Safety, tolerability, and pharmacokinetic of HY0721 in Chinese healthy subjects: A first-in-human randomized, double-blind, placebo-controlled dose escalation phase I study.

BACKGROUND: HY0721 is a novel inhibitor of sulfonylurea receptor 1-transient receptor potential melastatin 4 (SUR1-TRPM4) for the treatment of acute ischemic stroke. This study aimed to evaluate the safety, tolerability, and pharmacokinetic (PK) profiles of single and multiple intravenous administration of HY0721 in Chinese healthy subjects. METHODS: The study enrolled 48 and 30 healthy volunteers in the single-ascending dose (SAD) cohort (20, 60, 120, 240, and 320 mg) and multiple-ascending dose (MAD) cohort (60, 120, and 160 mg/bid), respectively, to receive the corresponding dosage of HY0721 or placebo. Safety monitoring included but was not limited to recording adverse events (AEs), vital signs, electrocardiograms, and laboratory tests. The blood samples were collected from subjects to determine the concentrations of HY0721 for PK evaluation. RESULTS: The administration of HY0721 showed good safety and tolerability up to 320 mg in the SAD study and up to 160 mg twice daily in the MAD study. The most common AE was injection site reaction, and no AE led to discontinuation of administration or subject dropout. The exposures of HY0721 increased greater than dose proportional manner at the dosages of 20 to 320 mg in the SAD study. A linear PK profile was observed following multiple doses ranging from 60 to 160 mg twice daily, with no evidence of accumulation. Additionally, the human effective dose of HY0721 was estimated to be 120 mg. CONCLUSION: This study demonstrated the intravenous administration of HY0721 is safe and well-tolerated in Chinese healthy subjects and provided 60 to 160 mg b.i.d. as the recommended dosing range for further clinical trials. TRIAL REGISTRATION: ChinaDrugTrials.Org.cn; No. CTR20202604, 18 December 2020.

Effects of Vaginal Microbiota on Human Papillomavirus Infection and Its related diseases.

With the knowledge of female reproductive tract microbiota gradually increasing, the connection between vaginal microbiota (VMB) and its related diseases is increasingly highlighted. Manifestation of VMB keeps changing with various dominated bacteria, which can affect the immune response of mucosal barrier and the entrance of pathogens. Human papillomavirus (HPV), as an oncogenic virus, is closely related to viral-associated cancer, such as cervical cancer. According to HPV infection status, VMB can transform into different types, and result in accelerating or restraining the progression of diseases,which have exposed the inner link between VMB and HPV. Therefore, probiotics therapy promises to be a new complementary therapy to rebuild a healthy VMB for patients, but there's still a long way to go before it's ready for the clinic. This review focuses on composition, immune response, and application of VMB in HPV and its associated diseases and aims to provide the new ideas and directions for the research on VMB.

Two-Time Scale Tracking Control of Flexible Robots With Primal-Dual Inverse Reinforcement Learning.

Flexible robots (FRs) are generally designed to be lightweight to achieve rapid motion. However, accompanying vibrations and modeling errors influence tracking control, especially in situations involving reference signal loss. This article develops a two-time scale primal-dual inverse reinforcement learning (PD-IRL) framework for FRs to perform tracking tasks with incomplete reference signals. First, consider the admissible policy as a nonconvex input constraint to guarantee the stable operation of the equipment. Then, FRs imitate the demonstration behaviors of an expert, including both rigid and flexible motions, to achieve a balance in tracking speed and vibration suppression. During the imitation process, nonconvex optimization problems of FRs are transformed into corresponding dual problems to obtain the global optimal policy. Moreover, employing multiple linearly independent paths to explore the state space simultaneously can improve convergence speed. Convergence and stability are studied rigorously. Finally, simulations and comparisons show the effectiveness and superiority of the proposed method.

TiO2-Ti3C2 Nanocomposites Utilize Their Photothermal Activity for Targeted Treatment of Colorectal Cancer.

