A phase Ib study evaluating the recommended phase II dose, safety, tolerability, and efficacy of mivavotinib in combination with nivolumab in advanced solid tumors.

Mivavotinib (TAK-659/CB-659), a dual SYK/FLT3 inhibitor, reduced immunosuppressive immune cell populations and suppressed tumor growth in combination with anti-PD-1 therapy in cancer models. This dose-escalation/expansion study investigated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of mivavotinib plus nivolumab in patients with advanced solid tumors. Patients received oral mivavotinib 60-100 mg once-daily plus intravenous nivolumab 3 mg/kg on days 1 and 15 in 28-day cycles until disease progression or unacceptable toxicity. The dose-escalation phase evaluated the recommended phase II dose (RP2D; primary endpoint). The expansion phase evaluated overall response rate (primary end point) at the RP2D in patients with triple-negative breast cancer (TNBC). During dose-escalation (n = 24), two dose-limiting toxicities (grade 4 lipase increased and grade 3 pyrexia) occurred in patients who received mivavotinib 80 mg and 100 mg, respectively. The determined RP2D was once-daily mivavotinib 80 mg plus nivolumab 3 mg/kg. The expansion phase was terminated at ~50% enrollment (n = 17) after failing to meet an ad hoc efficacy futility threshold. Among all 41 patients, common treatment-emergent adverse events (TEAEs) included dyspnea (48.8%), aspartate aminotransferase increased, and pyrexia (46.3% each). Common grade ≥3 TEAEs were hypophosphatemia and anemia (26.8% each). Mivavotinib plasma exposure was generally dose-proportional (60-100 mg). One patient had a partial response. Mivavotinib 80 mg plus nivolumab 3 mg/kg was well tolerated with no new safety signals beyond those of single-agent mivavotinib or nivolumab. Low response rates highlight the challenges of treating unresponsive tumor types, such as TNBC, with this combination and immunotherapies in general. TRIAL REGISTRATION ID: NCT02834247.

Origin and stability of pit lake water in Baiyinhua, Inner Mongolia, based on hydrochemistry and stable isotopes.

Isotope technology is widely used in geochemical mechanisms analysis; however, studies on the origin of pit lake water by isotopes in coal concentration areas in grassland are rare. In this study, 20 groups of water samples were collected, which were subjected to chemical analysis to determine the hydrogeochemical characteristics of pit lake water. The mechanisms of pit lake water formation and recharge-evaporation were ascertained through principal component analysis and the Rayleigh fractionation model. The results indicate that the phreatic water is least affected by evaporation, followed by confined water, surface water and pit lake water. The ionic composition of surface water, phreatic water and most of the confined water is mainly affected by leaching, some confined water can be recharged by surface or phreatic water; while the ionic composition of pit lake water is dominantly affected by evaporation (69.4 %) and is less affected by groundwater recharge (17.1 %) and human activities (11.5 %). The pit lake water is recharged by precipitation, phreatic water and the lateral runoff of confined water; however, the proportion of phreatic and confined water recharge is small. The evaporative loss of the pit lake water is 40-61 % of the initial water body.

Clinical Characterization of [18F]T-008, a Cholesterol 24-Hydroxylase PET Ligand: Dosimetry, Kinetic Modeling, Variability, and Soticlestat Occupancy.

