Safety, Pharmacokinetics and Pharmacodynamics of Multiple Escalating Doses of PEGylated Exenatide (PB-119) in Healthy Volunteers.

BACKGROUND AND OBJECTIVE: At present, the deficiency of ß-cell function is progressive in patients with type 2 diabetes mellitus. Exenatide cannot only control blood glucose well, but also promotes the regeneration and proliferation of islet ß-cells and improves the function of ß cells. However, it needs to be given twice a day, and there are many adverse reactions such as nausea. PEGylated exenatide (study code: PB-119) needs to be administered only once a week. The purpose of this experiment was to evaluate the safety, pharmacokinetics and pharmacodynamics of an escalating dose regimen of subcutaneous PEGylated exenatide injections in healthy subjects. METHODS: Twelve healthy young adult subjects in each group received once-weekly subcutaneous injections of 165 µg, 330 µg, and 660 µg PEGylated exenatide for 6 weeks. Plasma drug concentration was determined in venous blood collected across selected time points. Safety and tolerability were evaluated by monitoring adverse events, laboratory parameters, and electrocardiogram. Blood glucose, insulin,  glucagon and C peptide were monitored at different time points to evaluate the pharmacodynamics of PEGylated exenatide. RESULTS: A total of 11, 10, and 12 subjects completed the study in 165 µg, 330 µg, and 660 µg dose groups, respectively. After 6 consecutive weeks of administration, the t1/2 in the 165 µg, 330 µg, and 660 µg dose groups was 55.67 ± 11.03 h, 56.99 ± 21.37 h, and 54.81 ± 13.87 h, respectively. The Cavg was 4.22 ± 0.78 ng/ml, 6.03 ± 1.43 ng/ml, and 10.50 ± 3.06 ng/ml, respectively. AUCss was 708.59 ± 131.87 h•ng/ml, 1012.63 ± 240.79 h•ng/ml, and 1763.81 ± 514.50 h•ng/ml, respectively. The accumulation index was 1.15 ± 0.07, 1.17 ± 0.11, and 1.14 ± 0.07. The CLss/F was 241.25 ± 51.13 ml/h, 341.53 ± 73.62 ml/h, and 450.06 ± 313.76 ml/h, respectively. A total of 10 of 36 (27.78%) subjects in the three dose groups developed specific antibodies after consecutive subcutaneous injections of PEGylated exenatide. The Cavg and Cmax were higher than those of antibody-negative subjects. Furthermore, in antibody-positive subjects, CLss/F, t1/2, AUCτ, accumulation index, MRT(0-inf) and other parameters were lower than those of antibody-negative subjects. In the 165 µg dose group, two subjects (16.67%) experienced 4 adverse events. In the 330 µg dose group, no subjects reported adverse events. In the 660 µg dose group, 8 subjects (66.67%) reported 16 adverse events, which were mostly gastrointestinal. There were no significant changes in the pharmacodynamic parameters except the glucagon level at day 36 in the 660 µg dose group, the 2h postprandial insulin and C peptide levels at day 36 and day 50 in the 165 µg dose group compared with baseline (- 1 day). CONCLUSION: A once-weekly subcutaneous injection of 165 µg and 330 µg PEGylated exenatide is safe. No significant effects on blood glucose or pancreatic hormone levels were observed in the subjects within these dose groups. The pharmacokinetic parameters of PEGylated exenatide may be affected by immunogenicity. CLINICAL TRIALS REGISTRATION: The study is registered at clinicaltrials.gov (No. NCT03062774).

Clinical effectiveness of Er,Cr:YSGG lasers in non-surgical treatment of chronic periodontitis: a meta-analysis of randomized controlled trials.

