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??OBJECTIVE To explore the determination of pethidine hydrochloride injection by using Raman spectroscopy to realize in-site non-invasive inspection. METHODS CLS algorithm was used to eliminate the interference of the ampoule, correlation coefficient was used for identification, and PLS algorithm was used to establish the quantitative model. Moreover, the transfer performance of the models was investigated when used on different portable Raman instruments. RESULTS Nineteen samples of four different batches were used to verify the method. The RESULTS showed a good coincidence with reference RESULTS on both identification and quantification, and the relative deviation from HPLC method was within 5%. Meanwhile, the Raman method showed good accuracy and repeatability with relative deviation of mean and RSD value within 1% for samples from the same batch. The differences between instruments were controlled by the key index, and quantitative analysisRESULTS of 51 samples measured on three instruments all fell in the range of 90% to 110%, among which 96% fell in a more narrow range of 95% to 105%. CONCLUSION The Raman method established in this study could be used for the in-situ non-invasive determination of pethidine hydrochloride injection.     

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??OBJECTIVE To explore the effects of glucose on the growth of algae, the content of fucoxanthin, and expressions of genes related to biosynthesis of fucoxanthin. METHODS The cell growth of algae induced by glucose was researched by using spectrophotometric method. The content of fucoxanthin was measured by HPLC. The expressions of the genes which were related to biosynthesis of fucoxanthin were detected by using quantitative PCR. RESULTS At the end of the platform period, the density of cells treated by glucose was higher than that of the control group. The growth of P. tricornutum was promoted by glucose. The result of HPLC analysis showed that fucoxanthin content in the algae treated by different concentrations of glucose was decreased than that in the control group. When the concentration of glucose reached 50 mg??L^-1, the content of fucoxanthin was the lowest (0.26 mg??g^-1 DW), which was 67.5% lower than the control, indicating that glucose inhibited the biosynthesis of fucoxanthin in P. tricornutum. RT-qPCR result showed that the expression of genes related to the biosynthesis pathway of fucoxanthin, i.e., zep, pys, zds, lcyb, crtiso, and pds, were all lower than those of the control when the concentration of glucose was in the range from 10 to 50 mg??L^-1. This result was consistent with the change of fucoxanthin content. CONCLUSION This result further illustrates that glucose may inhibit the biosynthesis of fucoxanthin in P. tricornutum by down-regulating the expression of related genes.     

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??OBJECTIVE To synthesize 5-substituted indole-3-deoxypodophyllotoxin derivatives and study their antitumor activity. METHODS The target compounds were synthesized through a series of reactions and their anti-tumor activity in vitro were evaluated against Hela, K562 and K562/A02 cell lines by MTT as assay. RESULTS Ten target compounds were synthesized and confirmed by ¹H-NMR, ¹³C-NMR, and HR-ESI-MS. All the target compounds had different degrees of cytotoxic activity in vitro. Most of the compounds had significant anti-MDR activity in vitro. CONCLUSION 5-Substituted indole-3-deoxypodophyllotoxin derivatives have good antitumor activity and worth of further study.     

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??OBJECTIVE To clone and isolate the major facilitator superfamily(MFS)genes of Polyporus umbellatus and carry out bioinformatic analysis. METHODS Nine major facilitator superfamily(MFS)genes were cloned from Polyporus umbellatus sclerotia by RT-PCR and the expression analysis of the nine genes in different parts of Polyporus umbellatus sclerotia was carried out using quantitative Real-time PCR.RESULTS The full open reading frame cDNA sequence of these nine genes was between 1 321 and 1 860 bp, the putative encoding proteins were between 441 and 620 amino acids, the molecular weight was between 48.45??10³ and 64.79??10³ and the theoretical pI was between 6.59 and 9.56. The amino acids of these nine genes possessed 11 to 14 membrane-spanning domains. Phylogenetic tree analysis indicated that Comp34750,Comp34832, Comp29252, Comp42895, Comp32579 and Comp27555 had the highest similarity with MFS general substrate transporter,Comp28872 and Comp26306 had the highest similarity with MFS monosaccharide transporter, and Comp33117 had the highest similarity with MFS sugar transporter. Quantitative real-time PCR showed that these nine genes were expressed in both the symbiotic part and non-symbiotic part. Meanwhile,the expressions of seven genes were significantly up-regulated in the symbiotic part except Comp34382 and Comp32579. CONCLUSION The investigated nine genes might play an important role during the defense response and nutrient absorption of P.umbellatus.     