Purpose: The search for effective and low-risk treatment methods for colorectal cancer (CRC) is a pressing concern, given the inherent risks and adverse reactions associated with traditional therapies. Photothermal therapy (PTT) has emerged as a promising approach for cancer treatment, offering advantages such as non-radiation, non-invasiveness, and targeted treatment. Consequently, the development of nanoparticles with high stability, biocompatibility, and photothermal effects has become a significant research focus within the field of PTT. Methods: In this study, TiO2-Ti3C2 nanocomposites were synthesized and characterized, and their photothermal conversion efficiency in the near-infrared region II (NIR-II) was determined. Then studied the in vivo and in vitro photothermal activity and anti-tumor effect of TiO2-Ti3C2 in human colorectal cancer cell lines and nude mice subcutaneous tumor model. Results: The results showed that TiO2-Ti3C2 nanocomposites have strong absorption ability in the NIR-II, and have high photothermal conversion efficiency under 1064 nm (0.5 W/cm2, 6 min) laser stimulation. In addition, in vitro experiments showed that TiO2-Ti3C2 nanocomposites significantly inhibited the invasion, migration, and proliferation of colorectal cancer cells, and induced cell apoptosis; in vivo, experiments showed that TiO2-Ti3C2 nanocomposites-mediated PTT had good biocompatibility and efficient targeted inhibition of tumor growth. Conclusion: In conclusion, TiO2-Ti3C2 nanocomposites can be used as NIR-II absorption materials in PTT to suppress the invasion, migration, and proliferation of colorectal cancer cells, induce colorectal cancer cell apoptosis, and thus inhibit the development of CRC. Therefore, TiO2-Ti3C2 nanocomposites can be used as potential anti-tumor drugs for photothermal ablation of colorectal cancer cells.

Quantification of meropenem in serum and cerebrospinal fluid in children with bacterial meningitis with augmented renal clearance by UPLC-MS/MS.

Meropenem is an ultrabroad-spectrum antimicrobial agent that is often recommended for the treatment of bacterial meningitis (BM) in children. However, a subtherapeutic phenomenon occurred in BM children complicated with augmented renal clearance (ARC) at the recommended dose of meropenem. To support its pharmacokinetics, a sensitive, fast and robust ultra-liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed to measure meropenem concentrations in serum and cerebrospinal fluid (CSF). The method involved protein precipitation, and samples were diluted with a large proportion of water to eliminate solvent effects. The separation of samples was performed on a Waters Acquity™ BEH C18 column (2.1 × 50 mm i.d., 1.7 µm) with a gradient profile. The mobile phases were formic acid-water (1:1000, v/v) and acetonitrile. The linear range was good, with a concentration range of 0.100-100 µg/mL for serum and 0.0400-20.0 µg/mL for CSF. The intra-day and inter-day precisions were less than 8.0%, and the intra-day and inter-day accuracies varied -6.6% from 6.5% for the both serum and CSF. The selectivity, carry-over, dilution integrity, matrix effect, recovery and stability were validated according to international guidelines. The developed UPLC-MS/MS method successfully determined the meropenem concentrations in the serum and CSF of children with BM complicated with ARC. The results indicated that under the recommended dosing regimen (40 mg/kg every 8 h), the time to reach the effective treatment target of 50%T > MIC was only approximately 3 h and lower CSF concentrations of meropenem were observed in children with BM with ARC.

First-in-Human Safety, Tolerability, and Pharmacokinetics of Single-Dose Kukoamine B Mesylate in Healthy Subjects: A Randomized, Double-Blind, Placebo-Controlled Phase I Study.

