New outlook on safety of traditional Chinese medicine: concept and practice / 中国中药杂志

Profound changes have taken place in human disease spectrum, constitution spectrum, and drug use behavior, and the safety of traditional Chinese medicine(TCM) faces new trends and problems. In particular, serious adverse reactions/events such as liver injury and kidney injury caused by non-toxic TCM have been frequently reported, overturning people's understanding of TCM safety, and even shaking the public's confidence in the development of TCM. In the new era of globalization, correctly understanding the situation and problems of TCM safety and addressing the dilemmas in safety evaluation and risk prevention of TCM are the key missions to be undertaken by TCM practitioners. This paper suggests that the situation and problems of TCM safety should be viewed objectively and dialectically, and the use standard of TCM should be advanced with the times. Furthermore, this paper puts forward the new conception and methodology of TCM safety(including one innovative understanding, two types of evaluation modes, tri-elements injury hypothesis; four-quadrant risk decision processes, and five-grade safety evidence body) for the first time, hoping to provide new theories, new strategies, new methods and successful examples for solving the safety problems of TCM.

Problems and thoughts in clinical safety evaluation of traditional Chinese medicine / 中国中药杂志

Amid the modernization and internationalization of traditional Chinese medicine(TCM), the safety of TCM has attracted much attention. At the moment, the government, scientific research teams, and pharmaceutical enterprises have made great efforts to explore methods and techniques for clinical safety evaluation of TCM. Although considerable achievements have been made, there are still many problems, such as the non-standard terms of adverse reactions of TCM, unclear evaluation indicators, unreasonable judgment methods, lack of evaluation models, out-of-date evaluation standards, and unsound reporting systems. Therefore, it is urgent to further deepen the research mode and method of clinical safety evaluation of TCM. Based on the current national requirements for the life-cycle management of drugs, this study focused on the problems in the five dimensions of clinical safety evaluation of TCM, including normative terms, evaluation modes, judgment methods, evaluation standards, and reporting systems, and proposed suggestions on the development of a life-cycle clinical safety evaluation method that conformed to the characteristics of TCM, hoping to provide a reference for future research.

Interpretation of guidance on non-clinical safety evaluation for nanomedicines / 药学学报

With the rapid development of nanotechnology, the research and development of nanomedicines have become one of the development directions of drug innovation. Nanomedicines have special physical and chemical properties, such as nanoscale effects and nanostructure effects, so they have special biological properties, which may change the pharmacokinetic profiles such as absorption and tissue distribution of drug molecules, and thus affect their safety and effectiveness. There are many special concerns on the non-clinical safety evaluation of nanomedicines at the basis of ordinary drug because of the particularity of nanomedicines. On August 25, 2021, China issued Guidance on Non-clinical Safety Evaluation for Nanomedicines(interim). This article interprets comprehensively the guidance, focuses on the key points of non-clinical safety evaluation for nanomedicines, and expounds combined with some cases, aiming to provide reference for drug researchers.

Research progress on non-clinical safety evaluation of SARS-CoV-2 vaccine / 中国生物制品学杂志

@#The Coronavirus Disease 2019(COVID-19) pandemic is having a dramatic impact on human health,lives,and the global economy. The development of a safe and efficacious vaccine is the most effective intervention to protect the population from the disease and limit the spread of the virus. Based on the current guidelines and research progress of severe acute respiratory symptom coronavirus 2(SARS-CoV-2) vaccines in various countries,this review summarized the research progress on non-clinical safety evaluation of SARS-CoV-2 vaccines by referring to the guidelines and relevant literatures over the world,in order to provide a reference for non-clinical research of SARS-CoV-2 vaccines.

