Present Situation and Enlightenment of Post-Approval Change Management of Drugs in China,USA and EU

Objective To provide suggestions for further improvement of China’s drug post-approval change management system.Methods The current legal and regulatory requirements of post-approval change management systems of drugs in USA,EU and China were compared and analyzed.Results and Conclusion The post-approval change management of drugs is an important part of the whole life-cycle management of drugs.However,there are still some problems in China’s current post-approval change management systems.According to the model and requirements of the post-approval change management systems of the USA and EU,this paper proposes the following suggestions for the improvement of China’s post-approval change management system.Firstly,electronic files for licensed products should be created.Then,regulatory standards at the national level must be unified.Lastly,the concept of product life cycle management should be implemented.

A CMIP6-based assessment of regional climate change in the Chinese Tianshan Mountains

Climate warming profoundly affects hydrological changes,agricultural production,and human society.Arid and semi-arid areas of China are currently displaying a marked trend of warming and wetting.The Chinese Tianshan Mountains(CTM)have a high climate sensitivity,rendering the region particularly vulnerable to the effects of climate warming.In this study,we used monthly average temperature and monthly precipitation data from the CN05.1 gridded dataset(1961-2014)and 24 global climate models(GCMs)of the Coupled Model Intercomparison Project Phase 6(CMIP6)to assess the applicability of the CMIP6 GCMs in the CTM at the regional scale.Based on this,we conducted a systematic review of the interannual trends,dry-wet transitions(based on the standardized precipitation index(SPI)),and spatial distribution patterns of climate change in the CTM during 1961-2014.We further projected future temperature and precipitation changes over three terms(near-term(2021-2040),mid-term(2041-2060),and long-term(2081-2100))relative to the historical period(1961-2014)under four shared socio-economic pathway(SSP)scenarios(i.e.,SSP1-2.6,SSP2-4.5,SSP3-7.0,and SSP5-8.5).It was found that the CTM had experienced significant warming and wetting from 1961 to 2014,and will also experience warming in the future(2021-2100).Substantial warming in 1997 was captured by both the CN05.1 derived from interpolating meteorological station data and the multi-model ensemble(MME)from the CMIP6 GCMs.The MME simulation results indicated an apparent wetting in 2008,which occurred later than the wetting observed from the CN05.1 in 1989.The GCMs generally underestimated spring temperature and overestimated both winter temperature and spring precipitation in the CTM.Warming and wetting are more rapid in the northern part of the CTM.By the end of the 21st century,all the four SSP scenarios project warmer and wetter conditions in the CTM with multiple dry-wet transitions.However,the rise in precipitation fails to counterbalance the drought induced by escalating temperature in the future,so the nature of the drought in the CTM will not change at all.Additionally,the projected summer precipitation shows negative correlation with the radiative forcing.This study holds practical implications for the awareness of climate change and subsequent research in the CTM.

Down-regulation of Hsp90 could change cell cycle distribution and increase drug sensitivity of tumor cells

