OBJECTIVE To explore the key technical considerations in the drugs design of clinical trials for delaying the progression of chronic kidney disease. METHODS By reviewing domestic and foreign literature, and considering the characteristics of the disease, drug development and review experience, the important design considerations for clinical trials evaluating drugs that delay the progression of chronic kidney disease were suggested in this article. RESULTS and CONCLUSION We recommend an overall trial design that incorporates randomization, double-blinding, and placebo/standard treatment as control measures. The study population should be representative of a wide range of individuals who reflect the intended objectives of the trial. Inclusion criteria and efficacy evaluation should take into account etiology, staging, risk factors for disease progression, and combined treatments. We suggest the composite endpoints based on clinical events as primary efficacy endpoints,while the average change rate in glomerular filtration rate is recommended for early or slowly progressing chronic kidney disease cases. Safety evaluation indicators should not only adhere to general standards but also consider potential safety issues related to investigational drugs as well as safety signals associated with natural disease progression by setting corresponding safety assessment parameters for underlying diseases.

OBJECTIVE To discuss the characteristics of research and development on the new drugs of renal disease and technical considerations envolved. METHODS By investigating the advance of the regulatory agencies home and abroad and the related literature,the nephrotic drugs of the last decade in the market and in research were summerized domestically and overseas,the characteristics of research and key technical points were analyzed and relevant suggestions were put forward. RESULTS and CONCLUSIONS Ten new drugs have been approved by China,European Union and United States since 2013. The applications of the new drugs on this field has continued to increase in the recent 5 years, mainly on the chronic kidney disease and IgA nephropathy. To better promote the drug innovation development in this field, the following aspects should be paid attention to: The first is to further strengthen the basic scientific research about the pathogenesis of diseases, and screen the potential new drugs with new target and mechanism, so that make it possible to delay and even reverse the progression of the disease. The second is to better evaluate the patients beneifts by developing scientific and rational clinical outcome assessment tools with the basis of the patients' needs. The third is to choose the representative population by the combination of epidemiology, natural history, the feature of drugs and the aim of clinical trials since the pathology of renal diseases is complicated. The fourth, early management of renal disease is crucial. So it's of great significance to explore, develop and validate the surrogate endpoints since the disease progresses slowly and the investigation often requires both long study cycle of several years or even longer and a larger sample size. The surrogate indicators should be selected prudently. The sponsors are suggested to communicate with the regulatory agency when necessary. The fifth, a sufficent safety study can be very supportive to the general evaluation of benefit-risk balance.

OBJECTIVE To discuss technical considerations for the design of efficacy evaluation indicators for drugs used in the treatment of kidney disease. METHODS Based on practical experience in disease characteristics, drug development, and evaluation, technical recommendations were proposed for designing efficacy evaluation indicators for kidney disease treatment drugs. RESULTS and CONCLUSION Renal failure and cardiovascular death are considered as the primary clinical outcomes for evaluating the efficacy of drugs used in kidney disease treatment. Based of the urgent clinical need and slow progression of kidney disease, exploring the selection and application of intermediate/surrogate indicators holds significant clinical value. Some evidence suggests that improvement in estimated glomerular filtration rate (eGFR) slope can partially predict the clinical benefits of treatment on chronic kidney disease (CKD) progression, making it a potential alternative indicator for early or slowly progressing CKD patients in drug trials. The correlation between elevated urinary protein levels and duration with renal function loss in lupus nephritis, membranous nephropathy, and IgA nephropathy indicates their potential for predicting renal outcomes; however, further research evidence is still required. In conclusion, when selecting indicators to evaluate efficacy, scientific design should be based on trial objectives, target population characteristics, drug mechanisms of action, and effect intensity while carefully considering surrogate indicators.