The meta-analysis aimed to systematically evaluate all the available pieces of evidence concerning the clinical effectiveness of Er,Cr:YSGG lasers (erbium, chromium, yttrium scandium gallium garnet laser) in the non-surgical treatment of patients with chronic periodontitis, and provide guidance for clinicians about the application of Er,Cr:YSGG lasers during the process of non-surgical periodontal treatments. The meta-analysis was conducted with data extracted from 16 randomized controlled clinical trials (RCTs) that compare Er,Cr:YSGG lasers adjunct/substitute to scaling and root planing (SRP) with SRP alone for the treatment of chronic periodontitis published in English or Chinese from January 2000 to January 2020. The weighted mean differences (WMDs) and 95% confidence intervals (CIs) were counted for probing depth (PD) reduction, clinical attachment level (CAL) gain, and visual analogue scale (VAS) score. Heterogeneity of each study was evaluated with the Q test. The publication bias was measured using Begg's adjusted rank correlation test. Sixteen RCTs with 606 patients were included in the meta-analysis. There were statistically significant differences between Er,Cr:YSGG lasers adjunct/substitute to SRP and SRP alone in the PD reduction at 1-month follow-up (WMD = ­ 0.35, 95% CI [- 0.63, ­ 0.07], P = 0.013), 3-month follow-up (WMD = - 0.342, 95% CI [- 0.552, - 0.132], P = 0.001), CAL gain at 3-month follow-up (WMD = - 0.17, 95% CI [- 0.31, 0.03], P = 0.017), and VAS score (WMD = - 2.395, 95% CI [- 3.327, - 1.464], P = 0.000) immediately after treatment. There were no significant differences of PD reduction and CAL change at 6-month follow-up. The present meta-analysis indicated that Er,Cr:YSGG lasers provided additional effectiveness in PD reduction and CAL gain at short-term follow-ups and there was less pain compared with SRP alone.

Validation of Stenus (Hypostenus) primivenatus and Stenus (Hypostenus) yiae (Coleoptera, Staphylinidae, Steninae).

Holotype depository was not indicated for the new species, Stenus (Hypostenus) primivenatus and Stenus (Hypostenus) yiae, described as new in the publication Zhao Zhou (2008). Missing this important message made these two species-group names unavailable according to the fourth edition of the International Code of Zoological Nomenclature (the Code, ICZN, 1999: Article 16.4). This problem was first denoted by Schülke, M. Smetana, A. (2015).

Correction to: Safety, Tolerability and Pharmacokinetics of Single Dose Polyethylene Glycolated Exenatide Injection (PB-119) in Healthy Volunteers.

The original version of this article unfortunately contained a mistake.

Safety, Tolerability and Pharmacokinetics of Single Dose Polyethylene Glycolated Exenatide Injection (PB-119) in Healthy Volunteers.

BACKGROUND AND OBJECTIVE: Exenatide promotes insulin secretion and inhibits postprandial glucagon secretion. Polyethylene glycolated exenatide injection (PB-119), a derivative obtained by modification of exenatide, is more stable in metabolic behavior than exenatide in vivo. Our study aimed to evaluate the safety, tolerability and pharmacokinetic characteristics of polyethylene glycolated exenatide as a single subcutaneous injection in healthy volunteers. METHODS: Seventy subjects were randomly assigned to 8 incremental dosage groups (2, 5, 10, 25, 50, 100, 200 and 400 µg). The 2- to 50-µg groups had 8 subjects in each group (the ratio of test preparation to placebo was 3:1), and the 100- to 400-µg groups had 10 subjects in each group (the ratio of test preparation to placebo was 4:1). All the subjects received a single subcutaneous injection of polyethylene glycolated exenatide and placebo according to the dosage groups. The tolerability test was conducted in the 2- to 10-µg groups. The pharmacokinetic test was carried out in the 25- to 400-µg groups, and plasma samples were collected to determine the pharmacokinetics of polyethylene glycolated exenatide. After medication, the vital signs of the subjects were monitored, and laboratory tests and electrocardiogram tests were carried out regularly in all the subjects. RESULTS: All 70 subjects completed the experiment. Except for the 5-µg and 10-µg groups, the safety and tolerability tests showed no adverse reactions in the 2-µg to 50-µg groups. Several subjects in the 100-µg and 200-µg groups had tolerable gastrointestinal tract reactions, and all subjects in the 400-µg group experienced adverse reactions, mainly gastrointestinal tract reactions and liver dysfunction. The pharmacokinetics of polyethylene glycolated exenatide was studied in 36 subjects, which showed slow absorption, a mean peak time of 20-40 h, and a mean elimination half-life of 51-64 h. CONCLUSION: The administration of polyethylene glycolated exenatide injection at a single dose of 2-200 µg is safe and tolerable for healthy volunteers. Once-weekly polyethylene glycolated exenatide injection can be recommended. CLINICAL TRIALS REGISTRATION: The study was registered at clinicaltrials.gov (No. NCT02084251).