AIM:To construct Hsp90 antisense RNA eukaryotic expression vector, transfect it into SGC7901 and SGC7901/VCR of MDR-type human gastric cancer cell lines, HCC7402 of human hepatic cancer and Ec109 of human esophageal cancer cell lines, and to study the cell cycle distribution of the gene transected cells and their response to chemotherapeutic drugs.METHODS:A 1.03kb cDNA sequence of Hsp90beta was obtained from the primary plasmid phHSP90 by EcoR I and BamH I nuclease digestion and was cloned to the EcoR I and BamH I site of the pcDNA by T4DNA ligase and an antisense orientation of Hsp90beta expression vector was constructed. The constructs were transfected with lipofectamine and positive clones were selected with G418. The expression of RNA was determined with dot blotting and RNase protection assay, and the expression of Hsp90 protein determined with western blot. Cell cycle distribution of the transfectants was analyzed with flow cytometry, and the drug sensitivity of the transfectants to Adriamycin (ADR), vincrinstine (VCR), mitomycin (MMC) and cyclophosphamide (CTX) with MTT and intracellular drug concentration of the transfectants was determined with flow cytometry.RESULTS:In EcoR I and BamH I restriction analysis, the size and the direction of the cloned sequence of Hsp90beta remained what had been designed and the gene constructs were named pcDNA-Hsp90.AH-SGC7901, AH-SGC7901/VCR, AH-HCC7402 and AH-Ec109 cell clones all expressed Hsp90 anti-sense RNA. The expression of Hsp90 was down-regulated in AH-SGC7901, AH-SGC7901/VCR, AH-HCC7402 and AH-Ec109 cell clones. Cell cycle distribution was changed differently. In AH-SGC7901/VCR and AH-Ec109 cells, G(1) phase cells were increased; S phase and G(2) phase cells were decreased as compared with their parental cell lines. In AH-SGC7901 cell, G(1)phase cells were decreased, G(2) phase cells increased and S phase cells were not changed, and in AH-HCC7402 cells G(1), S and G(2) phase cells remained unchanged as compared with their parental cell lines. The sensitivity of AH-SGC7901, AH-SGC7901/VCR, AH-HCC7402 and AH-Ec109 to chemotherapeutic drugs, the sensitivity of AH-SGC7901/VCR to ADR, VCR, MMC and CTX the sensitivity of AH-HCC7402 to ADR and VCR, and the sensitivity of Ec109 to ADR, VCR and CTX all increased as compared with their parental cell lines. The mean fluorescence intensity of ADR in AH-SGC7901, AH-SGC7901/VCR, AH-HCC7402 and AH-Ec109 was also significantly elevated (P 【 0.05).CONCLUSION: Down-regulation of Hsp90 could change cell cycle distribution and increase the drug sensitivity of tumor cells.

An Investigation of the Dimensional Changes of Polymer Mixture Tablets Containing a Soluble Drug, Using an Image Analysis Method. Influence of These Characteristics on Drug Release and Its Mechanism

The properties and characteristics of the polymer used for the preparation of matrix drug delivery systems considerably influence their performance and the extent of drug release and its mechanism. The objective of this research was to examine the dimensional changes, and gel evolution of polymer matrices consisting of three different polymers Polyox, sodium alginate (hydrophilic) and Ethocel (hydrophobic), using an image analysis method. Furthermore to explore how these changes influence the release rate of a soluble drug namely, venlafaxine. All tablets displayed marked dimensional expansion and gel growth particularly those consisting of two hydrophilic polymers Polyox/sodium alginate (POL/SA/V) compared to those consisting of the hydrophilic/hydrophobic Polyox/Ethocel (POL/ET/V). Similarly the thickness of the gel layer in POL/SA/V matrices increased considerably with time up to 8 hours. In general our findings show that the POL/SA/V matrices, due to their thicker gel layer produced a more effective barrier which results in a more pronounced sustained release delivery. This accounts for the slower and smaller overall drug release observed with the POL/SA/V matrices compared to those containing POL/ET/V and indicates that the formation of a thick and durable gel barrier is a characteristic necessary for the preparation of sustained drug release systems. Moreover the solubility of venlafaxine in combination with the polymer’s properties appears to play an important role on the extent of drug release and the release mechanism. Overall the polymer mixtures examined comprise a useful and promising combination of materials for the development and manufacture of sustained release preparations based on these polymers.

Son of Heaven and Dynastic Changes in Historical China Compared to Biblical Standards

The Israelite people began to have kings hundreds of years after the Mosaic Law was given to them from God,and with kings from David and then his family,they experienced no substantial dynastic changes in the southern kingdom of Judah.Later,the Israelites were ruled by kings or emperors of other nations until the State of Israel was restored in its historical land after World War Two.Without any written law comparable to the Mosaic Law,the earliest Zhou kings of China claimed to be Sons of Heaven and Heaven worship was inherited by later emperors.Heaven worship has features in common with the monotheistic religion of the Israelites,such as that a king should obey the will of God.With changes of dynasties,Heaven worship actually means that heaven could be renamed and the former Son of Heaven had no life-long priesthood in serving Heaven.After the redemptive work of Jesus Christ had fulfilled the Mosaic Law,Heaven worship had little relation with faith in God,the Creator.

How China tackles climate change through standards

Climate change is a challenge faced by the whole humanity.As the world's largest developing country, China attaches great importance to climate change and has taken effective measures to address climate change issues despite its tremendous task to develop economy, eliminate poverty and improve people's livelihood.

