The covalent binding of drugs and their metabolites to proteins forms drug-protein adducts, which may cause adverse reactions in the body. The development of adductomics technology is helpful for the identification of covalent adducts between drugs and human plasma proteins. For many drugs, such as beta-lactam antibiotics, acyl glucuronides, covalent tyrosine kinases inhibitors, and reactive metabolites, human serum albumin (HSA) is a potential target and biomarker for the formation of drug-protein adducts. In this review, we will describe the relevant technical advances, describe the methods for the identification of covalent adducts of drugs and HSA, define the chemical reactions that form adducts, and preliminarily explore the role of drug-HSA adducts in adverse drug reactions and the potential effect on pharmacokinetics.

Human mass balance study is a pivotal research in the field of clinical pharmacology, aiming at elucidating the metabolic and excretion pathways of drugs in humans. Currently, human mass balance studies predominantly employ radiolabeling techniques. Recently, both the U.S. Food and Drug Administration (FDA) and the Center for Drug Evaluation (CDE) of the China National Medical Products Administration (NMPA) issued related research drafts and guidelines to encourage and guide the pharmaceutical industry to conduct research in compliance with established standards. The selection of radiolabeling sites is crucial for obtaining critical information on drug metabolism. However, in vivo biotransformation may lead to partial disintegration of the molecular structure, thereby resulting in the loss of metabolic product information of the unlabeled moiety. Administering drugs with different radiolabeling sites separately or in combination, or labeling multiple radioactive isotopes within one molecule, can effectively solve this problem. This article reviews relevant technological progress, analyzes radiolabeling strategies, and discusses the application of drugs with multiple radiolabeling sites in human mass balance studies.

The metabolism study of radiolabeled drugs plays an important role in the development of new drugs. It provides information on drug absorption, metabolism, tissue distribution and excretion, and plays an irreplaceable role in the metabolite safety evaluation and mass balance of new drugs. The new guidance draft on clinical trials of radiolabeled drugs recently released by the US FDA puts forward higher standards and has been widely concerned by the industry. In recent years, in the research and development of new drugs in China, ¹⁴C labeled drugs have been used to carry out clinical metabolism studies, which has overcome key technical bottlenecks and accumulated experience. This paper summarizes the above research progress, analyzes the existing problems, and preliminarily looks forward to the future technological development and application.

OBJECTIVES: To investigate the efficacy and required indicators of Children Neuropsychological and Behavioral Scale-Revision 2016 (CNBS-R2016) in the differential diagnosis of autism spectrum disorder (ASD) and global developmental delay (GDD). METHODS: A total of 277 children with ASD and 415 children with GDD, aged 18-48 months, were enrolled as subjects. CNBS-R2016 was used to assess the developmental levels of six domains, i.e., gross motor, fine motor, adaptive ability, language, social behavior, and warning behavior, and a total of 13 indicators on intelligence age and developmental quotient (DQ) were obtained as the input features. Five commonly used machine learning classifiers were used for training to calculate the classification accuracy, sensitivity, and specificity of each classifier. RESULTS: DQ of warning behavior was selected as the first feature in all five classifiers, and the use of this indicator alone had a classification accuracy of 78.90%. When the DQ of warning behavior was used in combination with the intelligence age of warning behavior, gross motor, and language, it had the highest classification accuracy of 86.71%. CONCLUSIONS Machine learning combined with CNBS-R2016 can effectively distinguish children with ASD from those with GDD. The DQ of warning behavior plays an important role in machine learning, and its combination with other features can improve classification accuracy, providing a basis for the efficient and accurate differential diagnosis of ASD and GDD in clinical practice.
Child ; Humans ; Autism Spectrum Disorder/psychology* ; Diagnosis, Differential ; Machine Learning ; Social Behavior

Pain is an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage. The processing of pain involves complicated modulation at the levels of the periphery, spinal cord, and brain. The pathogenesis of chronic pain is still not fully understood, which makes the clinical treatment challenging. Optogenetics, which combines optical and genetic technologies, can precisely intervene in the activity of specific groups of neurons and elements of the related circuits. Taking advantage of optogenetics, researchers have achieved a body of new findings that shed light on the cellular and circuit mechanisms of pain transmission, pain modulation, and chronic pain both in the periphery and the central nervous system. In this review, we summarize recent findings in pain research using optogenetic approaches and discuss their significance in understanding the pathogenesis of chronic pain.
Brain ; Chronic Pain ; Humans ; Neurons ; Optogenetics ; Spinal Cord

Rocuronium bromide is an acetylcholine N2 receptor antagonist, which can be used as an auxiliary drug for general anesthesia. It has been reported that rocuronium has two possible metabolic pathways: N-dealkylation and O-deacetylation, which are mainly taken up by liver and excreted by bile in the form of primary drugs. In this paper, the metabolites of rocuronium in human bile were detected by UHPLC-QE-orbitrap-MS, thirteen metabolites were detected, including eleven phase I metabolites and two phase II metabolites, eleven of which had not been previously reported. At the same time, HEK293 cells overexpressing transporter were used to explore the transmembrane transport mechanism of rocuronium, the results showed that rocuronium was the substrate of MATE1, OCT1, OATP1B1 and OATP1B3. The above research results enrich the metabolic pathway of rocuronium in vivo, and put forward the possible transport mechanism of liver uptake and bile excretion, which can better guide the accurate and safe clinical drug application. The collection of human bile samples in this study was approved by the ethics committee of Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (Approval Number: 2019-775-130-01).