Modern Research of Nasal Preparations of Traditional Chinese Medicine： A Review / 中国实验方剂学杂志

Nasal preparations have unique advantages in drug delivery and are widely used in the treatment of local and systemic diseases. Nasal administration of traditional Chinese medicine （TCM） has a long history in China. In recent years， nasal preparations of TCM have attracted wide attention. Based on the information about nasal preparations of TCM from the database of National Medical Products Administration （NMPA）， Yaozh.com and China National Knowledge Internet （CNKI） in the recent 30 years， the formulation， the listed products， commonly used TCM， pharmaceutical excipients， clinical application and safety research of modern nasal preparations of TCM were summarized and expounded. Focusing on many problems in the development of modern nasal preparations of TCM， such as inaccurate dosage of some products， incomplete quality standard system of pharmaceutical excipients， imperfect safety evaluation， lack of research and development of nasal drug delivery devices and so on， the possible solutions and prospects were put forward from the aspects of optimizing the extraction and separation process of TCM， the quality control and application method of pharmaceutical excipients， the development of new dosage forms， the safety evaluation of nasal administration of TCM， and the design and development of nasal administration devices. The aim is to provide ideas for the development of nasal preparations of TCM and provide scientific basis for its sustainable utilization.

Quercetin Against Cerebral Ischemia-reperfusion Injury： A Review / 中国实验方剂学杂志

Cerebral ischemia-reperfusion injury （CIRI） is a further injury of brain tissue after the recovery of blood supply in ischemic stroke， which seriously affects the quality of life of patients. The pathological mechanism of CIRI is complex， mainly involving excitatory amino acid toxicity， apoptosis， inflammation， and oxidative stress. Studies have proved that Chinese herbal medicines and their active components have unique advantages and good application prospects in the prevention and treatment of CIRI. Quercetin is a flavonoid ubiquitous in a variety of Chinese medicinal herbs. It can alleviate CIRI and reduce brain injury through inhibiting inflammation， oxidation， and apoptosis， protecting blood-brain barrier， and activating mitophagy. However， little is known about the specific mechanism and molecular targets. In view of the low bioavailability and poor solubility of quercetin， researchers have developed a variety of delivery systems to facilitate the dispersion of quercetin， improve chemical stability， and increase clinical application. Furthermore， researchers have tested the long-term safety of quercetin and confirmed that low-dose quercetin has good safety. By reviewing the relevant studies in recent years， we summarized the targets， mechanism， delivery， and safety of quercetin in the treatment of CIRI， aiming to provide a theoretical basis for the further development and application of quercetin.

Evaluation on Surgical Robotic Pose Repeatability Based on Laser Tracking Measurement / 中国医疗器械杂志

To provide accurate information for registration and safety evaluation of surgical robot, the pose repeatability measurement method was proposed. According to the terminal instrument of the master-slave surgical robot (such as high-frequency electric knife, ultrasonic knife), a suitable target ball fixture was designed. The node data at 10%, 50% and 100% rated speed were measured respectively. Through data analysis, the pose repeatability property of the tested samples at different speeds was obtained. It has high applicability and repeatability, and can meet the requirements of data traceability and registration testing.

Construction and exploration of pregnancy registries for medicine based on pharmaceutical service / 中华医院管理杂志

The pregnancy registry for medicine is a common method for risk evaluation for drug safety evaluation during pregnancy. The authors introduced the exploration and practice of the pregnancy drug registry mode based on pharmacy service in Women′s Hospital School of Medicine Zhejiang University. The registry of pregnancy medication with the drug consultation clinic as the fulcrum was managed by the pharmacist team in a homogenization way, and implemented according to the information process of consultation, pharmacy guidance and regular follow-up. In the consultation and follow-up work, the pharmacists established the consultation drug history through three data sources: independent report of the consultant, inquiry of pharmaceutical personnel and case sampling. The pharmacists designed and constructed information screening system, classified the consultation medicine history according to the pregnancy exposure of specific drugs. The prospective research method was designed to meet the characteristics of pregnancy medication. The study was carried out on the relationship between pregnancy exposure and birth defects of offspring. Relying on the improvement of standardization, refinement and information management level of pharmaceutical services, multi center cooperation will be strengthened in the future to carry out continuous research on pregnancy drug exposure registry and follow-up system.

Synthesis，anti-melanoma activity and acute toxicity of aporphine alkaloids in zebrafish / 中国药科大学学报

@#In this study, 10 aporphine alkaloids were synthesized with 1, 2-methylenedioxy substituent in ring A and 9, 10, 11-position with different substituents in ring D. Their structures were determined by ESI-MS,13C NMR and 1 H NMR.The potencial antitumor activity of these compounds against B16F10 melanoma cells were evaluated by MTT assay, and their structure-activity relationship was further analyzed.Meanwhile, zebrafish acute toxicity test was conducted to evaluate the safety of the active compounds.The results showed that some compounds had strong inhibitory activity on tumor cells, and could significantly inhibit the proliferation of B16F10 melanoma cells.Compound IVa has the best anti-melanoma activity with wide safety range, and can be used as a lead compound for further study on anti-proliferation of B16F10 melanoma cells.

