Single and multiple dose pharmacokinetics and safety of ZSP1273, an RNA polymerase PB2 protein inhibitor of the influenza A virus: a phase 1 double-blind study in healthy subjects.

BACKGROUND: Influenza is an acute respiratory illness. Treating with antiviral drugs can decrease the duration of illness and serious complications . ZSP1273 is a small-molecule anti-influenza drug targeting the RNA polymerase PB2 subunit of the influenza virus. The aim of this clinical trial was to evaluate the safety and pharmacokinetics (PKs) of ZSP1273 in healthy subjects. RESEARCH DESIGN AND METHODS: This was a double-blind, placebo-controlled phase 1 study consisting of three parts. 100 volunteers were enrolled and randomized to receive either single or multiple doses of ZSP1273 or placebo. RESULTS: A total of 31 (31.0%) subjects experienced at least one mild or moderate adverse event. The linear regression relationship between dose and plasma Cmax, AUC0-t, and AUC0-∞ showed an increasing trend and rapid absorption of ZSP1273. A high-fat diet had little effect on the PKs. The plasma concentration of ZSP1273 reached steady state on day 5 without drug accumulation. CONCLUSIONS: ZSP1273 was safe in healthy volunteers. Based on the preclinical resuilts, safety profile and PK characteristics of ZSP1273, the dose of ZSP1273 (≥200 mg) may be used for future clinical trials in influenza patients. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT03679143).

Effect of the Histone Deacetylase Inhibitor FRM-0334 on Progranulin Levels in Patients With Progranulin Gene Haploinsufficiency: A Randomized Clinical Trial.

Importance: Histone deacetylase inhibitors have been repeatedly shown to elevate progranulin levels in preclinical models. This report describes the first randomized clinical trial of a histone deacetylase inhibitor in frontotemporal dementia (FTD) resulting from progranulin (GRN) gene variations. Objective: To characterize the safety, tolerability, plasma pharmacokinetics, and pharmacodynamic effects of oral FRM-0334 on plasma progranulin and other exploratory biomarkers, including fluorodeoxyglucose (FDG)-positron emission tomography (PET), in individuals with GRN haploinsufficiency. Design, Setting, and Participants: In this randomized, double-blind, placebo-controlled, dose-escalating, phase 2a safety, tolerability, and pharmacodynamic clinical study, 2 doses of a histone deacetylase inhibitor (FRM-0334) were administered to participants with prodromal to moderate FTD with granulin variations. Participants were recruited from January 13, 2015, to April 13, 2016. The study included 27 participants with prodromal (n = 8) or mild-to-moderate symptoms of FTD (n = 19) and heterozygous pathogenic variations in GRN and was conducted at multiple centers in North America, the UK, and the European Union. Data were analyzed from June 9, 2019, to May 13, 2021. Interventions: Daily oral placebo (n = 5), 300 mg of FRM-0334 (n = 11), or 500 mg of FRM-0334 (n = 11) was administered for 28 days. Main Outcomes and Measures: Primary outcomes were safety and tolerability of FRM-0334 and its peripheral pharmacodynamic effect on plasma progranulin. Secondary outcomes were the plasma pharmacokinetic profile of FRM-0334 and its pharmacodynamic effect on cerebrospinal fluid progranulin. Exploratory outcomes were FDG-PET, FTD clinical severity, and cerebrospinal fluid biomarkers (neurofilament light chain [NfL], amyloid ß 1-42, phosphorylated tau 181, and total tau [t-tau]). Results: A total of 27 participants (mean [SD] age, 56.6 [10.5] years; 16 women [59.3%]; 26 White participants [96.3%]) with GRN variations were randomized and completed treatment. FRM-0334 was safe and well tolerated but did not affect plasma progranulin (4.3 pg/mL per day change after treatment; 95% CI, -10.1 to 18.8 pg/mL; P = .56), cerebrospinal fluid progranulin (0.42 pg/mL per day; 95% CI, -0.12 to 0.95 pg/mL; P = .13), or exploratory pharmacodynamic measures. Plasma FRM-0334 exposure did not increase proportionally with dose. Brain FDG-PET data were available in 26 of 27 randomized participants. In a cross-sectional analysis of 26 individuals, bifrontal cortical FDG hypometabolism was associated with worse Clinical Dementia Rating (CDR) plus National Alzheimer's Coordinating Center frontotemporal lobar degeneration sum of boxes score (b = -3.6 × 10-2 standardized uptake value ratio [SUVR] units/CDR units; 95% CI, -4.9 × 10-2 to -2.2 × 10-2; P < .001), high cerebrospinal fluid NfL (b = -9.2 × 10-5 SUVR units/pg NfL/mL; 95% CI, -1.3 × 10-4 to -5.6 × 10-5; P < .001), and high CSF t-tau (-7.2 × 10-4 SUVR units/pg t-tau/mL; 95% CI, -1.4 × 10-3 to -9.5 × 10-5; P = .03). Conclusions and Relevance: In this randomized clinical trial, the current formulation of FRM-0334 did not elevate PRGN levels, which could reflect a lack of efficacy at attained exposures, low bioavailability, or some combination of the 2 factors. Bifrontal FDG-PET is a sensitive measure of symptomatic GRN haploinsufficiency. International multicenter clinical trials of FTD-GRN are feasible. Trial Registration: ClinicalTrials.gov Identifier: NCT02149160.