Factors Influencing the Implementation of Drug Standards Improvement in China

Objective To explore the factors influencing the implementation of drug standards improvement in China,and to offer some suggestions for improving drug standards.Methods Factor analysis was used to investigate the influencing factors by referring to the literatures,experts’interview and collecting data through questionnaire,and then data were analyzed by SPSS21.0 statistical software.Results and Conclusion The results showed that there were four factors that affecting the plan of the national drug standards improvement.They were mechanism factor,design factor,constraint factor and motivation factor.And corresponding management suggestions for improving the efficiency of the plan were put forward.

Changes in cultivated land patterns and driving forces in the Three Gorges Reservoir area, China, from 1992 to 2015

Changes of cultivated land patterns caused by major water conservation projects are rarely reported. We selected the Three Gorges Reservoir area in China to study the change in area and landscape pattern of the cultivated land in the head,central, and tail areas of the reservoir that took place between 1992 and 2015;we then studied the spatial distribution of the cultivated land in the three parts of the reservoir;finally, we studied the driving forces behind the changes in the cultivated land. The results derived are as follows.(1) During the construction of the Three Gorges Project(TGP, 1992–2015), the area of cultivated land around the reservoir decreased by30.23 million ha. This reduction occurred in phases:the most severe change in cultivated land occurred during the later stage of the project(2002–2010);only 0.62 million ha of cultivated land did not change between 1992 and 2015.(2) Spatial pattern analysis showed that the cultivated land in the three parts of the reservoir changed from a northern distribution to a southern distribution;thus, the area of cultivated land in the north decreased over the time period. The area of cultivated land in the head and tail areas decreased by varying degrees, while it increased in the central area over the 23 years, indicating that the change in cultivated land showed regional differences.(3) The TGP, the policy of reverting farmland to forest,and urbanization were the main driving factors for the change of cultivated land, but there were differences in their impacts at different stages.(4) According to the patch dynamics of the land cover change, the degree of change gradually intensified during the early and later stages of the project and then stabilized during the operational period. Our research provides scientific support for the protection of cultivated land resources and food security in the reservoir area and for the coordination of social and economic development, which is of great significance to sustainable development in the reservoir area.

Comparative evaluation of impacts of climate change and droughts on river flow vulnerability in Iran

Rivers in arid and semi-arid regions are threatened by droughts and climate change.This study focused on a comparative evaluation of the impacts of climate change and droughts on the vulnerability of river flows in three basins with diverse climates in Iran.The standardized precipitation-evapotranspiration index(SPEI)and precipitation effectiveness variables(PEVs)extracted from the conjunctive precipitation effectiveness index(CPEI)were used to analyze the drought severity.To investigate hydrological droughts in the basins,the normalized difference water index(NDWI)and the streamflow drought index(SDI)were calculated and compared.The effects of droughts were assessed under various representative concentration pathway(RCP)scenarios.Changes in the number of wet days and precipitation depth restricted hydrological droughts,whereas an increasing number of dry days amplified their severity.The projected increases in dry days and precipitation over short durations throughout a year under future climate scenarios would produce changes in drought and flood periods and ultimately impact the frequency and severity of hydrological droughts.Under RCP 4.5,an increase in the frequencies of moderate and severe meteorological/hydrological droughts would further affect the Central Desert Basin.Under RCPs 2.6 and 8.5,the frequencies of severe and extreme droughts would increase,but the drought area would be smaller than that under RCP 4.5,demonstrating less severe drought conditions.Due to the shallow depths of most rivers,SDI was found to be more feasible than NDWI in detecting hydrological droughts.©2020 Hohai University.Production and hosting by Elsevier B.V.This is an open access article under the CC BY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Research for length change of four seasons over China in recent 47 years

Using daily temperature data from 599 Chinese weather stations during 1961-2007, the length change trends of four seasons dur- ing the past 47 years were analyzed. Results show that throughout the region, four seasons＇ lengths are： spring becomes shorter （-0.8 d/10yrs）, summer becomes longer （3.2 d/10yrs）, autumn （-0.5 d/10yrs） and winter （-1.6 d/10yrs） becomes shorter. This trend is different in spatial distribution, namely it is very obvious in northern than southern China, and also remarkable in eastern than western China. Summer change is most obvious, but autumn has little change comparatively. This trend is highly obvious in North, East, Central and South China. In the Southwest starting in the 21st century, summer becomes longer and winter shortens. The trend in the Plateau region since the 1980s is that spring becomes longer and winter shortens. The average annual temperature increased during the past 47 years, and the change of the average annual temperature precedes seasons＇ length. Thus, the average annual temperature has a certain influence on the length change of seasons.