INTRODUCTION: Kukoamine B mesylate (KB) is a mesylate chrysamine B targeting lipopolysaccharides and CpG DNA, two potential treatment targets in sepsis. METHODS: This first-in-human, randomized, double-blind, placebo-controlled, phase I study was conducted from July 2014 to May 2015 to explore the safety, tolerability, and pharmacokinetics of KB in healthy subjects. This study consisted of a pre-phase (four participants; KB at 0.005 mg/kg) and a dose escalation phase (eight participants/dose group, randomized 6:2 to KB or placebo; KB at 0.02, 0.04, 0.08, 0.12, 0.24, and 0.48 mg/kg). The primary endpoint was safety. RESULTS: Fifty-two participants were enrolled, including four in the pre-phase and 48 in the dose escalation phase. Among the 40 participants who received KB, 12 (30.0%) experienced adverse events (AEs), while two (16.7%) experienced AEs among 12 participants who received the placebo. The most common AEs in the KB group were headache (5.0%), influenza (5.0%) and positive white blood cell in urine (5.0%). After the administration of KB, the mean plasma elimination half was around 1.61-4.24 h. The relationship between the KB plasma exposure of KB and the administered dose was not linear. The percentage of cumulative urinary excretion of KB was similar among the different dose groups (21.7-35.2%) and the urinary excretion of KB decreased significantly about 8 h after administration. CONCLUSIONS: Single-dose KB demonstrated favorable safety and tolerability in healthy subjects at the dose level of 0.005-0.48 mg/kg. KB exhibited a non-linear pharmacokinetic profile with a half-life of about 1.61-4.24 h, which mainly distributed in plasma. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02219971.

Adaptive Dosage Strategy of Levetiracetam in Chinese Epileptic Patients: Focus on Pregnant Women.

There is presently no efficient dose individualization strategy for the use of antiseizure medications in epileptic pregnant patients. This study aimed to develop a population pharmacokinetics model for levetiracetam and propose a tailored adaptive individualized dosage strategy for epileptic pregnant patients. A total of 322 levetiracetam plasma concentrations from 238 patients with epilepsy were included, including 216 women with epilepsy (20.83% of whom were pregnant). The levetiracetam plasma concentration was measured using a validated ultra-performance liquid chromatography-tandem mass spectrometry assay, and the data were modeled using a nonlinear mixed-effects model. The resultant model served as the basis for simulating the dosage adjustment strategy. A one-compartment model with first-order elimination best described the pharmacokinetic data of levetiracetam. The apparent clearance (CL/F) was 3.43 L/h (95% CI 3.30-3.56) and the apparent volume of distribution was 43.7 L (95% CI 40.4-47.0) for a typical individual of 57.2 kg. Pregnancy and body weight were found to be significant covariates of CL/F of levetiracetam. The recommended regimen of levetiracetam could be predicted by the population pharmacokinetic model based on body weight, gestational age, and the daily dose of levetiracetam taken before pregnancy.

Quantitation of levetiracetam concentrations in plasma and saliva samples by ultra-performance liquid chromatography-tandem mass spectrometry: Application to therapeutic drug monitoring for pregnant women with epilepsy.

Although levetiracetam (LEV) has favorable linear pharmacokinetic properties, therapeutic drug monitoring (TDM) is necessary for pregnant women with epilepsy. This study aims to build a simple, reliable, and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for determining LEV concentrations in plasma and saliva samples, to support the routine TDM of LEV in Chinese pregnant women with epilepsy. The stable isotope-labeled LEV-d6 was used as the internal standard. The extracted samples were analyzed using a UPLC-MS/MS system with positive electrospray ionization. Mobile phase A was water containing 5 mM ammonium acetate and 0.1% formic acid, and phase B was 1:1 methanol-acetonitrile with 0.1% formic acid. The method was validated and utilized to determine LEV concentrations in non-pregnant and pregnant patients with epilepsy. The developed method was validated in both plasma and saliva samples over a concentration range of 0.1-50 µg/mL. The intra- and inter-batch accuracy for LEV ranged from -7.0% to 2.9%, with precisions between 2.7% and 9.3%. In pregnant patients, the mean dose-standardized LEV trough plasma concentrations were significantly lower than those in non-pregnant patients (4.73 ± 2.99 vs. 7.74 ± 3.59 ng/mL per mg/day; P < 0.0001). It is recommended that the TDM of LEV should be routinely performed during the different stages of pregnancy.