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??OBJECTIVE Taking aspirin as a model drug, the feasibility of the controlled release of aspirin tablets was discussed, which was based on the individual demand of 3D printing technology. METHODS The experiment selected 10 000 mPa??s hydroxypropyl methyl cellulose (HPMC10000) and polyacrylic acid (PAA) as a hydrophilic matrix sustained-release layer; hydroxypropyl methyl cellulose 100 mPa??s (HPMC100) as a quick release layer binder, sodium carboxymethyl starch (CMS-Na) and sodium carboxymethyl starch (SSG) as a quick release layer disintegrating agent, the use of 3D printer to print the slow release of aspirin tablets. Select 100 mg??mL^-1 and polyvinylpyrrolidone (PVPK30) as a quick release layer binder, crosslinking sodium carboxymethyl cellulose (CC-Na) as a quick release layer disintegrating agent, hydroxypropyl methyl cellulose (HPMC100) as the matrix material release layer, with the traditional press pressing speed of aspirin sustained-release tablet, as contrast agents. The physical and chemical properties of tablets produced in two different modes of production (film weight difference, hardness and thickness) and release profile were investigated. RESULTS The physical and chemical properties of the two tablets are all in the Pharmacopoeia. Comparison of two kinds of drug release curve showed that the ASA-HPMC (14%, ??) and the press release curve of double layer tablets printing film is similar, and the release rate is higher than the tablet (6% ??.ASA-HPMC double layer tablets), ASA-HPMC (8%, ??) and ASA-HPMC (10%, ??) printing film final release amount increased with hydrophilic matrix HPMC. CONCLUSION 3D printers print different shapes of tablets with different release profiles, in which the release of the package is higher than the other tablets.     

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?? Zingiber officinale has a long application history in China, it is used as medicine, also condiment, food and drinks. The chemical constituents of Zingiber officinale include volatile oil, gingerol,diaryl-heptnaoids and so on. Scientific research showed that Zingiber officinale is widely used in anti-nausea, resisting gastric ulcer, anti-bacterial, anti-phlogistic, analgesia, antioxidant, resisting motion sickness, anti-tumor, hypoglycemic,antilipidemic,and improving cardiocerebral vascular system and so on.Zingiber officinale is recommended as a healthy food by doctor of traditional Chinese medicine in all times. In summary, it's worth to be researched and developed in detail.     

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??OBJECTIVE To observe the effect and mechanism of Bauhinia championii flavones (BCF) on anti-hypoxia/reoxygenation injury in cardiomyocytes via inhibiting necroptosis. METHODS The cardiomyocytes hypoxia/reoxygenation injury model was developed and pretreated with Bauhinia championii flavones. ELISA was used to evaluate the contents of TNF-??, and the activities of T-AOC were determined by ultraviolet spectrophotometric method. The protein expression of RIPK3 was observed by Western-blotting, and the necroptosis rate was determined by using Annex v-FITC/PI double staining.RESULTS Compared with model group, Bauhinia championii flavones pretreatment alleviated cardiomyocytes injury, increased T-AOC level, decreased the activity of TNF-??, down-regulated the expression of RIPK3, and inhibited cardiomyocytes necroptosis(P<0.05). It had synergistic effect when combined BCF with necrostatin-1(P<0.05). CONCLUSION BCF can inhibit necroptosis and has protective effects on hypoxia/reoxygenation injury, which are associated with increasing the level of T-AOC, down-regulating TNF-?? and RIPK3, and decreasing the cardiomyocytes necroptosis rate.     

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??OBJECTIVE To evaluate the efficacy of glucagon-like peptide-1 receptor agonists (GLP-1RA) on nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM). METHODS The randomized controlled trials (RCTs) of GLP-1 RA, placebo, and anti-diabetes drugs in the treatment of NAFLD in patients with T2DM were collected from PubMed, Embase, CNKI, Wangfang database, VIP, and CBM. The trials were evaluated for the quality and selected, and the RESULTS of the studies were reviewed and analyzed using RevMan 5.2 software. RESULTS Four RCTs were included, involving 154 patients. The Meta-analysis showed that compared with the control group, GLP-1RA could significantly improve the ALT [MD:-8.36,95%CI(-13.41-3.31), P=0.001], HbA1c [MD:-0.43%,95%CI(-0.73-0.31), P=0.005], FBG [MD:-0.71%, 95%CI(-1.39-0.03),P=0.04],BMI [MD:-1.38%, 95%CI(-2.18-0.58), P=0.000 8], TG [MD:-0.49%, 95%CI(-0.82-0.16), P=0.004]. CONCLUSION GLP-1 RA can obviously improve the metabolic index of patients with NAFLD and T2DM. Given the quality and quantity of the literature, large RCTs are still needed in the future.     