OBJECTIVE To explore general technical considerations for the clinical trial design of drugs targeting lupus nephritis treatment. METHODS By conducting comprehensive research on relevant technical standards both domestically and internationally, synthesizing the experience gained from recent drug development endeavors, and integrating disease characteristics, treatment requirements, and evaluation practices, the holistic design of clinical trials for lupus nephritis drugs were explored from a technical evaluation perspective which including examining participant selection criteria, efficacy indicators, safety evaluations, and proposing key technical considerations. RESULTS and CONCLUSION The recommended research design is a multicenter, randomized, double-blind, parallel-controlled design typically conducted using standard treatment protocols. Including participants who have undergone renal biopsy within 6 months prior to randomization can enhance the representation of baseline characteristics. In terms of efficacy evaluation indicators, relying solely on a single indicator is insufficient to fully capture the effectiveness of the drug; therefore, composite indicators are commonly employed for comprehensive assessment purposes. The primary efficacy evaluation indicator should be the complete renal remission rate, with criteria that accurately reflect clinically significant improvement in kidney function. Secondary efficacy indicators should encompass multiple dimensions aligned with clinical treatment goals for lupus nephritis and include assessments of glucocorticoid and/or immunosuppressant dosage reductions, long-term renal outcomes (such as progression to end-stage kidney disease), as well as evaluations of SLE manifestations and overall activity levels. Safety aspects necessitate vigilant monitoring for risks such as infection, cardiovascular events, malignant tumors, and potential impacts on renal function posed by novel drugs.

Drug combination therapy is the combination of two or more drugs in the form of "formulas" to achieve the effect of increasing efficacy and reducing toxicity. It has achieved good results in the treatment of various complex diseases and overcoming drug resistance in patients. In the past few decades, Western medicine has gradually increased its efforts in the development of combination drugs and has achieved good results in the discovery and screening techniques of combination drugs. Traditional Chinese medicine (TCM), with the characteristics of “multi-components, multi-targets, and multi-pathways”, is a reliable ingredient library for synergistic drug combinations due to its years of clinical use. This paper summarizes the application of combinatorial drug discovery methods in the past decade, including systems biology, histology, machine learning, and mathematical modeling. It also explains the advantages and shortcomings of each method. It aims to provide new ideas and approaches for identifying potential combinations of active ingredients in traditional Chinese medicine, reducing blind tests and studies, and evaluating the interaction relationships of drug combinations.

OBJECTIVE To evaluate the quality consistency for the different qualities of Chinese medicine preparation (PCM) with the same raw material? and develop a method for measuring dissolution rate of Ginkgo biloba leaves tablets(GLT) as a model by flow-through cell(FTC) method. METHODS A closed-loop flow tank system was adopted, the GLT were placed in the circulating tank which was preloaded with glass beads, taking 150 mL water as the dissolution medium, with the flow rate of 8 mL·min^-1, the temperature was (37±0.5) ℃, the pulse frequency was 0 Hz, and sampling 3 mL each at 30, 60, 120, 180 and 240 min, respectively, at the same time, 3 mL of preheated fresh dissolution medium were replenished. HPLC analysis was conducted to determine the contents and cumulative dissolution rates of five ingredients (manghaslin, clitorin, rutin, nicotiflorin and narcissoside), and corresponding dissolution curves were plotted. Nine batches of markerted GLT from three manufactures were determined, and their similarity factors and dissolution models were fitted. RESULTS The contents of five flavonoids glycosides in GLT from the same specification of different manufacturers were consistent, but their cumulative dissolution rates in 4 hours were from 10% to 90% within different batches from different manufacturers, and most of them were lower than the conventional standard of 70%. It indicates that although the raw materials are same, different production processes details may lead to great differences in marketed product qualities and clinical efficacy. Therefore, to ensure the effectiveness and consistency of the quality of PCM, it is very important to carry out dissolution rate inspection in PCM quality standard. CONCLUSION The established FTC dissolution test method can distinguish the dissolution behavior of samples from different manufacturers, which could reflect the influences of technology and prescription on product quality, which has important practical value for regulating medicinal production.