Design, Preparation and Studies Regarding Cytotoxic Properties of Glycyrrhetinic Acid Derivatives.

Glycyrrhetinic acid (GA) is a natural product with certain antitumor activity. In order to enhance the cytotoxicity, a total of eighteen derivatives of GA were designed and synthesized. Their cytotoxicity against MDA-MB-231cells (human breast cancer cells) and HeLa cells (human cervical cancer cells), were evaluated by the MTT method (3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide). The results indicated that these target compounds have a wide molar activity range and some of them show better activity than the commercial drugs gefitinib and doxorubicin. Compound 6g induces apoptosis of 7, 10 and 44% of MDA-MB-231 cells at 5, 10, and 20 µM, respectively.

Low genetic differentiation yet high phenotypic variation in the invasive populations of Spartina alterniflora in Guangxi, China.

Genetic variation and population structure may reflect important information for invasion success of exotic plant species and thus help improve management of invasive plants. Spartina alterniflora is an invasive plant that is a major threat to the economy and environment of the coastal regions in China. We analyzed the genetic structure and diversity of six populations of S. alterniflora differing in invasion histories in Guangxi, China. A total of 176 individuals from the six populations produced 348 AFLP fragments. The average heterozygosity was significantly lower than in the native population. And genetic bottlenecks were also detected in most populations. Standardized FST statistics (Φpt = 0.015) and AMOVA results indicated weak genetic differentiation. Genetic admixture and obviously isolation by distance indicated populations in Guangxi come from a pre-admixed population by a single introduction. High phenotypic variations of S. alterniflora in Guangxi influenced by soil salinity and temperature might be an important reason for the successful invasion.

A First-in-Human Safety, Tolerability, and Pharmacokinetics Study of Benapenem in Healthy Chinese Volunteers.

The objective of this trial was to investigate the safety, tolerability, and pharmacokinetics (PK) of benapenem administered by single or multiple intravenous infusions in healthy Chinese volunteers. The trial was divided into 3 parts. In part A, 94 subjects were enrolled in a double-blind, placebo-controlled, sequential-ascending-single-dose study. The subjects were randomly assigned to groups receiving placebo or benapenem for injection at doses of 62.5, 125, 250, 500, 1,000, 2,000, or 3,000 mg. The effects of intravenous infusion time on the subjects of 250-, 500-, and 1,000-mg groups were explored. In part B, 12 subjects were enrolled in a single-dose PK study under fasting conditions and received 250, 500, or 1,000 mg of benapenem for injection. In part C, 36 subjects were given 250, 500, and 1,000 mg of benapenem for injection once daily for 7 consecutive days. The results showed that benapenem for injection was well tolerated during the studies. The major observed adverse events were mild, and all were resolved spontaneously without any medical intervention. Benapenem was mainly excreted through the kidneys in the form of parent molecule and metabolites. The PK and safety profiles of benapenem in healthy Chinese volunteers support its once-daily dosing in future clinical investigations. (Part A, part B, and part C have been registered at ClinicalTrials.gov under identifiers NCT03588156, NCT03578588, and NCT03570970, respectively.).

Taxonomic study on the Chinese Steninae (Coleoptera, Staphylinidae), with descriptions of three new species of the Genus Stenus Latreille.

This is a taxonomic study on the genus Stenus Latreille (Coleoptera, Staphylinidae) from China and includes descriptions of three new species: Stenus renjiafenicus Lv et Zhou, sp. nov., from Yunnan, Stenus longchishanicus Lv et Zhou, sp. nov., from Sichuan, and Stenus napoensis Lv et Zhou, sp. nov., from Guangxi, with illustrations and photos of the taxonomic characters. A latest key to all Chinese species of Stenus tenuimargo group is modified to include the new species. The following 4 Stenus species, S. feae Fauvel, 1895, S. claritarsis Puthz, 1971 S. malickyi Puthz, 2008, and S. iustus Puthz, 1976 are newly recorded to China and are redescribed, with illustrations and photos of the taxonomic characters.