Combination Activity of Standard Antituberculosis Drugs and Extracts of Medicinal Plants Commonly Used in Traditional Treatment of Tuberculosis in Uganda

Introduction: Resistance to antituberculosis drugs and adverse drug reactions remain the leading causes of tuberculosis therapeutic failure globally. Despite the increasing acceptance of medicinal plant use in combination with conventional antituberculosis drugs in treatment of tuberculosis (TB) in Uganda, there is paucity of knowledge on their combination effect. Aim: This research aimed to determine combination activity of standard antituberculosis drugs with extracts of Zanthoxylum leprieurii Guill. & Perr. and Rubia cordifolia L., the two common antituberculosis medicinal plants in Uganda, against pansensitive (H37Rv) and multi-drug resistant (MDR) Mycobacterium tuberculosis strains. Materials and Methods: Two reference MTB strains (H37Rv and MDR strain) were inoculated on Middlebrook 7H11 medium containing a combination of standard antituberculosis drugs and methanol extracts of Z. leprieurii and R. cordifolia at varying concentrations. The number of colonies on the plates was observed and counted weekly for up to 8 weeks. In vitro combination activity was determined using proportion method. Mean percentage inhibition was calculated for the reduction of number of colonies on drug-extract combination medium in relation to drug-extract-free control medium. Results: Drug-extract combinations showed good combination activity against Mycobacterium tuberculosis strains when compared with individual standard anti-TB drugs. This was more exhibited against MDR strain. There was however a reduction in percentage inhibition when extracts were combined with ethambutol and streptomycin against H37Rv strain. Conclusions: Zanthoxylum leprieurii and Rubia cordifolia in combination with standard anti-TB drugs exhibited increased in vitro activity against Mycobacterium tuberculosis, especially MDR-TB strain. This justifies the local use of these plants in traditional treatment of tuberculosis especially in resistant cases in Uganda.

Future Changes in Drought Characteristics over Southern South America Projected by a CMIP5 Multi-Model Ensemble

The impact of climate change on drought main characteristics was assessed over Southern South America. This was done through the precipitation outputs from a multi-model ensemble of 15 climate models of the Coupled Model Intercomparison Project Phase 5 (CMIP5). The Standardized Precipitation Index was used as a drought indicator, given its temporal flexibility and simplicity. Changes in drought characteristics were identified by the difference for early (2011-2040) and late (2071-2100) 21st century values with respect to the 1979-2008 baseline. In order to evaluate the multi-model outputs, model biases were identified through a comparison with the drought characteristics from the Global Precipitation Climatology Centre database for the baseline period. Future climate projections under moderate and high-emission scenarios showed that the occurrence of short-term and long-term droughts will be more frequent in the 21st century, with shorter durations and greater severities over much of the study area. These changes in drought characteristics are independent on the scenario considered, since no significant differences were observed on drought changes. The future changes scenario might be even more dramatic, taking into account that in most of the region the multi-model ensemble tends to produce less number of droughts, with higher duration and lower severity. Therefore, drought contingency plans should take these results into account in order to alleviate future water shortages that can have significant economic losses in the agricultural and water resources sectors of Southern South America.

Spatial Rainfall Variability and an Increasing Threat of Drought, According to Climate Change in Uttaradit Province, Thailand

This study presents the work commenced in northern Thailand on spatial and temporal variability of rainfall. Thirty years (1988-2017) rainfall data of eight meteorological stations were used for assessing temporal variability and trend analysis. The results showed decreasing trend in rainfall from its first half of the observed study period (1988-2002) to last half of the time period (2003-2017) in total average annual as well as monsoonal average rainfall by 14.92% and 15.50% respectively. It was predicted from linear regression results that by 2030 the average annual and monsoonal rainfall will drop by 35% and 34.10% respectively. All stations showed negative trend except Fakara met-station in annual rainfall. In the seasonal trend analysis, the results showed decreasing trend almost in all met-stations. Mann-Kendall trend test was applied to assess the trend. All met-stations show significant negative trend. To assess drought in the study area, Standardized Precipitation Index (SPI) was applied to 12-month temporal time period. The results predicted meteorological drought in the near future. The spatial distribution of rainfall presented changing phenomena in average annual, monsoonal, winter, and summer seasons in both analyzed periods.