Impact of COPD pulmonary structural remodeling on the prognosis of patients with advanced lung squamous cell carcinoma.

Background: By observing the changes of lung imaging airway structure in patients with advanced lung squamous cell carcinoma（ALUSC）, the relationship between the different types of COPD pulmonary structural remodeling and the prognosis of patients with ALUSC was analyzed. Methods: We reviewed the medical records of 278 patients with ALUSC. The degree of emphysema and the percentage of bronchial wall thickness（WT%） on chest HRCT were calculated by Synapse3D software, Lung structural remodeling can be divided into there types: airway remodeling dominated, emphysema dominated, and mixed types. Results: Compared with the diagnosis, the Goddard score increased, the proportion of airway remodeling dominated type decreased and the proportion of mixed type increased during the progression of ALUSC. In Kaplan-Meier analysis, whether with or without COPD, the mPFS and mOS of patients with mixed type were the shortest, and the difference was statistically significant. Univariate and multivariate Cox proportional hazard regression analysis showed that mixed type was an independent risk factor for poor PFS and OS in patients with ALUSC. Conclusion: Patients with ALUSC all have varying degrees of lung structural remodeling, and patients with mixed lung structural remodeling have the worst prognosis. In addition, the aggravation of emphysema during tumor progression is more pronounced than the thickening of the airway wall, and the changes of emphysema was more powerful in predicting the progression of ALUSC.Clinicians must pay more attention to the changes of COPD (especially emphysema) in the process of diagnosis and treatment of ALUSC.

Effect of Simmering Technology on Components and Activity of Myristica fragrans Houtt.

This study aims to optimize the processing of Myristica fragrans Houtt. by talcum powder simmering using single-factor and orthogonal experimental methods, and the overall desirability values of dehydrodiisoeugenol and essential oils content were selected as indicators of the process. The new process reduced the total content of the three toxic components, namely myristicin, safrole and elemicin, from 1.91% to 1.16% before and after processing, indicating that the toxic components were reduced by 39%. The IC50 of the essential oils before and after processing were 1.002 ± 0.05 and 0.233 ± 0.05 mg/mL for DPPH scavenging activity and 0.132 ± 0.04 and 0.057 ± 0.05 mg/mL for ABTS scavenging activity, respectively. And the absorbance of the antioxidant activity against Ferric reducing power ranged from 0.213 to 0.709 and from 0.225 to 0.755, respectively. The minimum inhibitory concentration for Staphylococcus aureus, Bacillus pumilus and Escherichia coli were all lower after processing than before. The antioxidant activity and antibacterial activity of the essential oils after processing were better than before. The results of the survival of zebrafish embryos at different concentrations of essential oils at 0-168 h post fertilisation were higher after processing than before. These findings suggest that processing plays the role of reducing toxicity and increasing beneficial effects. They provide a scientific basis not only for the processing of M. fragrans, but also for the processing of other foods.

Potential value of gastrointestinal myoelectrical activity in the diagnosis of anxiety-depression disorder: a population-based study.

BACKGROUND: Depression and anxiety are frequently coexisted mental illness. The lack of solid objective diagnostic criteria has led to a high rate of suicide. The brain-gut axis bridges the gastrointestinal system with neuropsychiatric disorders. However, it is still not possible to reflect mental disease with gastrointestinal information. The study aimed to explore the auxiliary diagnostic value of gastrointestinal myoelectrical activity in anxiety-depression disorders (ADD) without gastrointestinal disturbance. METHODS: A natural population cohort from 3 districts in Western China were established. The Patient Health Questionnaire-9 and the Generalized Anxiety Disorder-7 were used to assess ADD. Gastrointestinal myoelectrical activity of ADD were measured by multi-channel cutaneous electrogastroenterogram (EGEG). Then the parameters of EGEG between ADD and healthy controls were analyzed. RESULTS: The average amplitude and response area of intestinal channel in ADD were significantly lower than those of controls (153.49 ± 78.69 vs. 179.83 ± 103.90, 57.27 ± 29.05 vs. 67.70 ± 38.32), which were shown to be protective factors for ADD (OR = 0.944 and 0.844, respectively). Further, the scale item scores related to the core symptoms of anxiety and depression were also associated with these two channels (p < 0.05), and the gastrointestinal electrical signals of ADD are significantly changed in the elderly compared to the young adults. CONCLUSIONS: The intestinal myoelectrical activity has a certain auxiliary diagnostic value in psychiatric disorders and is expected to provide objective reference for the diagnosis of anxiety and depression.