In recent years, the real-world studies (RWS) have attracted extensive attention, and the real-world evidence (RWE) has been accepted to support the drug development in China and abroad. However, there is still a lack of standards for the evaluation of the quality of RWE. It is necessary to formulate a quality evaluation and reporting specification for RWE especially in traditional Chinese medicine (TCM). To this end, under the guidance of China Association of Chinese Medicine, the Quality Evaluation and Reporting Specification for Real-World Evidence of Traditional Chinese Medicine (QUERST) Group, including 24 experts (clinical epidemiologists, clinicians, pharmacologists, ethical reviewer and statisticians), was established to develop the specification. This specification contains the listing of classification of RWS design and RWE, the general principles and methods of RWE quality evaluation (26 tools or scales), 25 types of bias in RWS, the special considerations in evaluating the quality of RWE of TCM, and the 19 reporting standards of RWE. This specification aims to propose the quality evaluation principles and key points of RWE, and provide guidance for the proper use of RWE in the development of TCM new drugs.
Medicine, Chinese Traditional ; China

OBJECTIVE: To investigate the potential mechanisms of electroacupuncture (EA) to prevent ischemic stroke. METHODS: The method of middle cerebral artery occlusion (MCAO) was employed to establish a rat model of ischemic stroke. Seventy-eight Sprague-Dawley rats were divided into the sham group, MCAO + EA control (EC) group, and MCAO + EA (EA) group according to a random number table (n=26 per group). EA was applied to the acupoints of Baihui (DU 20) and Shenting (DU 24) 5 min and 6 h, respectively after the onset of MCAO. Rats in the sham and EC groups received only light isoflurane anesthesia for 30 min after MCAO. The neuroprotective effects of EA were evaluated by rota-rod test, neurological deficit scores and infarct volumes. Additionally, Nissl staining and immunostaining were performed to examine brain damage, rod formation, cellular apoptosis, and neuronal loss induced by ischemia. The activities of caspase-3, and expression levels of cofilin and p-cofilin in mitochondria and cytoplasm after ischemic injury were determined by Western blot. RESULTS: Compared with the EC group, EA significantly improved neuromotor function and cognitive ability after ischemic stroke (P<0.05 or P<0.01). Therapeutic use of EA also resulted in a significant decrease of cofilin rod formation and microtubule-associated protein-2 (MAP2) degradation in the cortical penumbra area compared with the EC rats (P<0.01). Furthermore, Western blot analysis showed that EA stimulation significantly inhibited mitochondrial translocation of cofilin and caspase-3 cleavage (P<0.05 or P<0.01). Additionally, brain damage (infarct volume and neuropathy), cellular apoptosis and neuronal loss induced by ischemia were remarkably suppressed by EA in the cortical penumbra of rats (P<0.05 or P<0.01). CONCLUSION EA treatment after ischemic stroke may attenuate ischemic brain injury and cellular apoptosis through the regulation of mitochondrial translocation of cofilin, a novel mechanism of EA therapy.

Six new tirucallane-type triterpenoids (1-6), along with ten known triterpenoids, were isolated from methylene chloride extract of the resin of Boswellia carterii Birdw. By the application of the comprehensive spectroscopic data, the structures of the compounds were clarified. The experimental electronic circular dichroism spectra were compared with those calculated, which allowed to assign the absolute configurations. Compounds 5 and 6 possesed a 2, 3-seco tirucallane-type triterpenoid skeleton, which were first reported. Their inhibitory activity against NO formation in LPS-activated BV-2 cells were evaluated. Compound 9 showed appreciable inhibitory effect, with an IC

Objective:To investigate the feasibility and clinical efficacy of anterolateral thigh chimeric perforator flap in repair of large area soft tissue defects around the knee joint.Methods:From January, 2015 to October, 2019, 9 patients with large area soft tissue defects around the knee joint were treated. All patients had different degrees of defect in knee joint capsule and joint opening. Before operation, the width of the flap was determined by "skin lifting and kneading test", and the location of perforators in anterolateral femoral region was confirmed and marked with the assistance of HHD detector. According to the size and shape of the wound surface, single leaf or lobulated perforator flap was designed based on the principle that the donor site should be closed directly. The minimum size of the flap was 14.0 cm×5.0 cm, there was 1 case of lobulated flap with the largest area, respectively was 17.0 cm×9.0 cm and 18.0 cm×8.5 cm. The chimeric tissue flap(muscle flap or fascia lata flap) was taken according to the location and severity of joint opening. The grafted tissue flap was used to fill the articular cavity, the flap was used to repair the wound of knee joint, the blood supply of the flap was reconstructed, and a drainage catheter was placed in the cavity of knee joint. The recovery follow-up conducted in outpatient department.Results:All flaps survived without vascular incident. The recipient site of flap in 1 patient was not thoroughly washed and drained, and there was more exudation. After dressing change and drainage, the rest recipient areas of the flap were healed in stage I. All patients entered 3 to 36(average 12) months of follow-up. The appearance and function of recipient area recovery were satisfactorily. Only a linear scar remained in donor site.Conclusion:Anterolateral thigh chemeric perforator flap is ideal for repairing large soft tissue defects around the knee joint.