Response of Vegetation Cover Change to Drought at Different Time-scales in the Beijing-Tianjin Sandstorm Source Region,China

Dominated by an arid and semiarid continental climate,the Beijing-Tianjin Sandstorm Source Region(BTSSR)is a typical ecologically fragile region with frequently occurring droughts.To provide information for regional vegetation protection and drought prevention,we assessed the relations between vegetation cover change(measured by the Normalized Difference Vegetation Index,NDVI)and the Standardized Precipitation Evapotranspiration Index(SPEI)at different time-scales,in different growth stages,in different subregions and for different vegetation types based on the Pearson's correlation coefficient in the BTSSR from 2000 to 2017.Results showed that 88.19%of the vegetated areas experienced increased NDVI in the growing season;48.3%of the vegetated areas experi-enced significantly increased NDVI(P<0.05)and were mainly in the south of the BTSSR.During the growing season,a wetter climate contributed to the increased vegetation cover from 2000 to 2017,and NDVI anomalies were closely related to SPEI.The maximum correlation coefficient in the growing season(Rmax)was significantly positive(P<0.05)in 97.84%of the total vegetated areas.In the vegetated areas with significantly positive Rmax,pixels with short time-scales(1-3 mon)accounted for the largest proportion(33.9%).The sensitivity of vegetation to the impact of drought rose first and then decreased in the growing season,with a peak in July.Compared with two subregions in the south,subregions in the north of the BTSSR were more sensitive to the impacts of drought variations,especially in the Xilingol Plateau and Wuzhumuqin Basin.All four major vegetation types were sensitive to the effects of drought variations,especially grasslands.The time-scales of the most impacting droughts varied with growth stages,regions,and vegetation types.These results can help us understand the relations between vegetation and droughts,which are important for ecological restoration and drought prevention.

Inspiration of Foreign Innovative Drug Pricing Methods and Medical Insurance Payment Standards to China

Objective To study the innovative drug pricing methods and medical insurance payment standards in foreign countries and to provide reference for China’s government.Methods The official websites were searched for information and related literature,and literature review was used.Results and Conclusion In foreign countries,the clinical value of innovative drugs and their impact on medical insurance funds were comprehensively evaluated based on factors such as quality-adjusted life years,clinical benefit,and improvement of clinical benefit.Then,the evaluation results were taken as an important basis for whether innovative drugs were admitted to the medical insurance catalog and establishing medical insurance payment standards.By using international experience for reference,innovative drug pricing methods and medical insurance payment standards for China’s national conditions can be improved by establishing a basic database of clinical value and drug economic evaluation of innovative drugs,as well as innovative drug payment models based on decision thresholds.

Institutional changes of China's drug regulation and improvement solutions

Drug regulation is the most important policy to ensure drug safety.In this article,we analyzed institutional changes and problems in China＇s drug regulation.In addition,suggestions were provided to enhance the capacity of drug regulation,including a clearer functional positioning for drug regulation,increased resource inputs in drug regulation at central level,a more rational allocation of vertical drug regulatory functions,and an improved supervision mechanism for regulatory departments.

Temperature variation and abrupt change analysis in the Three-River Headwaters Region during 1961-2010