Metal Oxide Nanoparticles: Evidence of Adverse Effects on the Male Reproductive System.

Metal oxide nanoparticles (MONPs) are inorganic materials that have become a valuable tool for many industrial sectors, especially in healthcare, due to their versatility, unique intrinsic properties, and relatively inexpensive production cost. As a consequence of their wide applications, human exposure to MONPs has increased dramatically. More recently, their use has become somehow controversial. On one hand, MONPs can interact with cellular macromolecules, which makes them useful platforms for diagnostic and therapeutic interventions. On the other hand, research suggests that these MONPs can cross the blood-testis barrier and accumulate in the testis. Although it has been demonstrated that some MONPs have protective effects on male germ cells, contradictory reports suggest that these nanoparticles compromise male fertility by interfering with spermatogenesis. In fact, in vitro and in vivo studies indicate that exposure to MONPs could induce the overproduction of reactive oxygen species, resulting in oxidative stress, which is the main suggested molecular mechanism that leads to germ cells' toxicity. The latter results in subsequent damage to proteins, cell membranes, and DNA, which ultimately may lead to the impairment of the male reproductive system. The present manuscript overviews the therapeutic potential of MONPs and their biomedical applications, followed by a critical view of their potential risks in mammalian male fertility, as suggested by recent scientific literature.

A Call for Increased Focus on Reproductive Health within Lab Safety Culture.

The approach to reproductive health and safety in academic laboratories requires increased focus and a shift in paradigm. Our analysis of the current guidance from more than 100 academic institutions' Chemical Hygiene Plans (CHPs) indicates that the burden to implement laboratory reproductive health and safety practices is often placed on those already pregnant or planning conception. We also found inconsistencies in the classification of potential reproductive toxins by resources generally considered to be authoritative, adding further confusion. In the interest of human health and safe laboratory practice, we suggest straightforward changes that institutions and individual laboratories can make to address these present deficiencies: Provide consistent and clear information to laboratory researchers about reproductive health and normalize the discussion of reproductive health among all researchers. Doing so will promote safer and more inclusive laboratory environments.

The relationship between occupational exposure to organic solvents and metabolic syndrome in petroleum refinery workers in Tehran, Iran.

AIMS: The rising prevalence of metabolic syndrome has made it a major health concern. Chronic occupational exposure to organic solvents affects different systems of the body. This study aimed to investigate the association between exposure to organic solvents and the prevalence of metabolic syndrome in petroleum refinery workers. METHOD: This study was conducted in 2019-2020 on workers employed in an Iranian petroleum refinery. The demographic and occupational information on the participants was obtained using the interview method. Their height, weight, and blood pressure were measured by the occupational health team, and fasting blood samples were taken from them to measure the paraclinical parameters. RESULTS: In this study, 1009 petroleum refinery workers were analyzed. The prevalence of metabolic syndrome in workers was 20.1% and it was about two times higher in exposed workers (CI 95%: 1.61-3.35) compared to non-exposed ones. Factors associated with the prevalence of metabolic syndrome include age, higher BMI, exercise, and longer exposure to organic solvents. CONCLUSION: Findings of this study suggested that exposure to organic solvents is associated with increased prevalence of metabolic syndrome (the highest association was observed with elevated serum triglycerides). Besides, longer exposure to organic solvents increased the risk of developing metabolic syndrome.

Mice derived from in vitro αMEM-cultured preimplantation embryos exhibit postprandial hyperglycemia and higher inflammatory gene expression in peripheral leukocytes.

We examined whether peripheral leukocytes of mice derived from in vitro αMEM-cultured embryos and exhibiting type 2 diabetes had higher expression of inflammatory-related genes associated with the development of atherosclerosis. Also, we examined the impact of a barley diet on inflammatory gene expression. Adult mice were produced by embryo transfer, after culturing two-cell embryos for 48 h in either α minimal essential media (α-MEM) or potassium simplex optimized medium control media. Mice were fed either a barley or rice diet for 10 weeks. Postprandial blood glucose and mRNA levels of several inflammatory genes, including Tnfa and Nox2, in blood leukocytes were significantly higher in MEM mice fed a rice diet compared with control mice. Barley intake reduced expression of S100a8 and Nox2. In summary, MEM mice exhibited postprandial hyperglycemia and peripheral leukocytes with higher expression of genes related to the development of atherosclerosis, and barley intake reduced some gene expression.

