Angiotensin_II_5-valine_DataSheet_MedChemExpress
Naglazyme（galsulfase）（抗生物）商品说明书
Naglazyme® (galsulfase)(Intravenous)Document Number: MH-0084 Last Review Date: 02/01/2022Date of Origin: 11/28/2011Dates Reviewed: 12/2011, 02/2013, 02/2014, 12/2014, 10/2015, 10/2016, 10/2017, 10/2018, 02/2019,02/2020, 02/2021, 02/2022I.Length of AuthorizationCoverage will be provided for 12 months and may be renewed.II.Dosing LimitsA.Quantity Limit (max daily dose) [NDC Unit]:•Naglazyme 5 mg vial: 23 vials per 7 daysB.Max Units (per dose and over time) [HCPCS Unit]:•115 billable units every 7 daysIII.Initial Approval Criteria 1Coverage is provided in the following conditions:•Patient is at least 5 years of age; AND•Documented baseline 12-minute walk test (12-MWT), 3-minute stair climb test (3-MSCT), and/or pulmonary function tests (e.g., FEV1, etc.); AND•Documented baseline value for urinary glycosaminoglycan (uGAG); ANDMucopolysaccharidosis VI (MPS VI, Maroteaux-Lamy syndrome) † Ф1,4,5•Patient has a definitive diagnosis of MPS VI as confirmed by the following:o Detection of pathogenic mutations in the ARSB gene by molecular genetic testing; ORo Arylsulfatase B (ASB) enzyme activity of <10% of the lower limit of normal in cultured fibroblasts or isolated leukocytes; AND▪Patient has normal enzyme activity of a different sulfatase (excluding patients with Multiple Sulfatase Deficiency [MSD]); AND▪Patient has an elevated urinary glycosaminoglycan (uGAG) level (i.e. dermatan sulfate or chondroitin sulfate) defined as being above the upper limit of normal bythe reference laboratory†FDA-approved indication(s); ‡Compendia recommended indication(s); ФOrphan DrugIV.Renewal Criteria 1,4,5Coverage can be renewed based on the following criteria:•Patient continues to meet indication-specific relevant criteria such as concomitant therapy requirements (not including prerequisite therapy), performance status, etc. identified insection III; AND•Absence of unacceptable toxicity from the drug. Examples of unacceptable toxicity include: anaphylaxis and hypersensitivity reactions, immune-mediated reactions, acute respiratorycomplications associated with administration, acute cardiorespiratory failure, severeinfusion reactions, spinal or cervical cord compression, etc.; AND•Disease response with treatment as defined by improvement or stability from pre-treatment baseline by the following:o Reduction in uGAG levels; AND▪Improvement in or stability of 12-minute walk test compared (12-MWT); OR▪Improvement in or stability of 3-minute stair climb test (3-MSCT); OR▪Improvement in or stability of pulmonary function testing (e.g., FEV1, etc.)V.Dosage/Administration 1Indication DoseMucopolysaccharidosis VI(MPS VI, Maroteaux-Lamy Syndrome) 1 mg/kg administered as an intravenous (IV) infusion oncea weekVI.Billing Code/Availability InformationHCPCS Code:•J1458 – Injection, galsulfase, 1 mg; 1 billable unit = 1 mgNDC:•Naglazyme 5 mg per 5 mL solution; single-use vial: 68135-0020-xxVII.References1.Naglazyme [package insert]. Novato, CA; BioMarin Pharmaceutical Inc.; December 2019.Accessed January 2022.2.Giugliani R, Harmatz P, Wraith JE. Management guidelines for mucopolysaccharidosis VI.Pediatrics. 