In this study, a monthly dataset of temperature time series （1961-2010） from 12 meteorological stations across the Three-River Headwater Region of Qinghai Province （THRHR） was used to analyze the climate change. The temperature variation and abrupt change analysis were examined by using moving average, linear regression, Spline interpolation, Mann-Kendall test and so on. Some important conclusions were obtained from this research, which mainly contained four aspects as follows. （1） There were several cold and warm fluctuations for the annual and seasonal average temperature in the THRHR and its three sub-headwater regions, but the temperature in these regions all had an obviously rising trend at the statistical significance level, especially after 2001. The spring, summer, autumn and annual average temperature increased evidently after the 1990s, and the winter average temperature exhibited an obvious upward trend after entering the 21st century. Except the standard value of spring temperature, the annual and seasonal temperature standard value in the THRHR and its three sub-headwater regions increased gradually, and the upward trend for the standard value of winter average temperature indicated significantly. （2） The tendency rate of annual average temperature in the THRHR was 0.36℃ 10a^-1, while the tendency rates in the Yellow River Headwater Region （YERHR）, Lancangjiang River Headwater Region （LARHR） and Yangtze River Headwater Region （YARHR） were 0.37℃ 10a^-1, 0.37℃ 10a^-1 and 0.34℃10a^-1 respectively. The temperature increased significantly in the south of Yushu County and the north of Nangqian County. The rising trends of temperature in winter and autumn were higher than the upward trends in spring and summer. （3） The abrupt changes of annual, summer, autumn and winter average temperature were found in the THRHR, LARHR and YARHR, and were detected for the summer and autumn average temperature in the YERHR. The abrupt changes of annual and summer average temperatures were mainly in the late 1990s, while the abrupt changes of autumn and winter average temperatures appeared primarily in the early 1990s and the early 21st century respectively. （4） With the global warming, the diversities of altitude and underlying surface in different parts of the Tibetan Plateau were possibly the main reasons for the high increasing rate of temperature in the THRHR.

Association between change of health care providers and pregnancy exposure to FDA category C, D and X drugs

Background Changing health care providers frequently breaks the continuity of care,which is associated with many health care problems.The purpose of this study was to examine the association between a change of health care providers and pregnancy exposure to FDA category C,D and X drugs.Methods A 50% random sample of women who gave a birth in Saskatchewan between January 1,1997 and December 31,2000 were chosen for this study.The association between the number of changes in health care providers and with pregnancy exposure to category C,D,and X drugs for those women with and without chronic diseases were evaluated using multiple logistical regression,with adjusted odds ratios （ORs） and its 95% confidence intervals （C/s） as the association measures.Results A total of 18 568 women were included in this study.Rates of FDA C,D,and X drug uses were 14.35%,17.07%,21.72%,and 31.14%,in women with no change of provider,1-2 changes,3-5 changes,and more than 5 changes of health care providers.An association between the number of changes of health care providers and pregnancy exposure to FDA C,D,and X drugs existed in women without chronic diseases but not in women with chronic disease.Conclusion Change of health care providers is associated with pregnancy exposure to FDA category C,D and X drugs in women without chronic diseases.

《超说明书用药标准》制订与解析

超说明书用药是指药品使用的适应证、剂量、疗程、途径或人群等未在国家药品监督管理部门批准的说明书记载范围内的用法。中国医院协会药事专业委员会基于国家相关法规、规范性文件,结合国内外相关指南文献、行业专家意见,遵循科学性、通用性、指导性和可操作性原则制订了《超说明书用药标准》。该标准对超说明书用药的制度与组织建设、流程管理、质量控制与评价改进的全过程进行了规范和标准化,是医疗机构开展超说明书用药管理的依据。该文介绍《超说明书用药标准》的制订过程,并解析该标准的重点内容,有助于医疗机构在超说明书用药管理实践中,更好地满足超说明书用药标准的各项要求。

1144例患者术后镇痛泵的使用情况调查及合理用药分析

目的:调查术后镇痛泵的使用情况,促进术后镇痛泵的合理规范使用。方法:抽取2023年5月1—10日该院进行手术的1 144例患者,回顾性分析术后镇痛泵的使用情况,包括使用率、不良反应、人均药品费和用药合理性。结果:1 144例患者中,术后使用镇痛泵的有788例,镇痛泵使用率为68.88%。788例术后使用镇痛泵的患者中,人均药品费用为799.18元;镇痛泵用药不合理557例(占70.68%);不合理用药主要表现为药物联合应用不适宜(506例,占64.21%)、药物遴选不适宜(517例,占65.61%)和存在配伍禁忌(35例,占4.44%)。结论:该院术后镇痛泵的使用存在较多不合理现象,临床药师应参与术后镇痛泵的管理,降低镇痛泵的用药不合理率及患者的经济负担。