Efficacy and safety of the novel glycine transporter inhibitor BI 425809 once daily in patients with schizophrenia: a double-blind, randomised, placebo-controlled phase 2 study.

BACKGROUND: Cognitive impairment associated with schizophrenia predicts poor functional outcomes, but currently no approved pharmacotherapy is available. This study investigated whether the glycine transporter-1 inhibitor BI 425809 improves cognition in patients with schizophrenia. METHODS: This phase 2, randomised, double-blind, placebo-controlled, parallel-group trial (81 centres, 11 countries), randomly assigned outpatients (aged 18-50 years) with schizophrenia on stable treatment to add-on once-daily oral BI 425809 2 mg, 5 mg, 10 mg, or 25 mg or placebo (1:1:1:1:2) for 12 weeks. Treatment was assigned in blocks using interactive response technology; patients, investigators, and all trial personnel were masked to group assignment. The primary endpoint was change from baseline in MATRICS Consensus Cognitive Battery (MCCB) overall composite T-score at week 12. Six predefined dose-response models were evaluated using a multiple comparison procedure and modelling approach with mixed model repeated measures to assess evidence for a non-flat dose-response relationship for cognitive improvements with BI 425809. Adverse events were monitored. Safety analyses included all randomly allocated patients who received one or more doses of trial medication; efficacy analyses included patients from this set who also had available baseline data and at least one post-baseline on-treatment measurement for the primary or secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT02832037. FINDINGS: 509 patients were randomly assigned between April 25, 2018, and Oct 4, 2019 (BI 425809 2 mg, n=85; 5 mg, n=84; 10 mg, n=85; 25 mg, n=85; placebo, n=170 444 (87%) completed the 12-week treatment. Five of six dose-response models showed a statistically significant benefit of BI 425809 over placebo (linear [t=2·55, p=0·015], linear in log [t=2·56, p=0·015]; Emax [t=2·75, p=0·0089], sigmoid Emax [t=2·98, p=0·0038], logistic [t=2·77, p=0·0085]). Pairwise comparisons showed greater mean improvement from baseline in MCCB overall composite T-score at week 12 with BI 425809 10 mg and 25 mg versus placebo (adjusted mean difference 1·98 [95% CI 0·43-3·53] for 10 mg and 1·73 [0·18-3·28] for 25 mg; standardised effect size 0·34 for 10 mg and 0·30 for 25 mg). Adverse events were balanced across groups, reported in 50 (59%) of 85 patients on BI 425809 2 mg, 44 (52%) of 84 on 5 mg, 35 (41%) of 85 on 10 mg, 36 (42%) of 85 on 25 mg, and 74 (44%) of 170 on placebo. INTERPRETATION: BI 425809 improved cognition after 12 weeks in patients with schizophrenia; doses of 10 mg and 25 mg showed the largest separation from placebo. If these encouraging results are confirmed in phase 3 trials, BI 425809 could provide an effective treatment for cognitive impairment associated with schizophrenia. FUNDING: Boehringer Ingelheim.

Phase I Study of Lysine-Specific Demethylase 1 Inhibitor, CC-90011, in Patients with Advanced Solid Tumors and Relapsed/Refractory Non-Hodgkin Lymphoma.

PURPOSE: Lysine-specific demethylase 1 (LSD1) is implicated in multiple tumor types, and its expression in cancer stem cells is associated with chemoresistance. CC-90011 is a potent, selective, and reversible oral LSD1 inhibitor. We examined CC-90011 in advanced solid tumors and relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL). PATIENTS AND METHODS: CC-90011-ST-001 (NCT02875223; 2015-005243-13) is a phase I, multicenter, first-in-human dose-escalation study. Nine dose levels of CC-90011 (1.25-120 mg) given once per week were explored. Primary objectives were to determine safety, maximum tolerated dose (MTD), and/or recommended phase II dose (RP2D). Secondary objectives were to evaluate preliminary efficacy and pharmacokinetics. RESULTS: Fifty patients were enrolled, 49 with solid tumors (27 neuroendocrine tumors/carcinomas) and 1 with R/R NHL. Median age was 61 years (range, 22-75). Patients received a median of three (range, 1-9) prior anticancer regimens. The RP2D was 60 mg once per week; the nontolerated dose (NTD) and MTD were 120 mg once per week and 80 mg once per week, respectively. Grade 3/4 treatment-related toxicities were thrombocytopenia (20%; an on-target effect unassociated with clinically significant bleeding), neutropenia (8%; in the context of thrombocytopenia at the highest doses), and fatigue (2%). The patient with R/R NHL had a complete response, currently ongoing in cycle 34, and 8 patients with neuroendocrine tumors/carcinomas had stable disease ≥6 months, including bronchial neuroendocrine tumors, kidney tumor, and paraganglioma. CONCLUSIONS: CC-90011 is well tolerated, with the RP2D established as 60 mg once per week. The MTD and NTD were determined to be 80 mg once per week and 120 mg once per week, respectively. Further evaluation of CC-90011 is warranted.