One New Species of the Genus Stenus Latreille (Coleoptera, Staphylinidae) from Hubei, China.

This paper treats the S. cephalotes group and S. indubius group (Coleoptera: Steninae) from China and includes description of one new species: Stenus wujiei Lv, Zhao Zhou, sp. nov. from Hubei, China. S. detestabilis Puthz and S. hui Tang Puthz are newly recorded to Hubei Province. Their diagnostic characters are illustrated.

[Effect of fertilization combinations of nitrogen, phosphorus, and potassium on four phenolic compounds of cultivated Rhodiola crenulata].

This study is aimed to explore the effect of nitrogen, phosphorus and potassium combined application on the active components of Rhodiola crenulata. R. crenulata was used as the research object, "3414" fertilization experiment were conducted with regular fertilization of NPK(N 60 kg·hm⁻², P2O5 100 kg·hm⁻²,KCl 160 kg·hm⁻²) to study the effect of different rates of NPK fertilization on the total amount of 4 phenolic constituents of gallic acid, salidroside, tyrol and ethyl gallate through field test. The results show that the content of salidroside was higher in the treatment of N1P2K1 and N1P2K2, andthe total amount of four phenols was higher in the treatment of N1P2K2 and N2P2K2. The suitable level of nitrogen, phosphorus and potassium promoted the accumulation of the 4 kinds of phenols.The amount of fertilizer recommended by the three factor fertilizer effect equation,(N 0 kg·hm⁻²,P2O5 150 kg·hm⁻²,KCl 31.71 kg·hm⁻²) obtained the highest content of salidroside, and it was 1.54%.（N 35.54 kg·hm⁻²,P2O5 150 kg·hm⁻²,KCl 237.73 kg·hm⁻²ï¼‰obtained the highest content of 4 kinds of phenolic compounds, and it was 1.93%. This study provides a reference for the standardization of artificial planting of endangered Tibetan medicine.

[Study on medication laws of Tibetan medicine in treatment of plateau disease based on data mining technology].

Traditional Chinese medicine inheritance support system (TCMISS, V2.5) was used in this study to analyze the common medicines, frequency of medicine combination, core herbal combinations and new prescriptions for the treatment of plateau disease from the Four-Volume Medical Code, Mannose Herbal Mirror and other related books. TCMISS V2.5 software was used to construct the database of drug treatment for plateau disease. The frequency analysis and association rules apriori algorithm, improved mutual information method and other data mining methods were used to explore the law of drug compatibility. After the analysis of 531 prescriptions for plateau disease, 20 common symptoms of plateau disease were summarized such as insomnia and tinnitus. There were 539 kinds of herbs in the plateau disease prescriptions, including 33 kinds of herbs whose medicinal frequency>=50, such as Terminalia chebula and Myristica fragrans, and T. chebula had the highest medicinal frequency; 14 commonly used herbal combinations, and "Aucklandia lappa-T. chebula" had the highest frequency; 13 core herbal combinations were obtained after entropy clustering analysis, including 8 combinations of three herbs such as "Allium sativum-Carum carvi-Ferula sinkiangensis" and 5 combinations of four herbs such as "A. lappa-Aquilaria sinensis-Ewgewia caryophyllata-Myristica fragrans", and 5 new prescriptions such as "A. sativum-C. carvi-F. sinkiangensis-A. lappa-Choerospondia axillaris-A. sinensis-M. fragrans". The main symptom of "insomnia" was chosen to analyze the treatment of insomnia, and the core herbal combinations mainly including A. sinensis, T. chebula, and C. axillaris as well as the new prescriptions mainly containing Carthamus tinctorius, Meconopsis horridnla, and Punica granatum were obtained. The prescriptions for the treatment of plateau disease were clarified by TCM inheritance system, and the clinical prescription regularity and characteristics of the combination of common medicines were summarized, to provide reference and new ideas for its clinical application and development of new drug research.