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??OBJECTIVE To develop an HPLC method for simultaneous determination of seven tannins in Chebulae Fructus, including gallic acid, chebulic acid, corilagin, ethyl gallate, ellagic acid, chebulagic acid and 1,2,3,4,6-O-pentagalloylglucose and determine the contents of the seven tannins in Chebulae Fructus Retz from different areas.METHODS The HPLC analysis was carried out on an Hypersil ODS2 C₁₈ (4.6 mm??250 mm,5 ??m) column with acetonitrile (A) and 0.05% formic acid solution in water (B) as mobile phase in a linear gradient elution mode. The UV detection wavelength was set at 290 nm and the flow rate was 1.0 mL??min^-1.RESULTS The calibration curves of the seven tannins all showed good linearity (r??0.999 8). The recovery rates were in the range of 95.2% to 98.4%. All the seven tannins could be detected in the two kinds of Chebulae Fructus Retz from eight regions, but the amounts of these tannins varied significantly. The contents of the seven tannins active ingredients in Chebulae Fructus of Terminalia chebula Retz from Hainan, Guangxi, Guangdong and Xinjiang were much higher than those from other areas, while those in Chebulae Fructus of Terminalia chebula Retz. var. tomentella Kurt were higher in Guangdong and Guangxi than other areas.CONCLUSION The method is proved to be accurate and valid, and can be used for the quality control of Terminalia chebula Retz.     

罕见病用药现状分析

罕见病用药指用于治疗、诊断和预防罕见病或罕见症状的药物。近年来罕见病用药的研发逐渐成为一个可获利的研发策略,受到高度关注和重视。从目前国外罕见病药品市场情况、参与罕见病药物研发的公司和重点品种、美国和欧盟等发达国家和地区罕见病药物的指定和批准情况等方面对罕见病用药的现状及发展趋势进行简述。通过借鉴这些国家和地区罕见病药物发展的成功经验,为制定中国罕见病药物开发的刺激措施提出建议,为相关研发人员提供参考。     

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??OBJECTIVE To introduce and compare research support for rare disease and orphan drug innovation in China and United States, and provide reference for relevant policies in China.METHODS Data of main source of funding for rare disease research in two countries ie. National Institutes of Health, Food and Drug Administration in the United States and National Natural Science Foundation of China were analyzed and compared. RESULTS US NIH gives substantial support for rare disease research every year with funded capital growing. FDA Orphan Products Grants program provides incentives for sponsors to develop products for rare diseases. In China, however, there is no specific support project for rare disease research, and there is a huge gap in funding efforts for rare disease research between China and the United States. CONCLUSION China should establish rare disease research center to promote rare disease research and set up specific funding for rare diseases research, increase efforts to support research and innovation for rare diseases and orphan drugs, in order to protect the health interests of patients with rare diseases.     

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??OBJECTIVE To search the orphan drug list from the countries which had initiated orphan drug policies and give reference to improve the orphan drug accessibility in our country. METHODS We searched the official medicine management websites of the United States??Singapore??Japan?? Australia??European Union?? Chinese Taiwan and South Korea and extracted information of orphan drugs which had been approved to the market. Then those orphan drugs were investigated whether had been imported and reimbursed in China, through the website of China Food and Drug Administration. Drug classification was according to the ??pharmacopoeia of the People's Republic of China?? (2010 version). Disease classification was according to the ICD-10.Insurance information was according to the ??national basic medical insurance?? employment injury insurance and maternity insurance drug catalogue??(2009 version).RESULTS The United States??Japan and Australia had launched orphan drug list. A total of 1 133 drugs were improved to the market, covering 26 diseases. 329 anticancer drugs??168 endocrine, nutritional and metabolic disease drugs??122 hematologic disease drug ranked in the top three, accounted for 29.04%??14.83% and 10.77% of all drugs respectively. China has imported no more than 30%, with the anticancer drugs??infectious and parasitic diseases drugs??endocrine, nutritional and metabolic disease drugs ranking in the top three. In the imported drugs, 33 were included in the insurance list.CONCLUSION Orphan drug accessibility is lack in our country. To improve this status, the related department were suggested to develop national drug policies for orphan drugs, evidence-based select the orphan drug list appling to burden of disease, establish priority approach for approval of imported orphan drug and motivate the R&D enthusiasm of local companies.     

孤儿药真实世界研究的方法学研究进展

真实世界研究在孤儿药临床应用中体现出了良好的外推性。我国的孤儿药真实世界数据目前尚未得到充分利用,方法学是重要的制约因素之一,说明孤儿药真实世界研究方法学亟待规范。笔者查阅近年来国内外孤儿药真实世界研究相关文献和政策,对真实世界研究应用于孤儿药的方法学进行综述。孤儿药真实世界数据的常见来源包括患者登记和卫生信息系统等,单臂对照试验和观察性研究是目前使用较多的研究类型,研究过程重点把控偏倚和混杂,提升数据相关性和可靠性,在此基础上得到的真实世界证据可用于支持孤儿药审批和上市后再评价。笔者在总结方法学研究进展的基础上,结合孤儿药真实世界研究的应用,为我国开展相关研究提供参考。     