Integrated In Silico Models for the Prediction of No-Observed-(Adverse)-Effect Levels and Lowest-Observed-(Adverse)-Effect Levels in Rats for Sub-chronic Repeated-Dose Toxicity.

Repeated-dose toxicity (RDT) is a critical endpoint for hazard characterization of chemicals and is assessed to derive safe levels of exposure for human health. Here we present the first attempt to model simultaneously no-observed-(adverse)-effect level (NO(A)EL) and lowest-observed-(adverse)-effect level (LO(A)EL). Classification and regression models were derived based on rat sub-chronic repeated dose toxicity data for 327 compounds from the Fraunhofer RepDose database. Multi-category classification models were built for both NO(A)EL and LO(A)EL though a consensus of statistics- and fragment-based algorithms, while regression models were based on quantitative relationships between the endpoints and SMILES-based attributes. NO(A)EL and LO(A)EL models were integrated, and predictions were compared to exclude inconsistent values. This strategy improved the performance of single models, leading to R2 greater than 0.70, root-mean-square error (RMSE) lower than 0.60 (for regression models), and accuracy of 0.61-0.73 (for classification models) on the validation set, based on the endpoint and the threshold applied for selecting predictions. This study confirms the effectiveness of the modeling strategy presented here for assessing RDT of chemicals using in silico models.

A phase I, randomized, double-blind study to assess the safety, tolerability and efficacy of the topical RORC2 inverse agonist PF-06763809 in participants with mild-to-moderate plaque psoriasis.

BACKGROUND: Transcription factor retinoic acid-related orphan receptor 2 (RORC2/RORγT) mediates interleukin (IL)-17A and IL-17F expression. IL-17A plays a central role in the pathogenesis of several inflammatory disorders, including psoriasis. The RORC2 inhibitor PF-06763809 has been hypothesized to inhibit IL-17A production in T-helper 17 (Th17) cells, thereby reducing psoriasis symptoms. AIM: To assess the safety, tolerability and effect on skin infiltrate thickness of PF-06763809 in participants with mild/moderate chronic plaque psoriasis. METHODS: This was a randomized, double-blind, first-in-human study (trial registration: ClinicalTrials.gov NCT03469336). Participants received each of the following six treatments once daily for 18 days: three topical doses (2.3%, 0.8%, 0.23%) of PF-06763809, a vehicle and two active comparators (betamethasone and calcipotriol). Primary endpoints included change from baseline in psoriatic skin infiltrate thickness [echo-poor band (EPB) on ultrasonography] at Day 19, and safety. Change in psoriasis-associated gene expression (Day 19), evaluated by real-time reverse transcription PCR of skin biopsies, was an exploratory endpoint. RESULTS: In total, 17 participants completed the study. Change from baseline in the EPB on Day 19 for all three doses of PF-06763809 was not significantly different from that of vehicle (P > 0.05). A significant reduction in EPB from baseline was observed with betamethasone on Day 19 relative to all other treatments (P < 0.0001). Treatment-related adverse events were mild/moderate. There were no significant differences in gene expression on Day 19 between vehicle and PF-06763809-treated skin lesions. CONCLUSION: Using a psoriasis plaque test design, PF-06763809 was found to be well tolerated with an acceptable safety profile in participants with psoriasis, but without reduction in skin infiltrate thickness or disease biomarkers.

A first-in-human study to evaluate the safety, tolerability and pharmacokinetics of RP3128, an oral calcium release-activated calcium (CRAC) channel modulator in healthy volunteers.