This series of studies characterized [18F]T-008, a PET radiotracer for imaging cholesterol 24-hydroxylase (CH24H), in healthy volunteers (ClinicalTrials.gov identifier NCT02497235). Assessments included radiation dosimetry, kinetic modeling, test-retest variability (TRT) evaluation, and a dose occupancy evaluation using soticlestat, a selective CH24H inhibitor. Soticlestat is currently in phase 3 development for the treatment of seizures in Dravet syndrome and Lennox-Gastaut syndrome. Methods: In the dosimetry study, 5 participants (3 men) underwent serial whole-body scans to estimate organ-absorbed doses and effective doses of [18F]T-008 using OLINDA/EXM 1.1. For the kinetic modeling and TRT study, 6 participants (all men) underwent two 210-min dynamic [18F]T-008 PET scans with arterial blood sampling. The regional total volume of distribution was estimated using a 1-tissue-compartment model, a 2-tissue-compartment model, and Logan graphic analysis. In the dose occupancy study, 11 participants (all men) underwent 120-min scans at baseline and 2 time points (peak and trough) after receiving single oral doses of soticlestat (50-600 mg). The relationship between effect-site soticlestat concentration and brain occupancy was evaluated with a specially developed pharmacokinetic model and a saturable maximal occupancy model. Results: The estimated mean whole-body effective dose was 0.0292 mSv/MBq (SD, 0.00147 mSv/MBq). [18F]T-008 entered the brain rapidly, with a distribution consistent with known CH24H distribution densities. The 2-tissue-compartment model and Logan graphic analysis best described the tracer kinetics. The mean TRT for estimating total volume of distribution was 7%-15%. Single doses of soticlestat in the range 50-600 mg resulted in occupancies of 64%-96% at 2 h and 11%-79% at 24 h. The estimated half-maximal effect-site concentration of soticlestat was 5.52 ng/mL. Conclusion: [18F]T-008 is a suitable PET radiotracer for quantitatively analyzing CH24H in the human brain. Using [18F]T-008 and PET, we demonstrated that soticlestat was brain-penetrant and established target engagement by displacing [18F]T-008 in a dose-dependent manner in the brain.

The correlation between Th17/Treg immune dysregulation and the disease severity in chronic spontaneous urticaria patients.

OBJECTIVE: Chronic spontaneous urticaria (CSU) has a profound impact on the sleep quality, productivity and overall quality of life of affected individuals. This study aimed to investigate the correlation between serum Th17/Treg immune dysregulation and the severity of CSU in patients. METHODS: Clinical baseline data of 120 CSU patients and matched healthy controls were recorded. The pruritus level, disease severity, and quality of life of CSU patients were assessed using the visual analogue scale, weekly Urticaria Activity Score and chronic urticaria quality of life questionnaire, respectively. The Th17/Treg cell ratio was detected by flow cytometry. ELISA was used to measure the levels of serum Th17 cytokines (IL-17, IL-21) and Treg cytokines (TGF-ß1, IL-35). Pearson's correlation analysis was conducted to examine the associations between these indicators. RESULTS: No significant differences were identified in terms of sex, age, and BMI between the two groups. However, CSU patients exhibited a significant increase in the Th17 cell ratio, as well as the elevated serum levels of TGF-ß1, IL-17 and, IL-21. Conversely, the proportion of Treg cells and the levels of IL-35 were remarkably decreased in CSU patients. Peripheral blood Th17 cells were negatively correlated with Treg cells. The severity of pruritus, life quality, and disease severity in CSU patients were positively correlated to Th17 cell ratio, and inversely correlated with Treg cell proportion. CONCLUSIONS: A positive correlation was found between the percentage of peripheral blood Th17 cell in CSU patients and the pruritus level, life quality, and disease severity. In constrast, there was a negative correlation between the proportion of peripheral blood Treg cells and these clinical parameters.

A phase I, first-in-human study of TAK-164, an antibody-drug conjugate, in patients with advanced gastrointestinal cancers expressing guanylyl cyclase C.