Comparison of intravenous ibuprofen pharmacokinetics between Caucasian and Chinese populations using physiologically based pharmacokinetics modeling and simulation.

BACKGROUND: Intravenous ibuprofen, a nonsteroidal anti-inflammatory drug, is widely used as an antipyretic and analgesic in adults and children. This study was designed to evaluate ethnic differences by comparing the pharmacokinetics of intravenous ibuprofen in Caucasian and Chinese populations using physiologically based pharmacokinetics (PBPK) modeling and simulation. METHODS: A PBPK model for intravenous ibuprofen was developed in adults and children utilizing the Simcyp Simulator. The model was tested and verified against published literature and unpublished data obtained from the Caucasian adult population, Caucasian pediatric population and Chinese adult population. RESULTS: The developed PBPK model could adequately pilot the pharmacokinetics of intravenous ibuprofen, and the major observed values were within the 90% prediction interval in both adults and children. Both folding errors of the maximum peak concentration (Cmax) and area under the concentration-time curve (AUC) were 1.5-fold less in the Caucasian and Chinese populations. In addition, no significant differences in weight-normalized Cmax and AUC were observed between the Caucasian and Chinese adult populations. Moreover, there were no obvious pharmacokinetic differences between the Caucasian and Chinese pediatric populations with intravenous infusion (10 minutes) of 10 mg/kg by age group. CONCLUSION: This study indicates that the pharmacokinetic profile and the parameters of intravenous ibuprofen are analogous in Caucasian and Chinese populations, either adults or children. In addition, this study provides effective evidence that the dosing scheme of intravenous ibuprofen in Chinese children can remain the same as the regimen that the original company (Caldolor®) provided.

A model incorporating clinicopathologic and liver imaging reporting and data system-based magnetic resonance imaging features to identify hepatocellular carcinoma in LR-M observations.

PURPOSE: To evaluate the predictive value of a combination model of Liver Imaging Reporting and Data System (LI-RADS)-based magnetic resonance imaging (MRI) and clinicopathologic features to identify atypical hepatocellular carcinoma (HCC) in LI-RADS category M (LR-M) observations. METHODS: A total of 105 patients with HCC based on surgery or biopsy who underwent preoperative MRI were retrospectively reviewed in the training group from hospital-1 between December 2016 and November 2020. The LI-RADS-based MRI features and clinicopathologic data were compared between LR-M HCC and non-HCC groups. Univariate and least absolute shrinkage and selection operator regression analyses were used to select the features. Binary logistic regression analysis was then conducted to estimate potential predictors of atypical HCC. A predictive nomogram was established based on the combination of MRI and clinicopathologic features and further validated using an independent external set of data from hospital-2. RESULTS: Of 113 observations from 105 patients (mean age, 61 years; 77 men) in the training set, 47 (41.59%) were classified as LR-M HCC. Following multivariate analysis, aspartate aminotransferase >40 U/L [odds ratio (OR): 4.65], alpha-fetoprotein >20 ng/mL (OR: 13.04), surface retraction (OR: 0.16), enhancing capsule (OR: 5.24), blood products in mass (OR: 8.2), and iso/hypoenhancement on delayed phase (OR: 10.26) were found to be independently correlated with LR-M HCC. The corresponding area under the curve for a combined model-based nomogram was 0.95 in the training patients (n = 113) and 0.90 in the validation cohort (n = 53). CONCLUSION: The combined model incorporating clinicopathologic and MRI features demonstrated a satisfactory prediction result for LR-M HCC.