WHAT IS KNOWN AND OBJECTIVE: RP3128, a novel, orally available modulator of calcium released activated calcium (CRAC) channel, is being developed for the potential treatment of autoimmune and inflammatory diseases. RP3128 showed nano-molar potency and activity in a range of in vitro and in vivo models of inflammation. We report a first-in-human study investigating the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of RP3128 in healthy subjects. METHODS: A randomized, double-blind, placebo-controlled trial of single (25, 50, 100, 200 and 400 mg) and multiple (7 days: 25, 100 and 400 mg once daily) doses of RP3128 were performed. Thirty-two and 24 subjects were randomized in the single ascending dose (SAD) and multiple ascending dose (MAD) parts, respectively. RESULTS AND DISCUSSION: RP3128 was well tolerated, with no dose-limiting toxicity at single and multiple doses. Incidence of treatment emergent adverse events (TEAEs) did not increase with ascending RP3128 doses. No changes were seen in cognitive function and ECG parameters. RP3128 was rapidly absorbed. Elimination was slow with a half-life of more than 80 h. Exposures increased with increasing doses. Accumulation was seen on repeated dosing. PD response, as evidenced by lower plasma levels of tumour necrosis factor-alfa (TNFα) and interleukin-4 (IL-4), was seen when compared to pre-dose values or placebo. WHAT IS NEW AND CONCLUSION: The safety, tolerability and PK/PD profile of RP3128 demonstrates its potential to be developed in inflammatory disorders and support further clinical development (ClinicalTrials.gov number: NCT02958982).

First-in-Human, Double-Blind, Randomized Controlled Trial of an Oral Dose of GnRH Antagonist TU2670 in Healthy Women.

OBJECTIVE: To evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of TU2670, a novel orally active, nonpeptide gonadotropin-releasing hormone (GnRH) antagonist administered to healthy female participants. METHODS: This was a first-in-human, multicenter, phase 1, randomized, double-blind, placebo-controlled, single-dose ascending trial that took place in multiple medical centers. A total of 16 healthy premenopausal women (23 to 45 years of age) were randomized and received 20, 40, 80, and 160 mg TU2670 (GnRH antagonist) or placebo 7 days (±1 day) after the onset of menstrual bleeding. We performed a noncompartmental analysis for pharmacokinetic parameters and calculated relative minimum concentration values (Cmin, % Baseline) of serum pharmacodynamic (PD) markers (luteinizing hormone [LH], follicle-stimulating hormone [FSH], and estradiol). RESULTS: There were no significant differences among treatments with respect to vital signs, electrocardiography, adverse events, ovulation test results, and ultrasonography. The median Tmax of TU2670 occurred 0.75 to 1.00 hours after dosing, and concentrations then declined, with a mean apparent half-life (t1/2) of 3.0 to 5.9 hours. AUClast (17.7-417.9 ng·h/mL) and Cmax (8.1-95.4 ng/mL) increased in a dose-dependent manner. The PD analysis after a single administration of TU2670 revealed dose-dependent suppression of LH, FSH, and estradiol. Maximal suppression of the pre-dose baseline (%) was 58% to 82% at 6 to 8 hours for LH, 28% to 39% at 6 to 12 hours for FSH, and 34% to 82% at 12 to 24 hours for estradiol. CONCLUSION: The single administration of TU2670 in healthy premenopausal women was well tolerated and resulted in the dose-dependent suppression of LH, FSH, and estradiol, suggesting rapid and significant inhibition of pituitary and ovarian hormones.

In Silico Assessment of Acute Oral Toxicity for Mixtures.

While exposure of humans to environmental hazards often occurs with complex chemical mixtures, the majority of existing toxicity data are for single compounds. The Globally Harmonized System of chemical classification (GHS) developed by the Organization for Economic Cooperation and Development uses the additivity formula for acute oral toxicity classification of mixtures, which is based on the acute toxicity estimate of individual ingredients. We evaluated the prediction of GHS category classifications for mixtures using toxicological data collected in the Integrated Chemical Environment (ICE) developed by the National Toxicology Program (United States Department of Health and Human Services). The ICE database contains in vivo acute oral toxicity data for ∼10,000 chemicals and for 582 mixtures with one or multiple active ingredients. By using the available experimental data for individual ingredients, we were able to calculate a GHS category for only half of the mixtures. To expand a set of components with acute oral toxicity data, we used the Collaborative Acute Toxicity Modeling Suite (CATMoS) implemented in the Open Structure-Activity/Property Relationship App to make predictions for active ingredients without available experimental data. As a result, we were able to make predictions for 503 mixtures/formulations with 72% accuracy for the GHS classification. For 186 mixtures with two or more active ingredients, the accuracy rate was 76%. The structure-based analysis of the misclassified mixtures did not reveal any specific structural features associated with the mispredictions. Our results demonstrate that CATMoS together with an additivity formula can be used to predict the GHS category for chemical mixtures.

[Evaluation of drug-drug interactions between yimitasvir phosphate capsules with sofosbuvir tablets, omeprazole magnesium enteric-coated tablets, and rosuvastatin calcium tablets].