2007 Aug;120(2):405-18.3.Giugliani R, Federhen A, Rojas MV, et al. Mucopolysaccharidosis I, II, and VI: Brief reviewand guidelines for treatment. Genet Mol Biol. 2010 Oct;33(4):589-604. Epub 2010 Dec 1.4.Vairo F, Federhen A, Baldo G, et al. Diagnostic and treatment strategies inmucopolysaccharidosis VI. Appl Clin Genet. 2015 Oct 30;8:245-55.5.Valaannopoulos V, Nicely H, Harmatz P, et al. Mucopolysaccharidosis VI. Orphanet J RareDis. 2010; 5: 5.6.Harmatz P, Giugliani R, Schwartz I, et al. Enzyme replacement therapy formucopolysaccharidosis VI: a phase 3, randomized, double-blind, placebo-controlled,multinational study of recombinant human N-acetylgalactosamine 4-sulfatase(recombinant human arylsulfatase B or rhASB) and follow-on, open-label extension study. JPediatr. 2006 Apr;148(4):533-539.Appendix 1 – Covered Diagnosis CodesICD-10 ICD-10 DescriptionE76.29 Other mucopolysaccharidosesAppendix 2 – Centers for Medicare and Medicaid Services (CMS)Medicare coverage for outpatient (Part B) drugs is outlined in the Medicare Benefit Policy Manual (Pub. 100-2), Chapter 15, §50 Drugs and Biologicals. In addition, National CoverageDetermination (NCD), Local Coverage Determinations (LCDs), and Local Coverage Articles (LCAs) may exist and compliance with these policies is required where applicable. They can be found at: https:///medicare-coverage-database/search.aspx. Additional indications may be covered at the discretion of the health plan.Medicare Part B Covered Diagnosis Codes (applicable to existing NCD/LCD/LCA): N/AMedicare Part B Administrative Contractor (MAC) JurisdictionsJurisdiction Applicable State/US Territory ContractorE (1) CA, HI, NV, AS, GU, CNMI Noridian Healthcare Solutions, LLCF (2 & 3) AK, WA, OR, ID, ND, SD, MT, WY, UT, AZ Noridian Healthcare Solutions, LLC5 KS, NE, IA, MO Wisconsin Physicians Service Insurance Corp (WPS)6 MN, WI, IL National Government Services, Inc. (NGS)H (4 & 7) LA, AR, MS, TX, OK, CO, NM Novitas Solutions, Inc.8 MI, IN Wisconsin Physicians Service Insurance Corp (WPS) N (9) FL, PR, VI First Coast Service Options, Inc.J (10) TN, GA, AL Palmetto GBA, LLCM (11) NC, SC, WV, VA (excluding below) Palmetto GBA, LLCNovitas Solutions, Inc.L (12) DE, MD, PA, NJ, DC (includes Arlington &Fairfax counties and the city of Alexandria in VA)K (13 & 14) NY, CT, MA, RI, VT, ME, NH National Government Services, Inc. (NGS)15 KY, OH CGS Administrators, LLC。
SGLT2_抑制剂联合二甲双胍治疗对糖尿病肾病患者血糖及疗效的影响
SGLT2抑制剂联合二甲双胍治疗对糖尿病肾病患者血糖及疗效的影响郑秋娥，程秋敏，刘江建福建省立医院药学部，福建福州350001[摘要]目的分析钠-葡萄糖共转运蛋白2（sodium-dependent glucose transporters 2, SGLT2）抑制剂联合二甲双胍治疗对糖尿病肾病患者血糖及疗效的影响。
方法选取2021年1月—2023年1月福建省立医院接诊的108例糖尿病肾病患者，按照随机数表法分为对照组与研究组，各54例。
对照组接受二甲双胍+百令胶囊治疗，研究组联合SGLT2抑制剂治疗，分析对比两组患者血糖指标、临床总有效率、肾功能指标及血清炎症指标。
结果与对照组相比，研究组治疗后的空腹血糖、餐后2 h血糖及糖化血红蛋白水平更低，差异有统计学意义（P<0.05）。
与对照组对比，研究组临床总有效率更高，差异有统计学意义（P<0.05）。
与对照组对比，研究组治疗后的血肌酐、尿素氮及尿白蛋白排泄率更低，差异有统计学意义（P<0.05）。
