[Clinical considerations in the design of clinical trial for innovative hepatitis B drugs].

The research and development of chronic hepatitis B (CHB) therapeutic drugs has been undergoing rapid development in recent years in order to achieve the World Health Organization's goal of eliminating viral hepatitis as a major public health threat by 2030. The focus of early stage clinical trials (including the first human trial) is the selection of subjects, study design, dose selection, administration method, dose escalation, monitoring, observation and reporting procedures for adverse events/reactions (tolerability evaluation), and criteria for subjects to continue and discontinue administration. Therefore, quantitative pharmacology knowledge is required to analyze the relationship between in vivo drug exposure, efficacy and adverse reactions, and the inclusion of exploratory indicators such as HBV RNA, hepatitis B virus core-related antigen (HBcrAg), etc., to analyze the mechanism and target of innovative drugs and the efficacy of cccDNA in anti-hepatocytes. On the other hand, Phase II-III clinical trials prioritize the optimal dose, efficacy and safety indicators to verify the efficacy and safety of new drugs in a wider range of subjects. This paper refers to the relevant domestic and foreign literature, combined with the author's practical experience in early clinical research, and then briefly introduces the clinical issues that should be paid attention to in the design of clinical trials of CHB innovative drugs.

[Systematic evaluation of clinical trial protocols of new drugs as a cure of chronic hepatitis B].

Objective: To describe the current status of registration and design characteristics of clinical trials of new drugs for curing hepatitis B through domestic and foreign websites, so as to provide references for the follow-up clinical trials of new hepatitis B drugs. Methods: A search was conducted on the US Clinical Trials Database and the Chinese Clinical Trial Registry Center. The search date was from the establishment of the database to May 26, 2020, and the registration trials of new drugs for curing hepatitis B at home and abroad were included. Two researchers independently searched and screened the literature and extracted the data. Results: A total of 106 registered clinical trials of new drugs for curing hepatitis B were included (94 English registration websites and 12 Chinese registration websites), and the number of registrations had increased year by year. Among them, the proportion of therapeutic vaccines and core protein inhibitors were the highest, accounting for 27.4% (n = 29) and 22.6% (n = 24), respectively. The vast majority of clinical trials (n = 96, 90.6%) were in the early stages (Phase I and II). The subjects in phase I clinical trial were mainly healthy people and treated CHB patients, while the subjects in phase II clinical trial were mainly CHB patients who had achieved viral suppression after initial or post-treatment. The main evaluation indicators of Phase I clinical trials were the safety and tolerability of new drugs. The main evaluation indicators in about half of Phase II clinical trials were HBsAg negative conversion/quantitative decline. Overall, the number of clinical trials with the new design was small, accounting for 3.8% (4 / 106). There were relatively few trials of new drugs for curing hepatitis B on domestic registration websites, and the information provided was incomplete. Conclusion: The number of clinical trials of new hepatitis B drugs at home and abroad is increasing year by year, but most of them are in phase I and II, with few adopting new designs. In addition, the information integrity of the domestic website registration center needs to be improved.

Utilizing machine learning techniques to predict the blood-brain barrier permeability of compounds detected using LCQTOF-MS in Malaysian Kelulut honey.

Current in silico modelling techniques, such as molecular dynamics, typically focus on compounds with the highest concentration from chromatographic analyses for bioactivity screening. Consequently, they reduce the need for labour-intensive in vitro studies but limit the utilization of extensive chromatographic data and molecular diversity for compound classification. Compound permeability across the blood-brain barrier (BBB) is a key concern in central nervous system (CNS) drug development, and this limitation can be addressed by applying cheminformatics with codeless machine learning (ML). Among the four models developed in this study, the Random Forest (RF) algorithm with the most robust performance in both internal and external validation was selected for model construction, with an accuracy (ACC) of 87.5% and 86.9% and area under the curve (AUC) of 0.907 and 0.726, respectively. The RF model was deployed to classify 285 compounds detected using liquid chromatography quadrupole time-of-flight mass spectrometry (LCQTOF-MS) in Kelulut honey; of which, 140 compounds were screened with 94 descriptors. Seventeen compounds were predicted to permeate the BBB, revealing their potential as drugs for treating neurodegenerative diseases. Our results highlight the importance of employing ML pattern recognition to identify compounds with neuroprotective potential from the entire pool of chromatographic data.