Objective: To evaluate the drug-drug interactions and the tolerability of combined medication between yimitasvir phosphate capsules with sofosbuvir tablets, omeprazole magnesium enteric-coated tablets, and rosuvastatin calcium tablets in healthy volunteers. Methods: A randomized, open, and continuous administration design was used in trial 1 (yimitasvir phosphate capsules with sofosbuvir tablets). 28 subjects were randomly divided into two groups. A non-randomized, open design was used in trial 2 (yimitasvir phosphate capsules with omeprazole magnesium enteric-coated tablets), and included 42 subjects divided into three groups. The open design method was used in trial 3 (yimitasvir phosphate capsules with rosuvastatin calcium tablets), and included 14 subjects. The plasma concentrations of yimitasvir phosphate, sofosbuvir and their main metabolites GS-331007, omeprazole and rosuvastatin were validated by a liquid chromatography/tandem mass spectrometry (LC-MS/MS). The pharmacokinetic parameters were calculated by Phoenix winNonlin software. Results: (1) in trial 1, after single and co-administration, the 90% CI of sofosbuvir C(max) and AUC(0-tau) geometric mean ratio (GMR) were 152.0% (118.0% ~ 197.0%) and 230.0% (184.0% ~ 287.0%), with an increase of 52.0% and 130.0% compared to single dose of sofosbuvir, respectively. The 90% CI of GS-331007 C(max) GMR was 74.0% (67.5% ~ 81.2%) and reduced by 26% compared to single dose of sofosbuvir. (2) in trial 2, the 90% CI of C(max) GMR after yimitasvir single or co-administration at the same time, with a 4-hours interval, or with a 12- hours interval were 68.9% (44.5% ~ 106.7%) , 64.0% (43.8% ~ 93.6%) and 56.4%(38.9% ~ 81.9%), and the 90% CI of AUC(0-t) GMR were 68.6% (46.5% ~ 101.2%), 68.3% (47.6% ~ 98.0%) and 60.5% (41.8% ~ 87.5%), respectively. Compared with single dose of yimitasvir, the C(max) and AUC(0-t) were decreased by 31.1% and 31.4%, 36.0% and 31.7%, 43.6% and 39.5%, respectively. (3) In trial 3, after single and co-administration, the 90% CI of rosuvastatin C(max) and AUC(0-72) GMR were 172.4% (153.6% ~ 193.5%) and 158.0% (144.3% ~ 172.9%), respectively, with an increase of 74.9% and 60.5% compared to single dose of rosuvastatin. There were no serious adverse events and adverse events leading to withdrawal from the trial. Conclusion: Yimitasvir phosphate capsules have drug-drug interactions with sofosbuvir tablets, omeprazole magnesium enteric-coated tablets, and rosuvastatin calcium tablets.

All-oral metronomic DEVEC schedule in elderly patients with peripheral T cell lymphoma.

PURPOSE: Peripheral T cell lymphomas (PTCLs) have an overall poor prognosis. Indeed, registry data in elderly patients show that the median progression-free survival (mPFS) following first- and second-line therapies are only 6.7 and 3.1 months, respectively. The aim of the study is to show the activity of metronomic chemotherapy, a regular administration of low chemotherapeutic drug doses allowing a favourable toxicity profile, on elderly PTCL patients. METHODS: We report a series of 17 PTCL patients, treated with the all-oral metronomic schedule DEVEC (prednisolone-etoposide-vinorelbine-cyclophosphamide) in four Italian centres. Patients 5/17 (29.4%) were treatment-naïve (naïve) and 12/17 (70.6%) were relapsed-refractory (RR), respectively. The median age was 83 years (range 71-87) and 71.5 years (range 56-85) for naïve and RR, respectively. In vitro activity of metronomic vinorelbine (VNR), etoposide (ETO) and their concomitant combination on HH, a PTCL cell line, was also assessed. RESULTS: Histology: PTCL-not-otherwise-specified = 12; angioimmunoblastic = 2; NK/T nasal type = 1; adult-type leukaemia lymphoma = 1, transformed Mycosis Fungoides = 1. The overall response rate was 80 and 58% in naïve and RR, respectively; whereas the PFS was 20 in naïve (95% CI 0-43) and 11 months (95% CI 4.2-17.8) in RR. The occurrence of relevant adverse events was 23.5%, which was managed with ETO dose reduction. In vitro experiments showed that both metronomic VNR and ETO caused a significant inhibitory activity on HH cells and a strong synergism when administered concomitantly. CONCLUSION: All-oral DEVEC showed an encouraging activity and acceptable toxicity. This schedule deserves further studies in elderly PTCL also for assessing combinations with targeted drugs.

Pharmacodynamic Activity of the Novel Neurokinin-3 Receptor Antagonist SJX-653 in Healthy Men.