结论SGLT2抑制剂联合二甲双胍治疗糖尿病肾病可降低血糖水平，改善肾功能，减轻机体炎症反应，提高临床总效率。
[关键词] SGLT2抑制剂；二甲双胍；糖尿病肾病；血糖[中图分类号] R4 [文献标识码] A [文章编号] 1672-4062（2023）10（b）-0076-04Effect of SGLT2 Inhibitor Combined with Metformin Treatment on Blood Glucose and Curative Effect in Patients with Diabetic NephropathyZHENG Qiu'e, CHENG Qiumin, LIU JiangjianDepartment of Pharmacy, Fujian Provincial Hospital, Fuzhou, Fujian Province, 350001 China[Abstract] Objective To analyze the effects of sodium-dependent glucose transporters 2 (SGLT2) inhibitor combined with metformin treatment on blood glucose and curative effect in patients with diabetic nephropathy.Methods 108 pa⁃tients with diabetes nephropathy who were treated in Fujian Provincial Hospital from January 2021 to January 2023 were selected and divided into the control group and the study group according to the random number table, with 54 patients in each group. The control group received treatment with metformin and Bailing capsules, while the study group received treatment with SGLT2 inhibitors. The blood glucose indicators, clinical total efficiency, renal function indicators, and serum inflammation indicators were analyzed and compared between the two groups.Results Compared with the control group, the study group had lower levels of FPG, 2 hPG, and HbA1c after treatment, the difference was statistically significant (P<0.05). Compared with the control group, the total clinical efficiency of the study group was higher, and the difference was statistically significant (P<0.05). Compared with the control group, the study group had lower Scr, BUN, and UAER after treatment, the difference was statistically significant (P<0.05).Conclusion SGLT2 in⁃hibitor combined with metformin in the treatment of diabetic nephropathy can reduce blood glucose level, improve re⁃nal function, reduce the inflammatory response of the body, and improve the overall clinical efficiency.[Key words] SGLT2 inhibitor; Metformin; Diabetic nephropathy; Blood glucose糖尿病肾病是糖尿病并发症之一，也是引发终末期肾衰竭的主要原因，近十年来随着糖尿病发病率的增高，糖尿病肾病发病率增加2倍以上[1]。
2015-2021年FDA批准的505b2药物
APPLICATIONNUMBERPROPRIETARY NAME ESTABLISHED NAME通用名APPLICANTNDA208746(1)PEMETREXED培美曲塞HOSPIRA INC NDA 206610ACETAMINOPHEN对乙酰氨基酚RISINGNDA 214313NOREPINEPHRINEBITARTRATE IN 5%DEXTROSENOREPINEPHRINEBITARTRATE酒石酸去甲肾上腺素BAXTER HEALTHCARECORPNDA 204803POSIMIR BUPIVACAINE布比卡因DURECT CORPNDA 204957ACETAMINOPHEN对乙酰氨基酚B BRAUN MEDICAL INCNDA 212994AZSTARYS SERDEXMETHYLPHENIDATE ANDDEXMETHYLPHENIDATE对甲苯磺酸盐和对甲苯磺酸盐COMMAVETHERAPEUTICS SANDA 211844MIDAZOLAM咪达唑仑INFORLIFE SANDA 213072ROSZET ROSUVASTATIN ANDEZETIMIBE瑞舒伐他汀和依折麦布ALTHERAPHARMACEUTICALSLLCNDA 214154NEXTSTELLIS DROSPIRENONE ANDESTETROL TABLETS屈螺酮和雌醇片MAYNE PHARMA LLCNDA 212045KLOXXADO NALOXONE HCL盐酸纳洛酮HIKMA PHARMACEUTICALS USA INCNDA214657(1)PEMETREXED SANDOZ INCNDA 211988ZYNRELEF BUPIVACAINE ANDMELOXICAM布比卡因和美洛昔康HERON THERAPEUTICSINCNDA 214253LEVOTHYROXINESODIUMCUSTOPHARM INCNDA 211488CAMCEVI LEUPROLIDE亮丙瑞林FORESEE PHARMACEUTICALS CO LTDNDA 214846MYFEMBREE RELUGOLIX 40 MG,ESTRADIOL 1 MG,AND NORETHINDRONEACETATE 0.5MGRELUGOLIX 40 mg、雌二醇 1 mg 和醋酸炔诺酮0.5 mgMYOVANT