OBJECTIVE To investigate the mechanism by which Viaminate treats hyperkeratosis of ear acne epidermis in rats. METHODS Thirty male SD rats were randomly divided into three groups: control group, model group, and viaminate-treated group. The formation of ear acne was induced by combining Propionibacterium acnes with a sebum smear. After successful modeling, viaminate was administered orally every 12 h for 30 d. Acne tissues were collected from the rats after the treatment, and immunohistochemical, Masson, and hematoxylin-eosin staining were performed to assess histopathology. Transcriptomic sequencing and molecular docking were conducted to analyze the target of viaminate. The effect of viaminate on the selected protein was confirmed using western blotting. Retinol binding protein 4 (RBP4) was silenced in HaCat cells to verify the targeting relationship between viaminate and RBP4. RESULTS After 30 days of treatment with viaminate, significant improvements were observed in the symptoms of rat ear swelling, epidermal thickening, and inflammation. Additionally, the expression of the keratinization-related proteins, vimentin and keratin 6 (KRT6), was inhibited. Transcriptomic analysis revealed that viaminate had a notable regulatory effect on the keratinization pathway. Molecular docking results suggested that RBP4 may be a critical target of viaminate. Western blotting results demonstrated that viaminate could upregulate the expression of RBP4/retinoic acid receptor γ (RARγ) protein in rats with acne. In addition, viaminate significantly inhibits abnormal proliferation and the expression of vimentin and KRT6 in HaCat cells induced by P. acnes. It also downregulates the phosphorylation of Akt. However, after transfection with RBP4 siRNA, the regulatory effects of viaminate on the aforementioned phenomena are significantly reversed. CONCLUSION Viaminate improves acne by reducing excessive keratinization in rat epidermis via activation of RBP4/RARγ and downregulation of Akt phosphorylation. It also inhibits the proliferation and keratinization of human epidermal keratinocytes induced by P. acnes in vitro.

OBJECTIVE To prepare crystallinesolid dispersion(CSD)with ketoconazole (KET) and sorafenib (SOR) as model drugs and poloxamer188 (P188) as carrie, improve the dissolution rate of drug by reducing the drug particle size in vitro and discuss the mechanism of intermolecular interaction on drug particle size regulation. METHODS The drug-P188-CSD was prepared by rotary evaporation method. The intermolecular interaction and crystallization kinetics of drug-P188 in CSD were studied by solubility parameter method (SP), differential scanning calorimetry (DSC) and polarizing microscope (POM). Then the crystal domain size of drug in CSD preparation was measured by powder X-ray diffraction (PXRD). Finally, the solubilization effect of CSD preparation on insoluble drugs was evaluated by dissolution in vitro. RESULTS SP and DSC results showed that in CSD, the two model drugs interacted with P188, and the interaction between SOR and P188 was more significant. The results of POM and PXRD showed that the interaction of drug-P188 would inhibit the crystallization of P188 and reduce the drug particle size by comprehensively regulating the nucleation rate and growth rate of the drug crystal. At the same time, the stronger the interaction force, the stronger the inhibition effect on P188, and the greater the reduction of drug particle size in CSD. The results of dissolution in vitro showed that CSD preparation can effectively improve the dissolution of the drug. The smaller the particle size, the greater the percentage cumulative dissolution rate. CONCLUSION The stronger the interaction between drug and P188 in CSD, the greater the reduction in drug particle size, and the more significant the solubilization effect.

OBJECTIVE To prepare bimodal mesoporous silica nanospheres loaded with doxorubicin, and evaluate their adsorption/ desorption properties and proliferation inhibition effects on cancer cells. METHODS bimodal mesoporous silica nanospheres(BMSNs) were prepared using sol-gel method and thermal treatment. The nanospheres were analyzed and characterized using scanning electron microscopy, specific surface area and porosity analyzer, Fourier transform infrared spectroscopy, and UV-VIS spectrometer. The adsorption/desorption characteristics of DOX by BMSNs were investigated by adsorption experiment. The proliferation inhibition effects of BMSNs-DOX on MCF-7 cells and A549 cells were detected using CCK8 method. RESULTS Compared with mesoporous MCM-41, which has typical uniform mesopores, BMSNs could provide more favorable matter diffusion and adsorption capacity towards DOX due to their more expansive pore structure. At pH=7.0, BMSNs exhibited a high adsorption capacity for DOX of 91.7 μmol·g^-1 (equivalent to a drug loading capacity of 5.32%), which was 1.6 times higher than that of MCM-41. In pH=5.0 buffer solution, BMSNs-DOX desorbed (released) DOX molecules with an efficiency of about 96%, in just 30 minutes. BMSNs-DOX exhibited a stronger inhibitory effect than MCM-41-DOX and DOX. At a concentration of 4 μg·mL^-1, the survival rate of MCF-7 cells and A549 cells was only 23.67% and 15.79% respectively. CONCLUSION Compared with MCM-41, BMSNs is expected to release DOX to cancer cells more efficiently. BMSNs-DOX exhibits a significant inhibitory effect on MCF-7 cells and A549 cells, suggesting its potential as a drug carrier to enhance the cytotoxicity of chemotherapy drugs on cancer cells.