Different methods establish a rat model of morphine drug discrimination with a fixed ratio 10 / 药学学报

In this study, a rat morphine drug discrimination model with a fixed ratio (FR) of 10 (FR10) was established using different methods to explore which methods can shorten the modeling time and test the dose-response relationship and median effective dose (ED50) value. Animal welfare and experimental procedures are in accordance with the provision of the Animal Ethics Committee of Shanghai InnoStar Bio-tech Co., Ltd. Forty rats were initially shaped to press lever under a fixed-ratio schedule of food reinforcement. The animals that were successfully trained under a FR10 schedule of food reinforcement were divided into two groups, namely the single-lever + double-lever training group 1 and the double-lever training group 2. In each group, rats were trained to discriminate morphine at 5.6 mg·kg-1 from saline by the intraperitoneal route. After training, different doses of morphine were used to substitute for training dose of morphine, the dose-response curve for morphine were identified in rats, and the ED50 value was calculated. The results showed that, in food training phase: 34 rats successfully entered the discrimination training during food training; in discrimination training phase: 14 animals in group 1 met the discrimination training standard for the first time, which took about (40.71 ± 2.93) days, and there were 13 animals in group 2 that met the discrimination training criteria for the first time, and it took about (51.15 ± 2.55) days. It can be seen that the method of single-lever + double-lever training is better than single-lever training, and the difference is significant compared with group 1 (P ˂ 0.05); in generalization test phase: there are 17 rats completed morphine generalization test, and the percentages of morphine-lever responses produced by the generalization test of different doses of morphine (0, 0.1, 0.5, 1, 3, 5.6, and 10 mg·kg-1) were (9.56 ± 3.13) %, (9.01 ± 5.83) %, (13.82 ± 7.95) %, (29.04 ± 10.13) %, (41.70 ± 10.65) %, (85.36 ± 7.16) %, (94.56 ± 2.76) %, respectively. The results showed that the discriminative stimulative effect induced by morphine dose between 0-10 mg·kg-1 increased in a dose-dependent manner, producing a good dose-response curve, and the ED50 value of morphine was 4.74 mg·kg-1 by linear fitting. The above results showed that, the FR10 morphine drug discrimination model has been successfully established using different methods; the single-lever + double-lever training method is better than the single-lever training, and can relatively shorten the discrimination training cycle.

Evaluation of self-prepared absorbable hemostatic cellulose fibrils / 浙江大学学报·医学版

To evaluate the effectiveness and safety of self-prepared absorbable hemostatic fibrils.A kind of absorbable hemostatic fibrils were prepared by self-developed patent technique. The physical form and molecular structure of the fibrils and a marketed product Surgicel were characterized by general observation and infrared spectroscopy; the carboxyl content, pH value and relative molecular mass of fibrils were determined by potentiometric titration method, pH meter and copper ethylenediamine method, respectively. The behavior of the fibrils and Surgicel in contact with blood was observed by inverted microscope, the cytotoxicity was evaluated by agarose diffusion cell assay . The external iliac artery hemorrhage model and the back muscle infiltration model in rats were established. The hemostatic effectiveness of the fibrils was investigated by hemostasis time and blood weight, and the degradation and biosafety of fibrils were investigated by observation photography, immune organ weighing, hematology and coagulation index measuring, and histopathological examination. The fibrils and Surgicel had similar molecular structures. Compared with the raw material regenerated cellulose, the typical carboxyl stretching vibration absorption peak of -COOH appeared near in both fibrils and Surgicel. The carboxyl content of the two materials was about 20%, and the pH value was about 3. The relative molecular mass of the fibers after oxidation was 4466±79, which was close to that of Surgicel(>0.05). After contacting with blood, the volume of fibrils and Surgicel expanded, and absorbed blood of dozens of times as their own weight. The results of agar diffusion test showed that the fibrils had no cytotoxicity. The results of animal experiments showed that the hemostasis completed within and there was no significant difference in blood weight and speed of hemostasis between two products (both >0.05). The fibrils could be degraded 1 week after being implanted to the bleeding sites of the muscle. There were no pathological effects on the appearance, body weight, food intake, immunological tissue thymus, spleen, lymph nodes, hematology and coagulation indexes of the rats, and no obvious abnormality found in the histopathological examination. The prepared absorbable hemostatic fibrils have excellent biological safety and effectiveness.