SCIENCESGMBHNDA 213378LYBALVI OLANZAPINE ANDSAMIDORPHAN奥氮平和沙美芬ALKERMES INCNDA 215025SODIUMPHENYLACETATE ANDSODIUM BENZOATE苯乙酸钠和苯甲酸钠MAIAPHARMACEUTICALSINCNDA 213218SOAANZ TORSEMIDE托拉塞米SARFEZ PHARMACEUTICALS INCNDA 213536REZIPRES EPHEDRINEHYDROCHLORIDE盐酸麻黄碱ETONPHARMACEUTICALSINCNDA 212156MICAFUNGIN米卡芬净PAR STERILE PRODUCTS LLCNDA 210282DAPTOMYCIN达托霉素HOSPIRA INC NDA 214965VERKAZIA CYCLOSPORINE环孢素SANTEN INCNDA 212303(1)DULUTEGRAVIR,LAMIVUDINE, ANDTENOFOVIRDISOPROXIL度替拉韦、拉米夫定和富马酸替诺福韦酯LUPIN LTDNDA 214902TWYNEO TRETINOIN ANDBENZOYL PEROXIDE维 A 酸和过氧化苯甲酰SOL-GELTECHNOLOGIES LTDNDA 215143SUCCINYLCHOLINECHLORIDE琥珀胆碱氯化物HIKMAPHARMACEUTICALSUSA INCNDA 210735CYCLOPHOSPHAMIDE环磷酰胺EUGIA PHARMA SPECIALITIES LTDNDA 213895VANCOMYCIN万古霉素XELLIA PHARMACEUTICALS APSNDA 214826LOREEV XR LORAZEPAM劳拉西泮ALMATICA PHARMA LLCNDA 211566(1)SITAGLIPTIN西他列汀ZYDUS WORLDWIDEDMCCNDA 213436TRUDHESA DIHYDROERGOTAMINEMESYLATE甲磺酸二氢麦角胺IMPEL NEUROPHARMANDA 215133SERTRALINEHYDROCHLORIDE盐酸舍曲林ALMATICA PHARMALLCNDA 212854ZIMHI NALOXONEHYDROCHLORIDE盐酸纳洛酮ADAMISPHARMACEUTICALSCORPNDA 213426SEGLENTIS CELECOXIB ANDTRAMADOLHYDROCHLORIDE塞来昔布和盐酸曲马多KOWAPHARMACEUTICALSAMERICA INCNDA 213978TYRVAYA VARENICLINESOLUTION伐尼克兰溶液OYSTER POINTPHARMA INCNDA 211950XIPERE TRIAMCINOLONEACETONIDE曲安奈德BAUSCH AND LOMBINCNDA 214028VUITY PILOCARPINEHYDROCHLORIDE盐酸匹洛卡品ABBVIE INCNDA 210526DYANAVEL XR AMPHETAMINE安非他明TRIS PHARMA INCNDA 213005(1)YUTREPIA TREPROSTINIL曲前列尼尔LIQUIDIATECHNOLOGIESNDA 214679EPRONTIA TOPIRAMATE托吡酯AZURITY PHARMACEUTICALS INCNDA 214869DHIVY CARBIDOPA ANDLEVODOPACARBIDOPA 和左旋多巴AVIONPHARMACEUTICALSLLCNDA 215668(1)BENDAMUSTINEHYDROCHLORIDE盐酸苯达莫司汀DR REDDYSLABORATORIES LTDNDA 213312FYARRO SIROLIMUS PROTEIN-BOUND PARTICLESSIROLIMUS 蛋白结合颗粒AADI BIOSCIENCEINCNDA 215422LYVISPAH BACLOFEN巴氯芬SAOL THERAPEUTICS RESEARCH LTDNDA 215650XACIATO CLINDAMYCINPHOSPHATE磷酸克林霉素DARE BIOSCIENCEINCNDA 215423ENTADFI TADALAFIL ANDFINASTERIDE他达拉非和非那雄胺VERU INCNDA 215935TARPEYO BUDESONIDE布地奈德CALLIDITAS THERAPEUTICS ABNDA 215019DARTISLA ODT GLYCOPYRROLATE甘氨酰吡咯酸EDENBRIDGE PHARMACEUTICALS LLCNDA 2I4032ILLUCCIX KIT FOR THEPREPARATION OF GA-68 PSMA-11GA-68 PSMA-11 制备试剂盒TELIXPHARMACEUTICALS USINCNDA 215395LANREOTIDE ACETATE醋酸来那度胺INVAGEN PHARMACEUTICALS INCNDA 214133RECORLEV LEVOKETOCONAZOLE左酮康唑STRONGBRIDGE DUBLIN LTDREVIEW CLASSIFI CATION 505(B)(2)APPROVALAPPROVAL DATE批准类型S Y1/8/2021Type 3 - New Dosage FormS Y1/15/2021Type 5 - New Formulation or New ManufacturerS Y1/15/2021Type 5 - New Formulation or New ManufacturerS Y2/1/2021Type 3 - New Dosage FormS Y2/18/2021Type 5 - New Formulation or New ManufacturerS Y3/2/2021Type 1 - New Molecular Entity and Type 4 - New CombinationS Y3/22/2021Type 5 - New Formulation or New ManufacturerS Y3/23/2021Type 4 - New CombinationS Y4/15/2021Type 1 - New Molecular EntityS Y4/29/2021Type 5 - New Formulation or New ManufacturerS Y5/6/2021Type 5 - New Formulation or New ManufacturerP Y5/12/2021Type 4 - New CombinationS Y5/17/2021Type 5 - New Formulation or New ManufacturerS Y5/25/2021Type 2 - New Active IngredientS Y5/26/2021Type 4 - New CombinationS Y5/28/2021Type 1 - New Molecular Entity and Type 4 - New CombinationS Y6/10/2021Type 5 - New Formulation or New ManufacturerS Y6/14/2021Type 5 - New Formulation or New ManufacturerS Y6/14/2021Type 5 - New Formulation or New ManufacturerNew ManufacturerS Y6/21/2021Type 5 - New Formulation or New ManufacturerS,O Y6/23/2021Type 5 - New Formulation or New ManufacturerS Y6/25/2021Type 4 - New Combination S Y7/26/2021Type 4 - New CombinationS Y8/20/2021Type 5 - New Formulation or New ManufacturerS Y8/25/2021Type 5 - New Formulation or New ManufacturerP Y8/26/2021Type 5 - New Formulation or New ManufacturerS Y8/27/2021Type 3 - New Dosage FormS Y9/2/2021Type 2 - New Active IngredientS Y9/2/2021Type 5 - New Formulation or New ManufacturerS Y10/4/2021Type 3 - New Dosage FormS Y10/15/2021Type 5 - New Formulation or New ManufacturerS Y10/15/2021Type 4 - New Combination S Y10/15/2021Type 3 - New Dosage Form S Y10/22/2021Type 3 - New Dosage FormS Y10/28/2021Type 5 - New Formulation or New ManufacturerS Y11/4/2021Type 3 - New Dosage Form S Y11/4/2021Type 3 - New Dosage FormS Y11/5/2021Type 3 - New Dosage FormS Y11/12/2021Type 5 - New Formulation or New ManufacturerNew ManufacturerP,O Y11/22/2021Type 5 - New Formulation or New ManufacturerS Y11/22/2021Type 3 - New Dosage FormP Y12/7/2021Type 5 - New Formulation or New ManufacturerS Y12/9/2021Type 4 - New CombinationP,O Y12/15/2021Type 5 - New Formulation or New ManufacturerS Y12/16/2021Type 3 - New Dosage FormS Y12/17/2021Type 3 - New Dosage Form and Type 4 - New CombinationS Y12/17/2021Type 5 - New Formulation or New ManufacturerS,O Y12/30/2021Type 2 - New Active Ingredient适应症NSCLC、Mesothelioma间皮瘤（注射剂）止痛、退烧（注射剂）升高低血压（注射剂）局部麻醉（注射剂）止痛、退烧CNS兴奋剂注射麻醉剂降低LDL-C预防妊娠阿片类拮抗剂，用于阿片类过量NSCLC、Mesothelioma间皮瘤术后止痛（注射剂）粘液性水肿昏迷myxedema coma晚期前列腺癌子宫平滑肌瘤月经量过多成人精神分裂症、成人双相 i 型障碍急性高血氨症成人心力衰竭、肾病相关水肿麻醉状态的低血压念珠菌血症、急性播散性念珠菌病、念珠菌腹膜炎和脓肿cSSSI、Bacteremia菌血症春季角结膜炎(Tentative Approval)痤疮局部治疗作为全身麻醉的辅助治疗、便于气管插管、在手术或机械通气期间提供骨骼肌松弛label not available败血症、感染性心内膜炎、皮肤和皮肤结构感染、骨感染、下呼吸道感染、艰难梭菌相关性腹泻、金黄色葡萄球菌引起的小肠结肠炎label not availablelabel not available偏头痛急性治疗MDD、OCD紧急治疗阿片类药物过量治疗需要阿片类镇痛剂且替代治疗效果不佳的成人急性疼痛。
黄素腺嘌呤二核苷酸（FAD）酶联免疫吸附测定试剂盒
5th Edition, revised in Dec, 2013（本试剂盒仅供体外研究使用，不用于临床诊断！）去甲肾上腺素(NA/NE)酶联免疫吸附测定试剂盒 使用说明书NA/NE (Noradrenaline/Norepinephrine) ELISA Kit 产品货号：E-EL-0047c使用前请仔细阅读说明书。
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试剂盒组成：特别说明：*: [96T/48T]（打开包装后请及时检查所有物品是否齐全完整）#:一周内使用可存于4℃，需长时间存放或多次使用建议存于-20℃.相关试剂在分装时会比标签上标明的体积稍多一些，请在使用时量取而非直接倒出！检测原理:本试剂盒采用竞争ELISA法。
用NA/NE抗原包被于酶标板上，实验时样品或标准品中的NA/NE 与包被的NA/NE竞争生物素标记的抗NA/NE单抗上的结合位点，游离的成分被洗去。
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加入显色底物(TMB)，TMB在辣根过氧化物酶的催化下呈现蓝色，加终止液后变成黄色。
氨噻肟酸卤代工艺的改进方法综述
氨噻肟酸卤代工艺的改进方法综述发布时间：2022-10-27T07:03:57.841Z 来源：《科学与技术》2022年12期6月作者：徐凯文[导读] 对氨噻肟酸工艺中的卤代工艺改进进行了总结,徐凯文上海诺美学校摘要:对氨噻肟酸工艺中的卤代工艺改进进行了总结,介绍了氨噻肟酸工艺中原有的卤代工艺和改进后的卤代工艺的详细操作过程，并总结出卤代工艺改进前后的优点和缺点。