OBJECTIVE To establish a high-throughput qualitative analysis method for the Zhuang medicine Tongfeng Li'an Capsule use by Q-exactive orbitrap HRMS mass spectrometry. METHODS HPLC part on GOLD C₁₈ column(2.1 mm×100 mm,1.9 μm) and the gradient elution was performed with mobile phase consisting of 0.1% formic acid acetonitrile -0.1% formic acid aqueous solution. Flow velocity was 0.3 mL·min^-1, injection volume was 3 μL, column temperature was maintained at 35 ℃, mass spectrometry part used HESI ion source, Full MS/dd-MS² mode, ion scan range 100-1 500, vertex excitation for 2-8 s. RESULTS A total of 49 compounds were identified from Tongfeng Li'an Capsule by orbitrap HRMS, including 19 phenylpropanoids, 11 terpenes, 10 organic acids, 3 phenols, 2 anthraquinone, 2 alkaloids and vitamins, and 2 sugars and glycols. Among them, 46 compounds were identified for the first time from Tongfeng Li'an Capsule. CONCLUSION Data for high-resolution gather with orbitrap HRMS method was the first time comprehensive qualitative characterization conducted on Tongfeng Li'an Capsule, This provides a material basis and new scientific research basis and reference for its multi-component analysis application, quality standard improvement, and pharmacological research.

OBJECTIVE To promote individualized mediaction of vancomycin in pediatric patients by model-informed precision dosing. METHODS The data of vancomycin serum concentration were collected, and the population pharmacokinetics model, which is suitable for Chinese children, was selected through literature search and external validation. The optimal model was embedded into the user-defined module of JPKD software, and a prediction program of individualized medication was established based on maximum a posteriori-Bayesian. This program was applied to individualized dose adjustment for pediatric patients. Case-based clinical practice was used to evaluate the application of this program. RESULTS A total of 32 vancomycin concentration data collected from 22 children with a median age of 6.04 years (44 weeks to 14.58 years) were used for external validation. Comparing the predicted concentration with the measured concentration, the mean prediction error, mean absolute prediction error and mean squared prediction error were (0.098 4±0.141) (0.109±0.133) mg·L^-1 and (0.029 0±0.087 2) mg²·L^-2, respectively. The results of external validation showed that the selected model had an acceptable predictive performance and was appropriate for the target group in this study. Dosing regimens of vancomycin were adjusted for four pediatric patients based on the predicted results of individualized adjuvant medication program, which led to an effectively improved target attainment situation of vancomycin trough concentration and AUC_{24 h}, significantly convalescent clinical symptoms and inflammatory indicators, while no adverse reactions occurred. CONCLUSION In the current study, a prediction program for individualized medication of vancomycin is successfully established by independent programming and applied to clinical cases. It guarantees the effectiveness and safety of anti-infective therapy for patients.

OBJECTIVE To explore the occurrence and characteristics of remdesivir-related bradyarrhythmia and provide references for clinical safe drug use. METHODS The case reports of remdesivir-related bradyarrhythmia published in PubMed, Embase, CNKI, Wanfang and VIP were searched from the establishment of each database to October 2023, and statistical analysis was conducted on relevant information and data. RESULTS A total of 32 cases from 23 articles were identified and included in the analysis. There were 16 males (50.0%) and 14 females (43.8%), aged from 3 months to 80 years, with an average age of (43.1±23.5) years. Twenty-seven patients (84.4%) experienced bradyarrhythmia within 3 days after medication. When bradyarrhythmia occurred, the heart rate decreased by 25.0% to 76.0% from baseline, and 20 patients (62.5%) presented with severe bradyarrhythmia. After withdrawal or continuation of treatment and symptomatic management such as atropine or cardiac pacing, all patients had a good outcome except for 2 cases (6.3%) who eventually died from exacerbation of the primary disease. CONCLUSIONS Clinical monitoring of the patient's heart rate should be strengthened during the use of remdesivir, especially in the first 3 days after medication. Once bradyarrhythmia is found, the patient's condition should be comprehensively considered to decide whether to stop remdesivir, and atropine or cardiac pacing can be inserted if necessary.