PURPOSE: Guanylyl cyclase C (GCC) is highly expressed in several gastrointestinal malignancies and preclinical studies suggest that it is a promising target for antibody-based therapeutics. This phase I trial assessed the safety and tolerability of TAK-164, an investigational, anti-GCC antibody-drug conjugate (NCT03449030). METHODS: Thirty-one patients with GCC-positive, advanced gastrointestinal cancers received intravenous TAK-164 on day 1 of 21-day cycles. Dose escalation proceeded based on cycle 1 safety data via a Bayesian model. RESULTS: Median age was 58 years (range 32-72), 25 patients (80.6%) had colorectal carcinoma, and median number of prior therapies was four. No dose-limiting toxicities (DLTs) were reported during cycle 1 DLT evaluation period. After cycle 2 dosing, 3 patients reported dose-limiting treatment-emergent adverse events (TEAEs): grade 3 pyrexia and grade 5 hepatic failure (0.19 mg/kg), grade 4 hepatic failure and platelet count decreased (0.25 mg/kg), grade 3 nausea, grade 4 platelet and neutrophil count decreased (0.25 mg/kg). The recommended phase II dose (RP2D) was 0.064 mg/kg. Common TAK-164-related TEAEs included platelet count decreased (58.1%), fatigue (38.7%), and anemia (32.3%). There was a dose-dependent increase in TAK-164 exposure over the range, 0.032-0.25 mg/kg. TAK-164 half-life ranged from 63.5 to 159 h. One patient (0.008 mg/kg) with high baseline GCC expression had an unconfirmed partial response. CONCLUSIONS: TAK-164 appeared to have a manageable safety profile at 0.064 mg/kg. Hepatic toxicity was identified as a potential risk. The RP2D of 0.064 mg/kg was considered insufficient to derive clinical benefit; there are no plans for further clinical development. CLINICAL TRIAL REGISTRATION: NCT03449030.

Spleen tyrosine kinase/FMS-like tyrosine kinase-3 inhibition in relapsed/refractory B-cell lymphoma, including diffuse large B-cell lymphoma: updated data with mivavotinib (TAK-659/CB-659).

We report an updated analysis from a phase I study of the spleen tyrosine kinase (SYK) and FMS-like tyrosine kinase 3 inhibitor mivavotinib, presenting data for the overall cohort of lymphoma patients, and the subgroup of patients with diffuse large B-cell lymphoma (DLBCL; including an expanded cohort not included in the initial report). Patients with relapsed/refractory lymphoma for which no standard treatment was available received mivavotinib 60-120 mg once daily in 28-day cycles until disease progression/unacceptable toxicity. A total of 124 patients with lymphoma, including 89 with DLBCL, were enrolled. Overall response rates (ORR) in response-evaluable patients were 45% (43/95) and 38% (26/69), respectively. Median duration of response was 28.1 months overall and not reached in DLBCL responders. In subgroups with DLBCL of germinal center B-cell (GCB) and non-GCB origin, ORR was 28% (11/40) and 58% (7/12), respectively. Median progression free survival was 2.0 and 1.6 months in the lymphoma and DLBCL cohorts, respectively. Grade ≥3 treatment-emergent adverse events occurred in 96% of all lymphoma patients, many of which were limited to asymptomatic laboratory abnormalities; the most common were increased amylase (29%), neutropenia (27%), and hypophosphatemia (26%). These findings support SYK as a potential therapeutic target for the treatment of patients with B-cell lymphomas, including DLBCL. Trial registration: ClinicalTrials.gov number: NCT02000934.

Population Pharmacokinetics of Mivavotinib (TAK-659), a Dual Spleen Tyrosine Kinase and FMS-Like Tyrosine Kinase 3 Inhibitor, in Patients With Advanced Solid Tumors or Hematologic Malignancies.

Mivavotinib (TAK-659), an orally administered, small-molecule, dual inhibitor of spleen tyrosine kinase and FMS-like tyrosine kinase 3 (SYK/FLT3), is under development for the treatment of patients with advanced malignancies. In this analysis, we evaluated the population pharmacokinetics (PK) of mivavotinib and its sources of variability (covariates) in adult patients with advanced solid tumors, or relapsed/refractory B-cell lymphomas or acute myeloid leukemia, using pooled data from 159 patients enrolled in 2 phase 1/2 clinical studies. A 2-compartment model with first-order linear elimination and a first-order absorption rate (and associated lag time) adequately described the PK of mivavotinib in this patient population. The population estimates of apparent clearance (CL/F) and apparent central compartment volume (Vc /F) were 31.6 L/h and 893 L, respectively, resulting in a half-life of ≈20 hours. In the final model, creatinine clearance was included as a covariate of CL/F, and sex as a covariate of Vc /F. Simulations showed that steady-state exposure to mivavotinib increased with decreasing renal function. Expanding eligibility by enrolling patients with moderate renal impairment in phase 1 increased the diversity of patients in early trials and allowed the model to inform dose adjustment in patients with moderate renal impairment in future trials. In addition, simulations showed median steady-state trough concentration of mivavotinib following 70 mg twice daily and 160 mg daily dosing to be commensurate with 100 ng/mL, the level leading to >90% FLT3 inhibition per ex vivo plasma immune assays and considered a potential exposure threshold required for FLT3-driven efficacy.