Safety of Alginate-based Gastric Mucosal Protective Adhesive and Feasibility Study of Its Use as Submucosal Injection / 中国医疗器械杂志

OBJECTIVE@#To study the safety of alginate based gastric mucosal protective adhesive and its feasibility as a submucosal injection.@*METHODS@#The feasibility of using alginate-based gastric mucosal protective gel as submucosal injection was evaluated by @*RESULTS@#After injection of different concentrations of alginate base mucosal protective adhesive solution, the uplift height was significantly higher than that of normal saline (@*CONCLUSIONS@#Gastric mucosa protector is a promising new medical device product with feasibility and good biocompatibility as submucosal uplift injection agent.

Withania somnifera: a kind of food-medicine plant popular in world in recent years / 中国中药杂志

Withania somnifera, also known as Indian ginseng, is an important traditional medicine in the Ayurvedic medical system of India, which has a significant effect of adaptation. Modern studies have shown that the main chemical components of W. somnifera are withanolides, which have antioxidant, anti-tumor, enhancing immunity, cardiovascular protection, neuroprotection, anti-stress, anti-stress reaction and hypoglycemic activities. Studies on human, animal, mutagenesis, genotoxicity, reproductive toxicity and drug interaction showed that W. somnifera had good safety. Clinical trials have proved that W. somnifera is effective in treating a variety of human diseases. As a famous traditional medicine and modern dietary supplement, it has a high reputation and market in the international health product market, but in China, there is little scientific research, market development, product introduction and application. In this paper, the traditional application, chemical composition, pharmacological activity, safety evaluation and clinical study of the plant were introduced, so as to increase the understanding of the dual use of the plant, and to provide reference for the future introduction of the product, the service to the health of the Chinese people and the promotion of the "double cycle" of the trade of health products between China and the international community.

Analysis on the suspected adverse events following immunization surveillance reports of pneumonia vaccine in Shanghai， 2010‒2020 / 上海预防医学

Objective:To analyze the collected data of adverse events （AEFI） of pneumonia vaccine in Shanghai from 2010 to 2020，， so as to provide the appropriate immunization strategy and popularization of science for pneumonia vaccine . Methods:the data of suspected adverse events were collected from National AEFI Surveillance System during 2010 to 2020， and the vaccination information of pneumonia vaccine was obtained from Shanghai Vaccination Information System. Descriptive epidemiological method was used to analysis. Results:The total 18 446 AEFI cases were reported in Shanghai from 2010 to 2020， and the incidence rate was 425.0/100 000 doses. The general reactions were reported as 18 003 cases （97.6%）， with 393 cases of abnormal reactions （2.0%）， 57 cases of coincidences （0.3%）， 2 cases of psychogenic reactions （<0.1%） and no vaccine quality accident or vaccination accident was reported. There was no significant difference in the incidence rate between male and female； The incidence rate of AEFI decreased with the age of the old. The incidence rate of 23 valent pneumococcal polysaccharide vaccine （PPV23） AEFI was 476.5/100 000 doses， which was significantly lower than that of other kinds of pneumonia vaccine. The first dose was also significantly higher than that of non-first dose. Conclusion:The various types of pneumonia vaccines being used in Shanghai have high safety.