仿制药质量和疗效一致性评价工作建议

目前,中国医药产业正处于蓬勃发展期,国家在此时推行仿制药质量一致性评价对提升中国制药行业整体水平,保障公众用药安全等具有重大意义。本建议针对当前中国制药行业在药品质量一致性评价中面临的困惑,结合国外药品评价相关制度和经验,从药品分类及其申报原则、药品终点评价指标及其科学内涵、仿制药生物等效性评价相关原则等方面进行了细致剖析,并归纳总结了药品质量一致性和优劣性的评价原则及注意事项。此外,作者还针对中国制药行业的现状和存在的一些具体问题,提出了仿制药质量和疗效一致性评价的一些具体工作建议。     

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??OBJECTIVE To compare the setting methods for biologics data protection period between America and Japan, in order to provide suggestions for China. METHODS We made a contrastive study of American ??break even?? model and Japanese ??risk management evaluation?? model by using method introduction and characteristic analysis. RESULTS The two setting methods in the US and Japan focus on different system objectives, respectively. The Chinese choice of setting method needs to combine the feasibility of setting methods and the national conditions and policy goals for comprehensive consideration. CONCLUSION At present and the future for a long time, China's pharmaceutical industry is still in the ??imitation to innovation?? stage, and drug safety issues remain the core task. Therefore, the period of biologics data protection should be rationally set up by using ??risk management evaluation?? model as the base, ??break even?? model as supplement, so as to bring the three policy effects such as innovation incentive, the improvement of innovative drugs availability and strengthening the drug post-market safety monitoring.     

全球化研发背景下中药新药研发面临的形势和机遇

自2017年我国加入人用药品注册技术要求国际协调会议(ICH)组织以来,新药研发标准正式与国际接轨,中国化学药和生物药创新发展进入全新时代。然而,与化学药和生物药对比,中药新药研发略显不足,新药申报数量和批准数量不多,工业产值增长放缓,这是由于全球经济放缓的大背景及中国加入ICH之后研发规则和标准提高造成的。目前中医药得到国家政策支持,同时大健康时代来临带给中医药重大发展机遇。中药企业应顺势而为,努力提高中药产品的供给侧水平。同时应正确认识中药发展困境、挑战和机遇,加大中药创新力度和上市产品二次研发的力度。分析目前全球化研发背景下中药新药研发面临的形势,剖析中药新药研发和申报出现的困局及存在的机遇和挑战,对新时代下中药产业健康发展具有重要意义。     

The Present Scenario, Challenges, and Future Anticipation of Traditional Mongolian Medicine in China

The objective was to study the present scenario, challenges, and future anticipation of traditional Mongolian medicine(TMM) in China. The literature was retrieved using various sources of information such as meetings with TMM experts, research and review articles, national health databases, and government websites and authoritative papers. Health care using TMM, TMM education and research, and the pharmaceutical industry of TMM has been improved by implementing TMM growth policies. TMM has been extensively used for health care in Mongolia and in various regions of China including Beijing. The national education system of China contains a stream of TMM education. There is a yearly increase in research productivity in the field of TMM due to extensive research funding by the government. The rapidly growing pharmaceutical industry of TMM has provided more availability of TMM to more patients. The literature search revealed good preservation and development of TMM in China, urging the need to take steps for the promotion of its spread and development in China and worldwide.     

天然药物对肿瘤组织中血管内皮生长因子调节作用的研究现状

目的：对天然药物对肿瘤组织中血管内皮生长因子（VEGF）调节作用研究现状进行综述。方法：以单药及复方研究划分,对国内外天然药物的研究现状进行分析。结果：国内外研究机构对天然药物抗肿瘤血管再生研究方面积累了大量资料,其中大部分将主要靶点集中在VEGF调节作用方面。结论：目前对肿瘤组织中VEGF调节作用研究的实验方法与技术已经得到很大发展,对其作用机制研究已达到基因表达水平。国内外研究对象及研究方法上仍存在一些差异,可以相互启发借鉴。     

我国化学药品申报资料中关于生产线相关要求的审评考虑

目的药品的生产场所是为满足药品生产要求的一系列生产要素的组合,其既是药品生产的硬件条件,也是注册申报时审评的物质基础。笔者旨在初步探讨我国化学药品申报资料中生产线的内涵、外延,以期为规范药品注册申报提供一定的参考。方法在梳理我国化学药品申报资料中关于生产场所信息的历次要求的基础上,结合日常药学审评工作以及具体案例进行分析。结果与结论应明确申报资料中拟定生产线的内涵及边界,强化不同监管部门之间的有效沟通,及时更新相关证明性信息,同时还应持续关注我国关于生产线相关变更的法律法规修订进展。