A phase Ib trial of mivavotinib (TAK-659), a dual SYK/FLT3 inhibitor, in patients with relapsed/refractory acute myeloid leukemia.

Mivavotinib (TAK-659) is an investigational type 1 tyrosine kinase inhibitor with dual activity against spleen tyrosine kinase (SYK) and FMS-like tyrosine kinase 3 (FLT3). We conducted a phase Ib study to investigate the safety, tolerability, and efficacy of mivavotinib in patients with refractory and/or relapsed (R/R) acute myeloid leukemia (AML). Both daily (QD) and twice daily (BID) dosing regimens were evaluated. A total of 43 patients were enrolled, and there were 5 complete responses (4 with incomplete count recovery). In the QD dosing regimen, the maximum tolerated dose (MTD) was not reached up to 160 mg QD per protocol; 140 mg QD was identified as the recommended phase II dose. In the BID dosing regimen, the MTD was 60 mg BID. Thirty patients (70%) experienced a bleeding event on study; the majority were grades 1 or 2, were resolved without mivavotinib modification, and were not considered related to study treatment. Eleven patients (26%) experienced grade ≥3 bleeding events, which were observed most frequently with the 80 mg BID dose. We conducted platelet aggregation studies to investigate the potential role of mivavotinib-mediated SYK inhibition on platelet function. The bleeding events observed may have been the result of several confounding factors, including AML disease status, associated thrombocytopenia, and high doses of mivavotinib. Overall, these findings indicate that the activity of mivavotinib in R/R AML is modest. Furthermore, any future clinical investigation of this agent should be undertaken with caution, particularly in thrombocytopenic patients, due to the potential bleeding risk of SYK inhibition. ClinicalTrials.gov: NCT02323113.

The Role of Aldose Reductase in Beta-Amyloid-Induced Microglia Activation.

The occurrence of Alzheimer's disease has been associated with the accumulation of beta-amyloid (ß-amyloid) plaques. These plaques activate microglia to secrete inflammatory molecules, which damage neurons in the brain. Thus, understanding the underlying mechanism of microglia activation can provide a therapeutic strategy for alleviating microglia-induced neuroinflammation. The aldose reductase (AR) enzyme catalyzes the reduction of glucose to sorbitol in the polyol pathway. In addition to mediating diabetic complications in hyperglycemic environments, AR also helps regulate inflammation in microglia. However, little is known about the role of AR in ß-amyloid-induced inflammation in microglia and subsequent neuronal death. In this study, we confirmed that AR inhibition attenuates increased ß-amyloid-induced reactive oxygen species and tumor necrosis factor α secretion by suppressing ERK signaling in BV2 cells. In addition, we are the first to report that AR inhibition reduced the phagocytotic capability and cell migration of BV2 cells in response to ß-amyloid. To further investigate the protective role of the AR inhibitor sorbinil in neurons, we co-cultured ß-amyloid-induced microglia with stem cell-induced neurons. sorbinil ameliorated neuronal damage in both cells in the co-culture system. In summary, our findings reveal AR regulation of microglia activation as a novel therapeutic target for Alzheimer's disease.

Experimental and Simulation Studies of the Adsorption of Methylbenzene by Fe(III)-Doped NU-1000 (Zr).