Chiral pharmacokinetics of ibuprofen enantiomers in Chinese preterm neonates with patent ductus arteriosus using a validated UHPLC-MS/MS method.

Persistent patent ductus arteriosus (PDA) is generally observed in preterm neonates. Oral ibuprofen is the standard treatment for closing PDA in China. To investigate the chiral pharmacokinetics of ibuprofen enantiomers in Chinese premature infants with PDA, a simple, fast, and sensitive analytical enantioselective technology was developed with ultra-performance liquid chromatography (UPLC) - tandem mass spectrometry (MS/MS). Chromatographic separation of (R)-ibuprofen and (S)-ibuprofen was accomplished on a Lux® 3 µm Cellulose-3 (150 mm × 2.0 mm, 3 µm) at a flow rate of 0.2 mL/min within 6 min. UPLC separation was achieved by isocratic elution with a mobile phase consisting of formic acid:water (75:1000000, v/v) and acetonitrile:methanol (1:1, v/v). Only 50 µL of plasma samples were pre-treated with acetonitrile precipitation. Ibuprofen-d3 was used as an internal standard. The standard curves of both enantiomers were linear over a concentration range of 0.0500 µg/mL to 50.00 µg/mL. The method has been validated for selectivity, carryover effect, lower limit of quantification, precision, accuracy, matrix effect, extraction recovery, dilution integrity, and stability based on the existing guidelines of the National Medical Products Administration, the United States Food and Drug Administration, and the European Medicines Agency. This method has been successfully applied to investigate the pharmacokinetics of ibuprofen enantiomers in 9 preterm infants with PDA. Our results showed that a high chiral inversion ratio of (R)- to (S)-ibuprofen exists in Chinese preterm neonates. Further studies should be conducted to monitor drug concentration following oral administration of ibuprofen and to consider the effect of individual variations and ethnic differences in metabolizing enantiomers of ibuprofen in premature neonates with PDA.

Highly Efficient Visible-Blind Ultraviolet Photodetector Based on Scalably Produced Titanium Dioxide Nanowire Arrays.

Here, we report a novel, feasible, and cost-effective method for the preparation of one-dimensional TiO2 nanowire arrays using a super-aligned carbon nanotube film as a template. Pure-anatase-phase TiO2 nanowires were scalably prepared in a suspended manner, and a high-performance ultraviolet (UV) photodetector was realized on a flexible substrate. The large surface area and one-dimensional nanostructure of the TiO2 nanowire array led to a high detectivity (1.35 × 1016 Jones) and an ultrahigh photo gain (2.6 × 104), respectively. A high photoresponsivity of 7.7 × 103 A/W was achieved under 7 µW/cm2 UV (λ = 365 nm) illumination at a 10 V bias voltage, which is much higher than those of commercial UV photodetectors. Additionally, by taking advantage of its anisotropic geometry, we found the TiO2 nanowire array showed polarized photodetection. The concept of using nanomaterial systems shows the potential for realization of nanostructured photodetectors for practical applications.

Safety, Tolerability, and Pharmacokinetics of Kukoamine B in Healthy Volunteers: A Randomized, Double-Blind, Placebo-Controlled, Multiple-Dose Phase I Study.