In Vivo Pharmacodynamics and Safety Evaluation of Lactose-Doxorubicin Drug-Drug Conjugate Nanomicelle / 中国药学杂志

OBJECTIVE: The lactose-doxorubicin amphiphilic small molecule nanomicelles and evaluate its liver cancer targeting and antitumor efficacy and safety in vivo. METHODS: Lactose-doxorubicin nanomicelles (Lac-DOX NMs) were prepared by thin film hydration method. The particle size was determined by dynamic light scattering and observed by transmission electron microscopy. The effect of Lac-DOX NMs on the targeting of tumor cell was investigated by cell uptake experiments.Cytotoxicity of nanomicelles and free doxorubicin were evaluated by CCK-8 assay.The subcutaneous xenograft model of BALB/c-nu mice was constructed to investigate the anti-tumor effect of Lac-DOX NMs; the effect of the preparation on liver function of mice was examined by blood biochemical test to evaluate the safety of the preparation.RESULTS: Lac-DOX NMs were successfully prepared with a particle size of (169.2±0.9) nm. Cellular uptake experiments indicated that Lac-DOX NMs are targeted to HuH-7 hepatoma cells.The IC50 of nanomicelle and free DOX were 3.596 and 2.131 μg•mL-1, respectively. The results of pharmacodynamic experiments showed that Lac-DOX NMs could significantly inhibit the growth of transplanted tumors in mice. The tumor inhibition rates of high and low doses of Lac-DOX NMs were 69.72% and 52.40%, respectively, which were higher than those of free DOX (52.27%). P values are 0.000 16 and 0.94. CONCLUSION: Modification of doxorubicin with lactose and its preparation into nanometer preparations can significantly improve the targeting of doxorubicin to liver cancer cells, enhance the anti-tumor effect, reduce the side effects of doxorubicin, and improve the safety of medication.

Bioaccessibility Measurement and Safety Evaluation of Elements in Decoction of Zhebawei Traditional Chinese Medicines / 中国药学杂志

OBJECTIVE: To study the bioaccessibility and evaluate the safety of inorganic elements in decoction of "Zhebawei" traditional Chinese medicines (TCMs). METHODSE: The bioaccessibility of inorganic elements in decoction of "Zhebawei" TCMs was measured based on in vitro digestion and inductively coupled plasma atomic emission spectrometer (ICP-AES) and the safety of these elements were evaluated by comparing with the safe limits issued by the FAO and WHO. RESULTS: The bioaccessibility of the inorganic elements was less than 1, and varied among different elements of the same herbal medicine or for the same element among different herbal medicines. Cd, V, Se, Cr, Sn, and As were not detected in the dialysate of some TCMs' decoction after in vitro digestion because of the total content being low or undetected in decoction. The result of safety evaluation showed that the daily intakes of Ni, Fe, Mn, Se, Cu, Zn, Co, V, Cr from the decoction of "Zhebawei" TCMs were all within safe limits. The daily intakes of Cd and Sn did not exceed the level of personal acceptable daily intake instituted by the FAO and WHO. The total content in the decoction of Rhizoma Corydalis was more than the level of personal acceptable daily intake instituted by FAO and WHO, however the amount in the dislysate of "Zhebawei" TCMs' decoction after in vitro digestion were under the standard. The analysis of total content may exaggerate the risk of toxicity. CONCLUSION: The results will provide the basis for further researches such as bioavailability and safety of inorganic elements in "Zhebawei" TCMs, and will provide references for ensuring the rational use of TCM according to the analysis of inorganic elements.

Effects of Dendrobium officinale flowers on testivular tissue and sperm quality in parent and offspring rats / 预防医学

Objective@#To learn the effects of Dendrobium officinale flowers on testivular tissue morphology and sperm quality in parent and offspring rats,so as to provide reference for safety evaluation of Dendrobium officinale flowers.@*Methods@#The 40 SD rats was randomly divided into the low-,middle-,high-dose and the control group,given 2.0,4.0,6.4 and 0 g/kgbw Dendrobium officinale flowers,respectively. After three months,the body weight,mass and organ/body coefficients of testis and epididymis of parent （P） and offspring （F1,F2） rats were measured;the number,activity and deformity of sperms were observed under microscope;the changes of testis and epididymis were observed by hematoxylin eosin staining. @* Results@#There were no significantly statistical differences in the body weight,mass and organ/body coefficients of testis and epididymis,sperm quantity,sperm motility rate among four groups of P、F1、F2 male rats （P>0.05）. There were no significantly statistical differences in sperm malformation rate between the high-dose group and the control group （P>0.05）. There was no significant change in testis and epididymis of P,F1 and F2 male rats. @*Conclusion@#Dendrobium officinale flowers did not show obviously adverse effects on testivular tissue morphology and sperm quality in parent and offsping rats.