Metal-organic framework (MOF) materials, NU-1000(Zr) and Fe(III)-doped NU-1000(Zr), were prepared through the hydrothermal method and used to remove methylbenzene in this work. The pore structure, crystal structure, adsorption capacity, adsorption heat, and adsorption density of Fe(III)-doped NU-1000(Zr) were analyzed based on the experimental and Giant Canonical Monte Carlo (GCMC) simulation methods. The results show that Fe3+ has a uniform distribution and a stable structure after NU-1000(Zr) was modified with Fe3+. The adsorption-penetration experiments of NU-1000 doped with different concentrations of Fe3+ have shown that the adsorption capacity of methylbenzene on the material surface is up to 231 mg g-1 at Fe/Zr = 0.1, which is due to the less doping of Fe elements and more defective sites in the structure. The GCMC simulation shows that NU-1000(Zr) and Fe(III)-NU-1000(Zr) adsorbed methylbenzene through π-π interaction, and the adsorption effect is good and close to the experimental result. The conclusions of this paper provide important support for the modification of MOF materials and the removal of methylbenzene.

A Longitudinal Nine-Year Study of the Molecular Epidemiology of Carbapenemase-Producing Enterobacterales Isolated From a Regional Hospital in Taiwan: Predominance of Carbapenemase KPC-2 and OXA-48.

Enterobacterales clinical isolates are now being resistant to clinically achievable concentrations of most commonly used antibiotics that makes treatment of hospitalized patients very challenging. We hereby determine the molecular characteristics of carbapenemase genes in carbapenem-resistant Enterobacterales (CRE) isolates in Taiwan. A total of 455 CRE isolates were identified between August 2011 to July 2020. Minimum inhibitory concentrations for selected carbapenems were tested using Vitek 2, and carbapenemase genes were determined using polymerase chain reaction in combination with sequencing. Phenotypic detection of carbapenemase was determined by modified carbapenem inactivation method (mCIM) and EDTA-modified carbapenem inactivation method (eCIM) to validate our PCR screening results. Pulsed-field gel electrophoresis (PFGE) was used to determine the clonality of carbapenemase-producing Enterobacterales (CPE) isolates, and the transferability of carbapenemase-carrying plasmids was determined by conjugation assays. A slight increase in carbapenem-resistant E. coli (CREC) was observed, however, the prevalence of carbapenem-resistant K. pneumoniae (CRKP) was steady, during 2011-2020. The dominant species among our CRE was K. pneumoniae (270/455, 59.3%), followed by E. coli (81/455, 17.8%), Morganella morganii (32/455, 7.0%), and Enterobacter cloacae (25/455, 5.5%). From 2011 to 2020, the total percentage of CPE increased steadily, accounting for 61.0% of CRE in 2020. Moreover, 122 of 455 CRE isolates (26.8%) were CPE. Among the CPE isolates, the dominant carbapenemase gene was bla OXA-48-like (54/122, 44.3%), and the second most common carbapenemase gene was bla KPC-2 (47/122, 38.5%). The sensitivity and specificity for mCIM to detect carbapenemase in the 455 isolates were both 100% in this study. The PFGE results showed that 39 carbapenemase-producing E. coli and 69 carbapenemase-producing K. pneumoniae isolates carrying bla KPC-2 and/or bla NDM-5 could be classified into 5 and 12 clusters, respectively. In conclusion, our results showed an increase in CPE isolates in Taiwan. Moreover, the distribution of carbapenemase and antimicrobial susceptibility in CPE were associated with PFGE typing.

Adapt-Kcr: a novel deep learning framework for accurate prediction of lysine crotonylation sites based on learning embedding features and attention architecture.

Protein lysine crotonylation (Kcr) is an important type of posttranslational modification that is associated with a wide range of biological processes. The identification of Kcr sites is critical to better understanding their functional mechanisms. However, the existing experimental techniques for detecting Kcr sites are cost-ineffective, to a great need for new computational methods to address this problem. We here describe Adapt-Kcr, an advanced deep learning model that utilizes adaptive embedding and is based on a convolutional neural network together with a bidirectional long short-term memory network and attention architecture. On the independent testing set, Adapt-Kcr outperformed the current state-of-the-art Kcr prediction model, with an improvement of 3.2% in accuracy and 1.9% in the area under the receiver operating characteristic curve. Compared to other Kcr models, Adapt-Kcr additionally had a more robust ability to distinguish between crotonylation and other lysine modifications. Another model (Adapt-ST) was trained to predict phosphorylation sites in SARS-CoV-2, and outperformed the equivalent state-of-the-art phosphorylation site prediction model. These results indicate that self-adaptive embedding features perform better than handcrafted features in capturing discriminative information; when used in attention architecture, this could be an effective way of identifying protein Kcr sites. Together, our Adapt framework (including learning embedding features and attention architecture) has a strong potential for prediction of other protein posttranslational modification sites.