Critical domain-wall dynamics of model B.

With Monte Carlo methods, we simulate the critical domain-wall dynamics of model B, taking the two-dimensional Ising model as an example. In the macroscopic short-time regime, a dynamic scaling form is revealed. Due to the existence of the quasirandom walkers, the magnetization shows intrinsic dependence on the lattice size L . An exponent which governs the L dependence of the magnetization is measured to be sigma=0.243(8) .

In situ precision electrospinning as an effective delivery technique for cyanoacrylate medical glue with high efficiency and low toxicity.

The side effects or toxicity of cyanoacrylate used in vivo have been argued since its first application in wound closure. We propose an airflow-assisted in situ precision electrospinning apparatus as an applicator and make a detailed comparison with traditional spraying via in vitro and in vivo experiments. This novel method can not only improve operational performance and safety by precisely depositing cyanoacrylate fibers onto a wound, but significantly reduce the dosage of cyanoacrylate by almost 80%. A white blood cell count, liver function test and histological analysis prove that the in situ precision electrospinning applicator produces a better postoperative outcome, e.g., minor hepatocyte injury, moderate inflammation and the significant ability for liver regeneration. This in situ precision electrospinning method may thus dramatically broaden both civilian and military applications of cyanoacrylates.

Preliminary application of Gamma Knife in the treatment of nasopharyngeal carcinoma.

Nasopharyngeal carcinoma is a malignant tumor which occurs frequently in China. Currently, radiotherapy using 60Co is the main method of treatment. However, the 5-year survival rate is only 49.5%. There is no effective method today for treating residual or recurrent tumor following radiotherapy. In principle, the Leksell Gamma Knife could contribute to better results. Since December 1993, we have treated 36 patients suffering from nasopharyngeal carcinoma with the Gamma Knife: 32 were relapses after radiotherapy and 4 were primary cases. Treatment was very effective for a short period. The rate of improvement of such symptoms as headache, facial paralysis, reduced vision, nasal obstruction and nasal bleeding was 70-100%. After treatment, tumors became smaller or even disappeared. A new nasopharyngeal biopsy was performed in 12 patients and demonstrated that the pathological tissue had returned to normal. The short duration of the survey precludes conclusions about the long-term effects of the treatment.

[The pathological changes of nasopharyngeal carcinoma cases treated by stereotactic radiosurgery].

OBJECTIVE: To study the pathological changes of nasopharyngeal carcinoma cases after the treatment of stereotactic radiosurgery. METHOD: 15 cases with recurrent or residual squamous cell carcinoma of nasopharynx diagnosed as T1-4 N0M0 were selected, which had undergone previous radiotherapy. The patients were treated by Gamma Knife while the isodose curve was 50% and the margin dose was 20 Gy. The nasopharynx biopsy was performed before the treatment and 1, 3, 6, 12 months after the treatment. The biopsy specimen was taken to make a pathological examination. RESULT: 1. Before the Gamma Knife treatment, carcinoma cell could be seen in the tissue; 2. 1-3 months after the treatment, cell necrosis and acute inflammation cell infiltration could be seen in the target; 3. 6-12 months after the treatment, infiltration of chronic inflammation cell, proliferation of fibrous tissue and capillary could be found in the target. CONCLUSION: This research implies that the short-term pathological changes after the treatment of stereotactic radiosurgery can be defined as two phases: The first phase occurs from 1 to 3 months after the treatment called necrosis period. The second phase occurs from 6 to 12 months after the Gamma Knife treatment named as absorption period.