INTRODUCTION: Kukoamine B (KB) is a novel sepsis therapeutic drug targeting lipopolysaccharide and CpG DNA. This study aims to evaluate the safety, tolerability, and pharmacokinetic (PK) profile of multiple doses of KB in healthy volunteers. METHODS: Healthy volunteers were randomized at a 1:1:1:1 ratio to receive multiple intravenous infusion doses of KB 0.06 mg/kg, 0.12 mg/kg, 0.24 mg/kg or placebo (administered every 8 h per day) for 7 days and subsequently followed up for another 7 days at Peking Union Medical College Hospital. Primary endpoints were adverse events (AEs), and the secondary endpoints were PK parameters of the first administration and the last administration. RESULTS: Data of the 18 health volunteers in KB groups and 6 in the placebo group were pooled and analyzed. AEs occurred in 12 (66.67%) volunteers in the KB groups and 4 (66.67%) volunteers in the placebo group. Treatment-related adverse events (TRAEs) occurred in 8 (44.44%) volunteers in the KB groups and 2 (33.33%) volunteers in the placebo group. Hypertriglyceridemia (4 [22.22%] vs. 2 [33.33%]) and sinus bradycardia (3 [16.67%] vs. 0) were the most common AEs. The mean elimination half-life, clearance, and distribution volume of KB were 3.40-4.88 h, 9.35-13.49 L/h, and 45.74-101.90 L, respectively. The average accumulation ratios of area under the plasma concentration-time curve and maximum plasma concentration were 1.06 and 1.02, respectively. CONCLUSION: Single and multiple intravenous infusions of KB at a dose range of 0.06-0.24 mg/kg are safe and tolerable in healthy volunteers. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02690961.

The pharmacokinetics and safety of lidocaine in liver cancer patients undergoing hepatic resection.

PURPOSE: The purpose of this study was to explore the pharmacokinetics (PK) characteristics and safety of continuous lidocaine infusion during hepatectomy in liver cancer patients. METHODS: This study included thirty-five patients undergoing laparoscopic hepatectomy from January 2021 to December 2021. Patients received a short infusion of 1% lidocaine at a dose of 1.5 mg/kg based on ideal body weight, followed by a continuous infusion of 1 mg/kg/h during the operation. The plasma concentrations of lidocaine and its active metabolites were measured using validated ultra-performance liquid chromatography-tandem mass spectrometry. Safety was evaluated by monitoring and recording all adverse events (AEs). RESULTS: The concentrations of lidocaine were within the safe range, except one patient's concentration of lidocaine which reached the toxic range (> 5 µg/mL). The mean half-life (T1/2), the mean time to maximum observed concentration (Tmax), and the mean maximum observed concentration (Cmax) of lidocaine were 3.96 h, 2.85 h, and 2030 ng/mL, respectively; the mean T1/2, Tmax, and Cmax (n = 32) of MEGX were 6.59 h, 5.05 h, and 333.28 ng/mL, respectively; and the mean T1/2, Tmax, and Cmax of GX (n = 18) were 25.98 h, 7.33 h, and 75.81 ng/mL. Although eight subjects with AEs were reported, there were no serious AEs or deaths. No patients had serious postoperative complications. No deaths occurred within 30 days after the operation. CONCLUSIONS: Under the administration regimen of this study, intravenous infusion of lidocaine is safe and tolerable for liver cancer patients with laparoscopic hepatectomy. Fine safety and PK characteristics support the application of lidocaine in such patients and further clinical research. TRIAL REGISTRATION: China Clinical Trial Registration Center (ChiCTR2100042730), Registered 27 January 2021.

Safety, Tolerability, Pharmacokinetics, and Immunogenicity of a Novel Recombination Human Nerve Growth Factor in Healthy Chinese Subjects.