Population pharmacokinetic and exposure-response analyses from ALTA-1L: Model-based analyses supporting the brigatinib dose in ALK-positive NSCLC.

The ALK in Lung Cancer Trial of brigAtinib in First Line (ALTA-1L) compared brigatinib versus crizotinib in anaplastic lymphoma kinase (ALK) inhibitor-naive patients with ALK+ non-small cell lung cancer (NSCLC). A population pharmacokinetic (PK) model was used to estimate brigatinib exposures for exposure-efficacy and exposure-safety analyses in ALTA-1L. A previously developed population PK model for brigatinib was applied to estimate brigatinib PK parameters. Relationships between static (time-independent) and dynamic (time-varying) exposure metrics and efficacy (progression-free survival [PFS], objective response rate [ORR], and intracranial ORR [iORR]) and safety outcomes (selected grade ≥2 and grade ≥3 adverse events [AEs]) were evaluated using logistic regression and time-to-event analyses. There were no meaningful differences in brigatinib PK in the first-line and second-line settings, supporting use of the previous population PK model for the first-line population. Exposure-response analyses showed no significant effect of time-varying brigatinib exposure on PFS. Brigatinib exposure was not significantly related to ORR, but higher exposure was associated with higher iORR (odds ratio: 1.13, 95% confidence interval: 1.01-1.28, p = 0.049). Across the observed median exposure (5th-95th percentile) at steady state for 180 mg once daily, the predicted probability of iORR was 0.83 (0.58-0.99). AEs significantly associated with higher exposure were elevated lipase (grade ≥3) and amylase (grade ≥2). Time to first brigatinib dose reduction was not related to exposure. These results support the benefit-risk profile of first-line brigatinib 180 mg once daily (7-day lead-in dose at 90 mg once daily) in patients with ALK+ NSCLC.

Pharmacokinetics, pharmacodynamics and safety assessment of multiple doses of soticlestat in healthy volunteers.

AIMS: Soticlestat, a first-in-class inhibitor of cholesterol 24-hydroxylase (also known as cytochrome P450 46A1), is currently in development for the treatment of developmental and epileptic encephalopathies. Here, we report safety, tolerability, pharmacokinetic and pharmacodynamic outcomes from a phase I, randomized, double-blind, placebo-controlled, multiple-rising-dose study of soticlestat in healthy adults. METHODS: Five cohorts of healthy subjects (n = 8 each, randomized 6:2 soticlestat:placebo) received oral soticlestat 100-600 mg once daily (QD) or 300 mg twice daily (BID) for 10-14 days. Serial blood and urine samples were obtained on days 1, 7 (blood only) and 14. RESULTS: Soticlestat in the dose range 100-400 mg/day for up to 14 days was generally well tolerated. In total, 45 treatment-emergent adverse events (TEAEs) were reported; most (91%) were transient and mild in intensity. Two subjects experienced TEAEs leading to discontinuation: one receiving soticlestat 600 mg QD reported a severe event of acute psychosis; another receiving 300 mg BID reported a mild event of confusional state. Steady-state exposure to soticlestat increased in a slightly greater than dose-proportional manner across the dose range 100-400 mg QD. Peak plasma concentrations were reached within 0.33-0.5 hour, and soticlestat elimination half-life was approximately 4 hours. Renal excretion of soticlestat was negligible. Soticlestat 100-400 mg QD reduced 24S-hydroxycholesterol levels by 46.8 (coefficient of variation [CV%] -9.2) to -62.7% (CV% -7.3) at steady state; values of enzymatic inhibition were compatible with antiepileptic effects observed in preclinical models. CONCLUSION: The pharmacokinetic and pharmacodynamic profiles of soticlestat characterized here provided a data-driven rationale for clinical trial dose selection.