关键词:氨噻肟酸卤代工艺液溴液氯The Improvement of Halogenating reaction in Preparing 2-(2-Aminothiazole-4-yl)-2-Methoxyiminoacetic Acid, Kevin XuAbstract: The improvement of Halogenating reaction in Preparing 2-(2-Aminothiazole-4-yl)-2-Methoxyiminoacetic Acid. Understanding the detailed operation of the original Halogenation reaction and the improved Halogenation reaction in preparing 2-(2-Aminothiazole-4-yl)-2-Methoxyiminoacetic Acid. Then summarize the advantages and disadvantages of before and after improvement of Halogenation reaction.Key words: 2-(2-Aminothiazole-4-yl)-2-Methoxyiminoacetic Acid Halogenating reaction Liquid bromine Liquid chlorine1:背景信息1.1 氨噻肟酸氨噻肟酸结构式见图1。
Angiotensin_II_5-valine_SDS_MedChemExpress
Inhibitors, Agonists, Screening LibrariesSafety Data Sheet Revision Date:May-24-2017Print Date:May-24-20171. PRODUCT AND COMPANY IDENTIFICATION1.1 Product identifierProduct name :Angiotensin II 5-valineCatalog No. :HY-P0108CAS No. :58-49-11.2 Relevant identified uses of the substance or mixture and uses advised againstIdentified uses :Laboratory chemicals, manufacture of substances.1.3 Details of the supplier of the safety data sheetCompany:MedChemExpress USATel:609-228-6898Fax:609-228-5909E-mail:sales@1.4 Emergency telephone numberEmergency Phone #:609-228-68982. HAZARDS IDENTIFICATION2.1 Classification of the substance or mixtureNot a hazardous substance or mixture.2.2 GHS Label elements, including precautionary statementsNot a hazardous substance or mixture.2.3 Other hazardsNone.3. COMPOSITION/INFORMATION ON INGREDIENTS3.1 SubstancesSynonyms:Valine angiotensin II; 5⁻L⁻Valine angiotensin IIFormula:C49H69N13O12Molecular Weight:1032.15CAS No. :58-49-14. FIRST AID MEASURES4.1 Description of first aid measuresEye contactRemove any contact lenses, locate eye-wash station, and flush eyes immediately with large amounts of water. Separate eyelids with fingers to ensure adequate flushing. Promptly call a physician.Skin contactRinse skin thoroughly with large amounts of water. Remove contaminated clothing and shoes and call a physician.InhalationImmediately relocate self or casualty to fresh air. If breathing is difficult, give cardiopulmonary resuscitation (CPR). Avoid mouth-to-mouth resuscitation.IngestionWash out mouth with water; Do NOT induce vomiting; call a physician.4.2 Most important symptoms and effects, both acute and delayedThe most important known symptoms and effects are described in the labelling (see section 2.2).4.3 Indication of any immediate medical attention and special treatment neededTreat symptomatically.5. FIRE FIGHTING MEASURES5.1 Extinguishing mediaSuitable extinguishing mediaUse water spray, dry chemical, foam, and carbon dioxide fire extinguisher.5.2 Special hazards arising from the substance or mixtureDuring combustion, may emit irritant fumes.5.3 Advice for firefightersWear self-contained breathing apparatus and protective clothing.6. ACCIDENTAL RELEASE MEASURES6.1 Personal precautions, protective equipment and emergency proceduresUse full personal protective equipment. Avoid breathing vapors, mist, dust or gas. Ensure adequate ventilation. Evacuate personnel to safe areas.Refer to protective measures listed in sections 8.6.2 Environmental precautionsTry to prevent further