Research on entity relation extraction of Chinese adverse drug reaction reports based on deep learning method / 中国药科大学学报

@#Adverse drug reaction(ADR)reports are acting as primary sources for post-marketing drug safety evaluation, which have important reference value for drug safety evaluation. In this article, bidirectional gated recurrent unit, a kind of deep learning method, was applied as the model for relation extraction of drugs and adverse reactions in free-text section of ADR descriptions in Chinese ADR reports, with attention as well as character embedding and word segmentation embedding added into the network. The experimental results showed that our model achieved good performance in the classification task of confirming the relationship of “Drug-ADR” pair(denial, likely, direct and post-therapy)in the ADR description, and the final model achieved an F-value of 87. 52%. The extracted information can assist in evaluating ADR reports and at the same time be utilized in tasks like statistical analysis of certain drugs and adverse events and ADR knowledge base construction to provide more research techniques for drug safety researches.

Safety evaluation of a compound Chinese medicine preparation of gardenia / 预防医学

Objective@#To evaluate the toxicological safety of a compound Chinese medicine preparation of gardenia.@*Methods@#Eighty healthy SD rats with half males and half females were randomly divided into four groups. The low-,moderate- and high-dose group were given 1.00 g/kgbw,2.00 g/kgbw and 4.00 g/kgbw of the preparation,while the control group was given distilled water,by gavage for 30 days. The changes of diet,weight,hematological parameters and major organs of rats were observed,and the histopathological examination of the main organs was performed.@*Results@#The rats in the high-dose group reduced activities and their urine turned dark yellow or green,while the other rats showed no abnormality. No rats died during the experimental period. Compared with the control group,the weight,the total weight gain,the food utilization rate,the fasted weight of the rats in the high-dose group and the hemoglobin content of the female rats in the high-dose group were significantly decreased（P<0.05）;the ratio of liver to body weight,the ratio of kidney to body weight,the serum creatinine levels of the rats in the high-dose group and the serum urea nitrogen levels of the male rats in the high-dose group were significantly higher（P<0.05）. The livers and kidneys of the rats in high-dose group turned different degrees of dark green;the hepatic pigmentation,hepatocyte vacuolar degeneration,bile duct hyperplasia accompanied with inflammatory cell infiltration,renal pigmentation,renal tubular epithelial cellular swelling,and renal interstitial inflammatory cell infiltration were observed.@*Conclusion@#This preparation at a dose of 4.0 g/kgbw has hepatotoxicity and nephrotoxicity to rats. A dose of 2.0 g/kgbw has no harmful effect but less than 100 times of the possible human intake,the safety is not guaranteed.

Safety Evaluation of Over-ground Parts of Glycyrrhiza uralensis / 中国实验方剂学杂志

Objective: To evaluate the toxicological safety of over-ground parts of Glycyrrhiza uralensis, in order to provide basis for the rational utilization of over-ground parts of Glycyrrhizae Radix et Rhizoma recourses.Method: Mice acute oral toxicity test, micronucleus test of mice bone marrow, mice sperm shape abnormality test and toxicological test based on chronic nonbacterial prostatitis model were carried out.Result: Maximal tolerable dose(MTD) of over-ground parts of G.uralensis water extract (WE) and alcohol extract (AE) were 96,128 g·kg-1, respectively. Macro-porous resin enriched product of AE was harmful to mice, with gender differences. Micronucleus rates of each dose(8,16,32 g·kg-1) group and control group for female mouse were 0.28%, 0.34%, 0.26% and 0.22%, respectively. Micronucleus rates of each dose(8,16,32 g·kg-1) group and control group for male mouse were 0.32%, 0.30%, 0.36% and 0.28%, respectively. Sperm shape abnormality rates of each dose group and control group were 3.16%, 3.01%, 2.67% and 3.23%, respectively. Micronucleus rate and sperm shape abnormality rate had no significant increase compared with the negative control. The 30-day repeated intragastric WE and AE had no effect on the general conditions of the model rats. Compared with normal group, AE group showed a significant decrease in heart weight, and significant increases in liver weight, liver index and kidney index (PPConclusion: The results indicated that both of WE and AE have potential toxicity. WE does not show any genetic toxicity to mice. Therefore, further studies shall be made for toxicological safety of over-ground parts of G. uralensis.