specimens from 69 patients who were RT-PCR-positive at randomization were examined for a cytopathic effect (CPE)., Results: Some strains early in the trial belonged to clade 19 B, whereas the majority belonged to clade 20 B. The median time from the disease onset to negative CPE was 9 days. CPE was strongly correlated with the time from disease onset, viral load, age, and male sex. Among 23 patients for whom paired genomes were available, all except one had identical genomes. Two mutations were observed in one patient who received favipiravir, neither in the RdRp gene., Conclusions: The SARS-CoV-2 genome distribution in this clinical trial conducted in Japan reflected the early influx of strains from China followed by replacement by strains from Europe. CPE was significantly associated with age, male sex, and viral loads but not with favipiravir therapy. There was no evidence of resistance development during favipiravir therapy., (Copyright © 2021 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: The real-world virological efficacy and safety of an interferon (IFN)-free direct-acting antiviral (DAA) therapy with elbasvir (EBR) and grazoprevir (GZR) were evaluated in Japanese patients chronically infected with hepatitis C virus (HCV) genotype 1., Methods: The rate of sustained virologic response (SVR) and safety were analyzed in patients who started the EBR/GZR regimen between November 2016 and July 2017. SVR rates were compared based on patient baseline characteristics., Results: Overall, 371 of 381 patients (97.4%) achieved SVR. Multivariate analysis identified a history of failure to IFN-free DAA therapy and the presence of double resistance-associated substitutions (RASs) in HCV non-structural protein 5A (NS5A) as factors significantly associated with failure to EBR/GZR treatment. The SVR rates of patients with a history of IFN-free DAA therapy and those with double RASs were 55.6 and 63.6%, respectively. In all other subpopulations, the SVR rates were more than 90%. There were no severe adverse events associated with the treatment., Conclusions: The EBR/GZR regimen yielded high virological efficacy with acceptable safety. Patients with a history of failure to IFN-free DAA therapy or with double RASs in HCV-NS5A remained difficult to treat with this regimen.

We have previously reported a potent and specific cholesteryl ester transfer protein (CETP) inhibitor JTT-705 was a potentially anti-atherogenic compound (Nature 406 (2000) 203). In the present study, we investigated in vitro how this compound affects properties of high density lipoprotein (HDL) in Japanese white (JW) rabbits in terms of reverse cholesterol transport in J774 macrophages. Plasma HDL-cholesterol (C) level was significantly higher in the rabbits administered JTT-705 than in control rabbits on days 3 and 7. Both HDL(2) and HDL(3)-C levels were also significantly higher in JTT-705-administered rabbits than in control rabbits. During this period, plasma CETP activity was kept lower in JTT-705-administered rabbits than in controls. To determine how this compound affects the property of HDL particles, we investigated the C efflux induced by HDL from JTT-705-administered and control rabbits in J774 macrophages. Cholesterol ester (CE) concentration in J774 macrophages was reduced in proportion with increasing concentration of the added HDL to the culture media for J774 macrophages in both groups, suggesting that the HDL from JTT-705-administered rabbits was able to reduce CE concentration in J774 macrophages as efficiently as that from control rabbits. This result, together with the finding that the absolute HDL concentration increased in JW rabbits administered this CETP inhibitor, suggests that treatment with this new compound causes a beneficial effect on lipid metabolism in terms of anti-atherogenicity.