leakage or spillage. Keep the product away from drains or water courses.6.3 Methods and materials for containment and cleaning upAbsorb solutions with finely-powdered liquid-binding material (diatomite, universal binders); Decontaminate surfaces and equipment by scrubbing with alcohol; Dispose of contaminated material according to Section 13.7. HANDLING AND STORAGE7.1 Precautions for safe handlingAvoid inhalation, contact with eyes and skin. Avoid dust and aerosol formation. Use only in areas with appropriate exhaust ventilation.7.2 Conditions for safe storage, including any incompatibilitiesKeep container tightly sealed in cool, well-ventilated area. Keep away from direct sunlight and sources of ignition.Recommended storage temperature:Powder-20°C 3 years4°C 2 yearsIn solvent-80°C 6 months-20°C 1 monthShipping at room temperature if less than 2 weeks.7.3 Specific end use(s)No data available.8. EXPOSURE CONTROLS/PERSONAL PROTECTION8.1 Control parametersComponents with workplace control parametersThis product contains no substances with occupational exposure limit values.8.2 Exposure controlsEngineering controlsEnsure adequate ventilation. Provide accessible safety shower and eye wash station.Personal protective equipmentEye protection Safety goggles with side-shields.Hand protection Protective gloves.Skin and body protection Impervious clothing.Respiratory protection Suitable respirator.Environmental exposure controls Keep the product away from drains, water courses or the soil. Cleanspillages in a safe way as soon as possible.9. PHYSICAL AND CHEMICAL PROPERTIES9.1 Information on basic physical and chemical propertiesAppearance White to off-white (Solid)Odor No data availableOdor threshold No data availablepH No data availableMelting/freezing point No data availableBoiling point/range No data availableFlash point No data availableEvaporation rate No data availableFlammability (solid, gas)No data availableUpper/lower flammability or explosive limits No data availableVapor pressure No data availableVapor density No data availableRelative density No data availableWater Solubility No data availablePartition coefficient No data availableAuto-ignition temperature No data availableDecomposition temperature No data availableViscosity No data availableExplosive properties No data availableOxidizing properties No data available9.2 Other safety informationNo data available.10. STABILITY AND REACTIVITY10.1 ReactivityNo data available.10.2 Chemical stabilityStable under recommended storage conditions.10.3 Possibility of hazardous reactionsNo data available.10.4 Conditions to avoidNo data available.10.5 Incompatible materialsStrong acids/alkalis, strong oxidising/reducing agents.10.6 Hazardous decomposition productsUnder fire conditions, may decompose and emit toxic fumes.Other decomposition products - no data available.11.TOXICOLOGICAL INFORMATION11.1 Information on toxicological effectsAcute toxicityClassified based on available data. For more details, see section 2Skin corrosion/irritationClassified based on