CONTEXT: SJX-653 is a novel neurokinin 3 receptor (NK3R) antagonist. The NK3 pathway is a central regulator of gonadotropin releasing hormone (GnRH) secretion and has also been implicated in the generation of hot flashes. Therefore, decreases of luteinizing hormone (LH) and testosterone in men serve as sensitive pharmacodynamic (PD) markers of central NK3 antagonism. OBJECTIVE: To characterize the safety, tolerability, pharmacokinetics, and pharmacodynamic activity of SJX-653 in healthy men. DESIGN: A randomized, placebo-controlled, double-blind, single ascending dose study. SETTING: Phase 1 unit. PATIENTS OR OTHER PARTICIPANTS: Seven cohorts of 6 healthy men 18-45 years of age (4:2 randomization to SJX-653/placebo per cohort). INTERVENTION(S): Single oral doses of 0.5-90 mg SJX-653. MAIN OUTCOME MEASURE(S): Safety assessments and serial pharmacokinetic (PK)/PD measurements. RESULTS: SJX-653 was well tolerated at all dose levels. Cmax and AUC0-24 increased in a dose-proportional manner. The terminal elimination half-life ranged between 9.8 and 12.5 hours independent of dose. A statistically significant, dose-dependent, reversible reduction of LH and testosterone was observed with near maximal effect after 15 mg and little to no effect at 4.5 mg. Maximal LH reduction was 70 ±â€…7% (mean ±â€…sd) at 6 hours after 30 mg SJX-653 versus 10 ±â€…43% for placebo (P = 0.0006); maximal T reduction was of 68 ±â€…5% at 8 hours after 60 mg SJX-653 versus 18 ±â€…11% for placebo (P < 0.0001). The plasma IC50 for LH reduction was 33 ng/mL. CONCLUSIONS: These data demonstrate clinical proof-of-mechanism for SJX-653 as a potent centrally-acting NK3R antagonist.

Microglia depletion exacerbates demyelination and impairs remyelination in a neurotropic coronavirus infection.

Microglia are considered both pathogenic and protective during recovery from demyelination, but their precise role remains ill defined. Here, using an inhibitor of colony stimulating factor 1 receptor (CSF1R), PLX5622, and mice infected with a neurotropic coronavirus (mouse hepatitis virus [MHV], strain JHMV), we show that depletion of microglia during the time of JHMV clearance resulted in impaired myelin repair and prolonged clinical disease without affecting the kinetics of virus clearance. Microglia were required only during the early stages of remyelination. Notably, large deposits of extracellular vesiculated myelin and cellular debris were detected in the spinal cords of PLX5622-treated and not control mice, which correlated with decreased numbers of oligodendrocytes in demyelinating lesions in drug-treated mice. Furthermore, gene expression analyses demonstrated differential expression of genes involved in myelin debris clearance, lipid and cholesterol recycling, and promotion of oligodendrocyte function. The results also demonstrate that microglial functions affected by depletion could not be compensated by infiltrating macrophages. Together, these results demonstrate that microglia play key roles in debris clearance and in the initiation of remyelination following infection with a neurotropic coronavirus but are not necessary during later stages of remyelination.

Microfiber release from real soiled consumer laundry and the impact of fabric care products and washing conditions.

Fiber release during domestic textile washing is a cause of marine microplastic pollution, but better understanding of the magnitude of the issue and role of fabric care products, appliances and washing cycles is needed. Soiled consumer wash loads from U.K. households were found to release a mean of 114 ± 66.8 ppm (mg microfiber per kg fabric) (n = 79) fibers during typical washing conditions and these were mainly composed of natural fibers. Microfiber release decreased with increasing wash load size and hence decreasing water to fabric ratio, with mean microfiber release from wash loads in the mass range 1.0-3.5 kg (n = 57) found to be 132.4 ± 68.6 ppm, significantly (p = 3.3 x 10-8) higher than the 66.3 ± 27.0 ppm of those in the 3.5-6.0 kg range (n = 22). In further tests with similar soiled consumer wash loads, moving to colder and quicker washing cycles (i.e. 15°C for 30 mins, as opposed to 40°C for 85 mins) significantly reduced microfiber generation by 30% (p = 0.036) and reduced whiteness loss by 42% (p = 0.000) through reduced dye transfer and soil re-deposition, compared to conventional 40°C cycles. In multicycle technical testing, detergent pods were selected for investigation and found to have no impact on microfiber release compared to washing in water alone. Fabric softeners were also found to have no direct impact on microfiber release in testing under both European and North American washing conditions. Extended testing of polyester fleece garments up to a 48-wash cycle history under European conditions found that microfiber release significantly reduced to a consistent low level of 28.7 ± 10.9 ppm from eight through 64 washes. Emerging North American High-Efficiency top-loading washing machines generated significantly lower microfiber release than traditional top-loading machines, likely due to their lower water fill volumes and hence lower water to fabric ratio, with a 69.7% reduction observed for polyester fleece (n = 32, p = 7.9 x 10-6) and 37.4% reduction for polyester T-shirt (n = 32, p = 0.0032). These results conclude that consumers can directly reduce the levels of microfibers generated per wash during domestic textile washing by using colder and quicker wash cycles, washing complete (but not overfilled) loads, and (in North America) converting to High-Efficiency washing machines. Moving to colder and quicker cycles will also indirectly reduce microfiber release by extending the lifetime of clothing, leading to fewer new garments being purchased and hence lower incidence of the high microfiber release occurring during the first few washes of a new item.