Taxonomy of Stenus tenuimargo group (Coleoptera, Staphylinidae, Steninae) with descriptions of two new species from China.

This paper treats the Stenus tenuimargo group (Coleoptera: Steninae) from China and includes descriptions of two new species: Stenus nabanhensis Lv et Zhou, sp. nov., from Yunnan Province and Stenus zhangyejunianus Lv et Zhou, sp. nov., from Sichuan Province. Their diagnostic characters are illustrated and a key to all Chinese species of the group is provided.

[Correlation between flavonoids contents in Hippophae rhamnoides subsp. inensis leaf and ecological factors, and ecological suitability analysis of H. rhamnoides subsp. sinensis].

The study aims at providing a new suitable way to promote artificial cultivation, solving the problem of resources increasingly endangered wild medicine, and protecting the wild resources of Tibetan medicine. The content of quercetin,kaempferol and isorhamnetin was determined by HPLC. The correlation between flavonoids components and ecological factors was analyzed using partial least-squares regression (PLSR). Based on Maxent model combining using ArcGIS software, suitable regionalization for H.rhamnoides subsp. sinensis was studied.The results showed that the difference of quercetin,kaempferol and isorhamnetin content in samples from different regions were obvious. The main factors effecting quercetin content accumulation were the altitude andthe average monthly precipitation in January and August. The main factors effecting kaempferol accumulation were the altitude andthe average monthly precipitation in the coldest quarter and December. The main factors effecting isorhamnetin accumulation were the average monthly precipitation in August, January and the coldest quarter.The regional distribution suitability index for H.rhamnoides subsp. sinensis was 0-0.708. The suitable area 590 500 km², accounting for 6.13% of the total area. The preferably suitable area was 552 500 km², accounting for 5.73% of the total area.The methods used in the study is simple and feasible, the result is reliable which provide a new approach for Tibetan medicine resources sustainable exploitation and utilization.

Disentangling Environmental and Anthropogenic Impacts on the Distribution of Unintentionally Introduced Invasive Alien Insects in Mainland China.

Globalization increases the opportunities for unintentionally introduced invasive alien species, especially for insects, and most of these species could damage ecosystems and cause economic loss in China. In this study, we analyzed drivers of the distribution of unintentionally introduced invasive alien insects. Based on the number of unintentionally introduced invasive alien insects and their presence/absence records in each province in mainland China, regression trees were built to elucidate the roles of environmental and anthropogenic factors on the number distribution and similarity of species composition of these insects. Classification and regression trees indicated climatic suitability (the mean temperature in January) and human economic activity (sum of total freight) are primary drivers for the number distribution pattern of unintentionally introduced invasive alien insects at provincial scale, while only environmental factors (the mean January temperature, the annual precipitation and the areas of provinces) significantly affect the similarity of them based on the multivariate regression trees.

[Endangered situation and conservation strategy of Tibetan medicine in Qinghai-Tibet Plateau].

With the rapid development of Tibetan medicine industry, the study on plateau medicinal plants' endangered status is not enough, measures to protect is weak and the plateau ecological environment' inherent vulnerability, resulted in the shortage of Tibetan medicinal resources and affect the sustainable development . According to the existing endangered information of Tibetan medicine resources, how to formulate feasible protection plan, is an urgent problem of the rational development and utilization of Tibetan medicine resources to be solved. To find out the endangered Tibetan medicines in Qinghai Tibet Plateau, the Grade division method of Chinese Rare and Endangered Plants was applied, the endangered species were sorted out, which divided into class one (threatened) eleven species, class two (rare) twenty-one species, and class three (fading) forty-two species,a total of seventy-four species.In addition to national protection list in "Chinese rare and endangered plants". It's proposed to increase the endangered Tibetan medicinal species. Finally, according to the endangered status of the resources,from the survey of endangered Tibetan medicinal species regularly, the germplasm repository establishment of endangered Tibetan medicine, in situ conservation, artificial cultivation research and renew the idea, reasonable development and utilization, a total of 5 aspects to discussed the protection strategy, to provide a scientific basis for the protection and sustainable utilization of Tibetan medicine resources in Qinghai-Tibet Plateau.

