The PK bioanalysis method study of c-Met antibody-drug conjugate (RC108) in cynomolgus monkey / 药学学报

Antibody-drug conjugate (ADC) has the characteristics of low toxicity and high efficiency, and plays an important role in cancer treatment. However, due to the complexity of its structure, it brings difficulties in pharmacokinetic (PK) bioanalysis. This study established an analytical method for the detection of ADC (RC108) in cynomolgus monkey plasma by ligand-binding assay (LBA) and liquid chromatography tandem mass spectrometry (LC-MS/MS), which was used to analyze and quantify the total antibody, bound antibody and free drug in cynomolgus monkey plasma. Based on the LBA method, rabbit anti-RC108 Fab and mouse anti-MMAE (monomethyl auristatin E) mAb were pre-coated in 96-well plates as the total antibody and antibody binding reagents, respectively. The samples to be tested were added, and then the detection reagents were added in turn. Goat anti-human IgG (H+L)-HRP, chromogenic solution tetramethylbenzidine (TMB), H2SO4 terminate the reaction, read data at 450 nm/630 nm wavelength of microplate reader; LC-MS/MS analysis method quantifies MMAE concentration, and refer to relevant regulations for methodological validation. The analytical method for quantifying total antibody, bound antibody and free drug of RC108 drug obtained good accuracy and precision, and the selectivity, dilution linearity, hook effect, parallelism and stability were verified. Meet the requirements of biological analysis. Finally, a bioanalytical method for the determination of the concentration of the test substance RC108 (total antibody, conjugated antibody, free MMAE) in cynomolgus monkey plasma with high sensitivity and high throughput was established by LBA and LC-MS/MS method. Subsequent non-clinical research on PK research in cynomolgus monkeys will provide technical support.

Application of augmented reality and mixed reality navigation technology in laparoscopic limited right hepatectomy / 中华外科杂志

Objective: To investigate the application effect of augmented reality and mixed reality navigation technology in three-dimensional(3D) laparoscopic narrow right hepatectomy(LRH). Methods: A retrospective analysis was performed on the clinical data of 5 patients with hepatic malignancy admitted to the First Department of Hepatobiliary Surgery,Zhujiang Hospital,Southern Medical University from September 2020 to June 2021,all of whom were males,aged from 42 to 74 years.Preoperative evaluation was performed using the self-developed 3D abdominal medical image visualization system; if all the 5 patients were to receive right hemihepatectomy,the remnant liver volume would be insufficient,so LRH were planned.During the operation,the independently developed 3D laparoscopic augmented reality and mixed reality surgical navigation system was used to perform real-time multi-modal image fusion and interaction between the preoperative 3D model and 3D laparoscopic scene.Meanwhile,intraoperative ultrasound assisted indocyanine green fluorescence was used to determine the surgical path.In this way,the LRH under the guidance of augmented reality and mixed reality navigation was completed.The predicted liver resection volume was evaluated before surgery,actual resected liver volume,surgical indicators and postoperative complications were analyzed. Results: All the 5 patients completed LRH under the guidance of augmented reality and mixed reality navigation technology,with no conversion to laparotomy.The median operative time was 300 minutes(range:270 to 360 minutes),no intraoperative blood transfusion was performed,and the median postoperative hospital stay was 8 days(range:7 to 9 days).There were no perioperative deaths,or postoperative complications such as liver failure,bleeding,or biliary fistula. Conclusion: For patients who need to undergo LRH,the use of augmented and mixed reality navigation technology can safely and effectively guide the implementation of surgery,retain more functional liver volume,improve surgical safety,and reduce postoperative complications.

Pharmacokinetic characteristics of YZG-331, a promising sedative-hypnotic candidate agent / 药学学报