Combination of the phosphodiesterase 10A inhibitor, MR1916 with risperidone shows additive antipsychotic-like effects without affecting cognitive enhancement and cataleptic effects in rats.

AIM: Phosphodiesterase 10A (PDE10A) inhibitors not only have antipsychotic-like effects but also cause cognitive enhancement without affecting extrapyramidal side effects in rodents, suggesting that PDE10A may be a novel approach for the treatment of schizophrenia. However, how a combination of PDE10A inhibitor with a currently available antipsychotic drug, risperidone contributes to the effect of each compound in rats remains unclear. The purpose of the present study was to examine the combination effects of MR1916 with a currently available antipsychotic drug, risperidone, in rats. METHODS: We examined the combination effects of the PDE10A inhibitor, MR1916 with risperidone on conditioned avoidance response (CAR) to assess antipsychotic-like effects in rats. We also examined them on catalepsy as extrapyramidal side effects and novel object recognition test in cognitive functions in rats. RESULTS: MR1916 (0.025-0.2 mg/kg, p.o.) and risperidone (0.75-6 mg/kg, p.o.) alone attenuated the CAR in a dose-dependent manner. The combination of MR1916 (0.025 mg/kg, p.o.) with risperidone (0.75 mg/kg, p.o.) significantly enhanced the attenuation of CAR without increasing the escape failure response. At the same dosage, the cataleptic effects were not enhanced by combined treatment of MR1916 with risperidone. Furthermore, the enhancement of object recognition memory induced by MR1916 (0.3 mg/kg, p.o.) was not affected by the combination with risperidone (0.75 mg/kg, p.o.). CONCLUSION: The combination of MR1916 with risperidone may have additive antipsychotic-like effects without affecting extrapyramidal side effects, and the cognitive-enhancing effect of MR1916 may not be interfered with the addition of risperidone.

JNJ-56136379, an HBV Capsid Assembly Modulator, Is Well-Tolerated and Has Antiviral Activity in a Phase 1 Study of Patients With Chronic Infection.

BACKGROUND & AIMS: JNJ-56136379 (JNJ-6379), a capsid assembly modulator that blocks hepatitis B virus (HBV) replication, was well tolerated and demonstrated dose-proportional pharmacokinetics in healthy participants in part 1 of its first clinical trial. In part 2, we have evaluated the safety, pharmacokinetics, and antiviral activity of multiple doses of JNJ-6379 in patients with chronic HBV infection. METHODS: We performed a double-blind study of 57 treatment-naïve patients with HB e antigen-positive or -negative (74%) chronic HBV infection without cirrhosis. Patients were randomly assigned to groups given JNJ-6379 at 25 mg (100 mg loading dose), 75 mg, 150 mg, or 250 mg or placebo daily for 4 weeks with an 8-week follow-up period. RESULTS: Twenty-three (56%) of 41 patients given JNJ-6379 had at least 1 adverse event (AE) during treatment, compared with 10 (63%) of 16 patients given placebo. No serious AEs were reported during the treatment period. Three patients (7%) given JNJ-6379 vs none given placebo had grade 3 AEs; of these, 1 patient (150 mg) also had an isolated grade 4 increase in the level of alanine aminotransferase that led to treatment discontinuation. JNJ-6379 exposure increased with dose, with time-linear pharmacokinetics. HBV-DNA and HBV-RNA decreased from baseline in patients receiving all doses of JNJ-6379, independently of viral genotype and HB e antigen status. On day 29, 13 (32%) of 41 patients had levels of HBV DNA below the lower limit of quantification. No clinically significant changes in levels of HB surface antigen were observed. CONCLUSIONS: In a phase 1 study of treatment-naïve patients with chronic HBV infection, all doses tested of JNJ-6379 were well tolerated, showed dose-dependent pharmacokinetics, and had potent antiviral activity in patients with CHB. The findings support a phase 2a study to evaluate JNJ-6379 ± nucleos(t)ide analogs in patients with chronic HBV infection, which is under way. ClinicalTrials.gov identifier: NCT02662712.