Assessment of the key aroma compounds in rose-based products.

In this study, headspace solid phase microextraction-gas chromatography-mass spectrometry and GC-olfactometry were used to analyze the key aroma compounds in three types of rose-based products, including low-temperature extracts (LTEs), high-temperature extracts (HTEs), and rose drinks (RDs). In combination with the Guadagni theory, it was confirmed that the key aroma components of LTE were ß-phenyl ethyl alcohol, citronellol, geraniol, and eugenol. The main aroma compounds in HTE were ß-phenyl ethyl alcohol, citronellol, geraniol, eugenol, linalool, and rose oxide. The four key aroma compounds in RDs were ß-phenyl ethyl alcohol, eugenol, geraniol, and linalool.

[Research progress on resources and quality evaluation of Tibetan medicine in Qinghai-Tibet Plateau].

With the development of Tibetan medicine industry, the demands for Tibetan medicine were rising sharply. In addition, with the eco-environment vulnerability of Qinghai-Tibet Plateau region and the phenomenon of synonymies and homonymies in Tibetan medicine, there were a lack of resources and varieties in the clinical application of Tibetan medicine. At present, the shortage of Tibetan medicine and the inadequacy of its quality standard have become the two major problems that seriously restricted the sustainable development of Tibetan medicine industry. Therefore, it is important to develop the resources investigation and quality evaluation for Tibetan medicine, which were contribute to its resources protection and sustainable utilization. In this paper, current status of resources investigation, quality standardization, artificial breeding and germplasm resources of Tibetan medicine were presented by the integrated application of the new technologies, such as DNA barcoding and 1H-NMR, which provided a reference information for resources protection, sustainable utilization, variety identification and quality standardization of Tibetan medicine resources in Qinghai-Tibet Plateau.

[Occurrence and ecological consequences of transgenic rice gene flow: a review].

China is one of the origin centers of rice (Oryza sativa), with a distribution of abundant wild rice germplasm resources. Since the biosafety certificates were issued to Bt transgenic rice containing cry1Ac gene against lepidopteran pests, concerns are raised on the gene flow from transgenic rice to its wild relatives. This paper reviewed the occurrence of transgenic rice gene flow and its potential ecological consequences. Most studies suggested that transgenic rice could successfully hybridize with cultivated rice, wild rice (O. rufipogon), red rice (O. sativa f. spontanea), and barnyard grass (Echinochloa caudata), and the gene flow from transgenic rice had a lower occurrence frequency and was highly variable. Once the gene flow successfully occurred, the transgenes could introgress into a wild population within only a few generations because of the fitness advantage of transgenic rice due to the new selective traits of transgenes. When the transgenic plants invaded and persisted in a wild population, the dynamic changes of the mixed population would depend on the relative fitness and competition capability. To study the effects of the gene flow of transgenic rice and its long-term ecological consequences would have significance in rationally protecting and utilizing wild rice germplasm resources in China.

[Species diversity of ground-dwelling beetles on northern slope of Daba Mountain, China].

By using pitfall trapping, the species composition and quantitative distribution of ground-dwelling beetles in man-made plantations in forest farm (MPFF), secondary natural forests in farmland (SFF), and man-made plantations in farmland (MPF) on northern slope of Daba Mountain were analyzed, and detrended correspondence analysis and cluster analysis were adopted to study the similarity of the species composition and quantitative distribution of the beetles among the three forest types. 1094 individuals of ground-dwelling beetles were captured in August 9-13th, 2002. Of these beetles, Staphylinidae and Chrysomelidae accounted for 40.59% and 33.18% of the total, respectively, and Carabidae, Leiodidae, Scarabaeidae, Curculionidae, Ptiliidae, and Pselaphidae each took more than 1% of the total. These eight families were considered as the common-occurring groups in the study area. The individuals of ground-dwelling beetles decreased from MPFF to SFF to MPF, and the family richness was obviously lower in MPF than in MPFF and SFF. The family composition and abundance of the beetles were significantly different between MPFF and SFF, but partial similarity was observed between MPF and other two forest types.