Distinct Characteristics of Escherichia coli Isolated from Patients with Urinary Tract Infections in a Medical Center at a Ten-Year Interval.

Escherichia coli causing urinary tract infections (UTIs) are one of the most common outpatient bacterial infections. This study aimed to compare the characteristics of E. coli isolated from UTI patients in a single medical center in 2009-2010 (n = 504) and 2020 (n = 340). The antimicrobial susceptibility of E. coli was determined by the disk diffusion method. PCRs were conducted to detect phylogenetic groups, ST131, K1 capsule antigen, and 15 virulence factors. Phylogenetic group B2 dominated in our 2009-2010 and 2020 isolates. Moreover, no phylogenetic group E strains were isolated in 2020. E. coli isolates in 2020 were more susceptible to amoxicillin, ampicillin/sulbactam, cefuroxime, cefmetazole, ceftazidime, cefoxitin, tetracycline, and sulfamethoxazole/trimethoprim, compared to the isolates in 2009-2010. Extensively drug-resistant (XDR)-E. coli in 2009-2010 were detected in groups B1 (5 isolates), B2 (12 isolates), F (8 isolates), and unknown (1 isolate). In 2020, XDR-E. coli were only detected in groups A (2 isolates), B2 (5 isolates), D (1 isolate), and F (4 isolates). The prevalence of virulence factor genes aer and fimH were higher in E. coli in 2009-2010 compared to those in 2020. In contrast, afa and sat showed higher frequencies in E. coli isolates in 2020 compared to E. coli in 2009-2010.

Safety, tolerability, pharmacokinetics, pharmacodynamics, bioavailability and food effect of single doses of soticlestat in healthy subjects.

AIMS: Soticlestat is a first-in-class selective inhibitor of cholesterol 24-hydroxylase, the enzyme that converts brain cholesterol to 24S-hydroxycholesterol (24HC), a positive allosteric modulator of N-methyl-D-aspartate receptors. Soticlestat is under development as treatment for rare developmental and epileptic encephalopathies. METHODS: In this first-in-human study, 48 healthy men and women received single ascending doses of soticlestat oral solution or placebo. Subsequently, nine healthy subjects received soticlestat tablets under fed and fasting conditions to assess the relative oral bioavailability and effects of food. Serial blood and urine samples were collected for pharmacokinetic and pharmacodynamic assessments. RESULTS: Soticlestat appeared to be well tolerated up to a single dose of 1350 mg. Adverse events (AEs) were mild in intensity, and dose-dependent increase in AE prevalence was not apparent. Soticlestat administered via oral solution was rapidly absorbed (median time to maximum plasma concentration [Cmax ] 0.250-0.520 h). Mean Cmax and area under plasma concentration-time curve from zero to infinity increased by 183- and 581-fold, respectively, over a 90-fold dose increase. Mean terminal elimination half-life was 0.820-7.16 hours across doses. Renal excretion was negligible. Administration of soticlestat tablets, and with food, lowered Cmax but did not affect overall exposure. Plasma 24HC concentrations generally decreased with increasing dose. CONCLUSIONS: Soticlestat appeared to be well tolerated after a single oral administration of up to 1350 mg and dose-dependently reduced plasma 24HC concentrations. Systemic exposure increased in a greater than dose-proportional manner over the dose range evaluated but was not affected by formulation or administration with food.

Combination of modified carbapenem inactivation method (mCIM) and EDTA-CIM (eCIM) for phenotypic detection of carbapenemase-producing Enterobacteriaceae.