BACKGROUND: Nerve growth factor (NGF), the first-discovered member of the neurotrophin family, has long been regarded as a potential drug to combat acute and chronic neurodegenerative processes. However, the pharmacokinetic profile of NGF is poorly described. OBJECTIVES: The aim of this study was to investigate the safety, tolerability, pharmacokinetics, and immunogenicity of a novel recombinant human NGF (rhNGF) in healthy Chinese subjects. METHOD: The study randomized 48 and 36 subjects to receive (i) single-ascending dose (SAD group; 7.5, 15, 30, 45, 60, 75 µg or placebo) and (ii) multiple-ascending dose (MAD group; 15, 30, 45 µg, or placebo) rhNGF intramuscular injections, respectively. In the SAD group, all participants received rhNGF or placebo only once. In the MAD group, participants were randomly assigned to receive multiple doses of rhNGF or placebo once a day for 7 consecutive days. Adverse events (AEs) and anti-drug antibodies (ADAs) were monitored throughout the study. Recombinant human NGF serum concentrations were determined using a highly sensitive enzyme-linked immunosorbent assay. RESULTS: All AEs were mild, except for some injection-site pain and fibromyalgia, which were experienced as moderate AEs. Only one moderate AE was observed in the 15 µg cohort throughout the study and resolved within 24 hours of stopping dosing. Many participants (10% in 30 µg, 50% in 45 µg, and 50% in 60 µg in the SAD group; 10% in 15 µg, 30% in 30 µg, and 30% in 45 µg in the MAD group) experienced moderate fibromyalgia. However, all moderate fibromyalgia were resolved by the end of the subject's participation in the study. No severe AEs or clinically significant abnormalities were reported. All subjects in the 75 µg cohort experienced positive ADA in the SAD group, and one subject in the 30 µg dose and four subjects in the 45 µg dose also experienced positive ADA in the MAD group. Recombinant human nerve growth factor was absorbed (median Tmax, 4.0-5.3 h) and eliminated biexponentially (mean t1/2, 4.53-6.09 h) with a moderate speed. The Cmax and AUC increased in an approximately dose-proportional manner over the dose range of 7.5-45 µg, and at doses higher than 45 µg these parameters increased more than dose proportionally. There was no obvious accumulation after 7 days of daily dosing of rhNGF. CONCLUSION: The favorable safety and tolerability and predictable pharmacokinetic profile of rhNGF in healthy Chinese subjects support its continuing clinical development for the treatment of nerve injury and neurodegenerative diseases. The AEs and immunogenicity of rhNGF will continue to be monitored in future clinical trials. TRIAL REGISTRATION: This study was registered with Chinadrugtrials.org.cn (ChiCTR2100042094) on January 13th, 2021.

Pharmacokinetics and pharmacodynamics of sacubitril/valsartan in peritoneal dialysis patients.

BACKGROUND: There is little information on the pharmacokinetics and pharmacodynamics of sacubitril/valsartan (SV) in patients undergoing peritoneal dialysis (PD) complicated with hypertension or heart failure (HF). This study was designed to evaluate the pharmacokinetics and pharmacodynamics of SV in PD patients with complications of hypertension or HF. METHODS: This was an open-label and cross-sectional study investigating PD patients diagnosed with hypertension or New York Heart Association Class II-IV HF. The concentrations of valsartan, sacubitril and sacubitrilat (LBQ657) were measured by ultra-performance liquid chromatography tandem mass spectrometry in plasma, urine and peritoneal dialysate samples. Pharmacodynamics were evaluated by comparing changes in mean sitting systolic blood pressure (msSBP), mean sitting diastolic blood pressure (msDBP), mean sitting heart rate, N-terminal-pro B-type natriuretic peptide (NT-proBNP) and left ventricular ejection fraction (LVEF). RESULTS: Forty patients with PD were enrolled including 27 (67.5%) patients with hypertension, 4 (10%) patients with HF and 9 (22.5%) patients with both hypertension and HF. This study included three treatment cohorts: 50 mg twice daily (BID), 100 mg once daily and 100 mg BID. The plasma maximum drug concentrations in the 100 mg BID group were 1995 ± 1499 ng/mL for valsartan, 171 ± 148 ng/mL for sacubitril and 13 686 ± 7418 ng/mL for LBQ657. The 24-h recovery rate of LBQ657 was 3.77% in urine and 2.23% in peritoneal dialysate. After taking SV, msSBP and msDBP decreased by 19.25 ± 10.32 mmHg and 10.10 ± 8.00 mmHg from baseline, respectively. NT-proBNP decreased by 1436.50 (0.00-18 198.00) from baseline, while LVEF increased by 5.00 (-0.25 to 9.25) from baseline after SV treatment. CONCLUSIONS: PD and residual renal function contributed only to a minor degree to the elimination of LBQ657. Additionally, a dose of 100 mg BID SV is safe and effective in patients with PD with complications of hypertension or HF.