The purpose of this article was to study the pharmacokinetic characteristics of YZG-331, plasma protein binding and metabolic stability in vivo and in vitro. Plasma and tissue concentrations of YZG-331 were determined in mice and rats after administration by LC-MS/MS analysis orally or intravenously. The plasma protein binding of YZG-331 with human, dog, monkey, rat and mouse were measured by ultrafiltration method. The stability of YZG-331 in animal and human plasma, liver microsomes, intestinal bacteria and artificial gastrointestinal fluid was also investigated in vitro. The results show that YZG-331 was absorbed rapidly in both mice and rats after oral administration, while the absorption and elimination saturation YZG-331 were also observed. The bioavailability of YZG-331 was much higher in male mice (51.2%) than that in female mice (27.7%), however, the bioavailability in male rats (27.1%) was lower than that in female rats (78.7%). YZG-331 was widely distributed in different tissues of mice, especially in certain regains of brain, including thalamus, hippocampi, cortical and striatal. YZG-331 was found to bind to human, dog, monkey, rat and mouse plasma protein in vitro (93.3%-98.9%) without significant concentration dependences and species differences. YZG-331 was stable in animal and human plasma, simulated gastric/intestinal fluid and liver microsomal incubations, except rat liver microsomes and intestinal flora. Therefore, we concluded that:the pharmacokinetics of YZG-331 in mice and rats have gender and species differences; YZG-331 was widely distributed in vivo including brain, the targets of the agent; YZG-331 had a high affinity to plasma protein and was metabolized by rat liver microsomes and intestinal flora.

Progress in regulation of drug transporters and metabolic enzymes by resveratrol / 药学学报

Drug transporters and metabolic enzymes are two major factors in the regulation of disposition of drug in the body. Interestingly, resveratrol, as a new star of anticancer drug, has a close relationship with transporters and metabolic enzymes. It is known that resveratrol can activate or inhibit the function of several transporters directly. Furthermore, the expression of several transporters was changed. Meanwhile, resveratrol is able to inhibit the function of metabolic enzymes (cytochrome P450, CYP450) and regulate the expression of metabolic enzymes. For this reason, when resveratrol is administrated in combination with other drugs, drug-drug interaction (DDI) should be considered. In this review, we summarize the distribution of transporters and metabolic enzymes in the body, the effect of resveratrol on transporters and metabolic enzymes as well as the drug-resveratrol interaction mediated by transporters and metabolic enzymes.

Modulation of nuclear receptors on drug-metabolizing enzymes and transporters / 药学学报

PXR, CAR and PPAR, widely distributed in the body, are important members of the nuclear receptors (NRs) family. The activities and gene expressions of drug-metabolizing enzymes (DMEs) and transporters can be regulated by the activation of NRs, which effect the drug disposition. Multidrug resistance (MDR) is the leading cause of failure in cancer therapy. NRs, including PXR, CAR and PPAR, were shown to regulate the expressions of DMEs and transporters involved in the drug metabolism and clearance, suggesting that the modulation of NRs can be considered as a new target to overcome MDR. This review described the research progress of NR family members PXR, CAR, PPAR and their transcriptional activation mechanism, the regulation of DMEs and transporters by NRs, which may provide a valuable reference for clinical medication and overcome of MDR.

The transporters of intestinal tract and their study methods / 药学学报

The absorption of oral drug in the intestine is an important factor to determine the drug bioavailability. There are many intestinal transporters mediating drug absorption, distribution, excretion and drug-drug interaction. Understanding the transport mechanism can improve the effectiveness and safety of drug and guide clinical rational use of drugs. The in vivo and in vitro methods are used to predict the transport mechanism of drugs by intestinal transporters in the intestine. The purposes of this article are to introduce the main transporters in the intestinal tract, to explain the transport mechanism and to summarize the advantages and disadvantages of the research methods of them.

Acceptability of male circumcision among male miners in Baise of Guangxi / 中国医学科学院学报

<p><b>OBJECTIVE</b>To investigate the acceptability of male circumcision among male miners in Baise, Guangxi, China.</p><p><b>METHODS</b>A questionnaire-based survey on the willingness to be circumcised (WTC) and its influential factors were conducted among Guangxi male miners recruited by random cluster sampling.</p><p><b>RESULTS</b>Of 569 subjects who were surveyed, 143 (25.13%) expressed their willingness to be circumcised. Univariate analysis showed that marital status, education level, and the awareness of the hazards of phimosis and redundant prepuce and reasons for circumcision were significantly different between WTC group and the non-WTC group (all P<0.05). Furthermore, the incidence of phimosis or redundant prepuce also significantly differed between these two groups (P=0.0001). Logistic regression analysis found marital status (OR=0.498ì95%CI=0.272-0.913), history of foreskin disease (OR=8.181, 95%CI=4.252-15.741), and awareness of the risk that a redundant prepuce may cause smegma (OR=1.713ì95%CI=1.090-2.693) were significantly correlated with the male miners WTC.</p><p><b>CONCLUSIONS</b>Male miners in this area have low WTC. Education on the basic knowledge of acquired immunodeficiency syndrome and circumcision may help promote the application of circumcision.</p>