BACKGROUND: Carbapenemase-resistant Enterobacteriaceae (CRE) cause many serious infections resulting in increasing treatment cost, prolonged hospitalization, and mortality rate. Reduced expression and/or mutations of porins and the presence of carbapenemase promote Enterobacteriaceae survival under carbapenem treatments. Development of accurate methods for the detection of antimicrobial resistance is required not only for therapy but also to monitor the spread of resistant bacteria or resistance genes throughout the hospital and community. In this study, we aimed to evaluate the phenotypic methods, Modified Hodge test (MHT), modified carbapenem inactivation method (mCIM), and EDTA-CIM (eCIM) for the detection of carbapenemase-producing Enterobacteriaceae (CPE). RESULTS: The results showed that mCIM had a sensitivity of 100% and a specificity of 100%, whereas the MHT had a sensitivity of 84.8% and a specificity of 97.8% for the 195 CRE isolates tested (105 CPE and 90 non-CPE isolates). The sensitivity of the mCIM/eCIM to detect metallo-carbapenemases in this study was 89.3% and the specificity was 98.7% as compared to the genotypic PCR detection. CONCLUSIONS: These findings indicate that the mCIM combined with eCIM is useful for detecting and distinguishing different types of carbapenemase in Enterobacteriaceae.

Phase I Study of TAK-659, an Investigational, Dual SYK/FLT3 Inhibitor, in Patients with B-Cell Lymphoma.

PURPOSE: TAK-659 is an investigational, dual SYK/FLT3 inhibitor with preclinical activity in B-cell malignancy models. This first-in-human, dose-escalation/expansion study aimed to determine the safety, tolerability, MTD/recommended phase II dose (RP2D), and preliminary efficacy of TAK-659 in relapsed/refractory solid tumors and B-cell lymphomas. PATIENTS AND METHODS: Patients received continuous, once-daily oral TAK-659, 60-120 mg in 28-day cycles, until disease progression or unacceptable toxicity. The study applied an accelerated dose-escalation design to determine the MTD and RP2D. In the expansion phase, patients with lymphoma were enrolled in five disease cohorts at the MTD. RESULTS: Overall, 105 patients were enrolled [dose escalation, n = 36 (solid tumors, n = 19; lymphoma, n = 17); expansion, n = 69]. The MTD was 100 mg once daily. TAK-659 absorption was fast (T max ∼2 hours) with a long terminal half-life (∼37 hours). Exposure generally increased with dose (60-120 mg), with moderate variability. The most common treatment-related adverse events were generally asymptomatic and reversible elevations in clinical laboratory values. Among 43 response-evaluable patients with diffuse large B-cell lymphoma, 8 (19%) achieved a complete response (CR) with an overall response rate (ORR) of 28% [23% intent-to-treat (ITT)]. Responses were seen in both de novo and transformed disease and appeared independent of cell-of-origin classification. Among 9 response-evaluable patients with follicular lymphoma, 2 (22%) achieved CR with an ORR of 89% (57% ITT). CONCLUSIONS: TAK-659 has single-agent activity in patients with B-cell lymphoma. Further studies of the drug in combination, including an evaluation of the biologically optimal and safest long-term dose and schedule, are warranted.

Effects of Intrinsic Factors on the Clinical Pharmacokinetics of Vortioxetine.

Vortioxetine is an antidepressant agent with multimodal activity that is approved for the treatment of major depressive disorder at doses of 5 to 20 mg once daily. Vortioxetine is a medium-clearance drug that undergoes extensive metabolism via several cytochrome P450 isozymes. A series of single- and multiple-dose pharmacokinetic studies were performed to evaluate the impact of intrinsic (ie, subject-related) factors, such as age, sex, race, and renal and hepatic function, on the pharmacokinetics of vortioxetine. The point estimates on the ratios and their 90% confidence intervals (CIs) for the central values of AUC (area under the concentration-time curve) and Cmax (maximum plasma concentration) were obtained by taking the antilog of the differences and 90%CIs in the log-transformed least-squares means. The results demonstrate that there were no clinically meaningful differences (defined as exposure difference between 50% and 2-fold change) in the exposure to vortioxetine (as assessed by AUC and Cmax ) between elderly and younger subjects, men and women, and blacks and whites and among subjects with varying degrees of renal or hepatic impairment. These results suggest that no dosing adjustments of vortioxetine are required for the intrinsic factors investigated in these studies.