available data. For more details, see section 2Serious eye damage/irritationClassified based on available data. For more details, see section 2Respiratory or skin sensitizationClassified based on available data. For more details, see section 2Germ cell mutagenicityClassified based on available data. For more details, see section 2CarcinogenicityIARC: No component of this product present at a level equal to or greater than 0.1% is identified as probable, possible or confirmed human carcinogen by IARC.ACGIH: No component of this product present at a level equal to or greater than 0.1% is identified as a potential or confirmed carcinogen by ACGIH.NTP: No component of this product present at a level equal to or greater than 0.1% is identified as a anticipated or confirmed carcinogen by NTP.OSHA: No component of this product present at a level equal to or greater than 0.1% is identified as a potential or confirmed carcinogen by OSHA.Reproductive toxicityClassified based on available data. For more details, see section 2Specific target organ toxicity - single exposureClassified based on available data. For more details, see section 2Specific target organ toxicity - repeated exposureClassified based on available data. For more details, see section 2Aspiration hazardClassified based on available data. For more details, see section 212. ECOLOGICAL INFORMATION12.1 ToxicityNo data available.12.2 Persistence and degradabilityNo data available.12.3 Bioaccumlative potentialNo data available.12.4 Mobility in soilNo data available.12.5 Results of PBT and vPvB assessmentPBT/vPvB assessment unavailable as chemical safety assessment not required or not conducted.12.6 Other adverse effectsNo data available.13. DISPOSAL CONSIDERATIONS13.1 Waste treatment methodsProductDispose substance in accordance with prevailing country, federal, state and local regulations.Contaminated packagingConduct recycling or disposal in accordance with prevailing country, federal, state and local regulations.14. TRANSPORT INFORMATIONDOT (US)This substance is considered to be non-hazardous for transport.IMDGThis substance is considered to be non-hazardous for transport.IATAThis substance is considered to be non-hazardous for transport.15. REGULATORY INFORMATIONSARA 302 Components:No chemicals in this material are subject to the reporting requirements of SARA Title III, Section 302.SARA 313 Components:This material does not contain any chemical components with known CAS numbers that exceed the threshold (De Minimis) reporting levels established by SARA Title III, Section 313.SARA 311/312 Hazards:No SARA Hazards.Massachusetts Right To Know Components:No components are subject to the Massachusetts Right to Know Act.Pennsylvania Right To Know Components:No components are subject to the Pennsylvania Right to Know Act.New Jersey Right To Know Components:No components are subject to the New Jersey Right to Know Act.California Prop. 65 Components:This product does not contain any chemicals known to State of California to cause cancer, birth defects, or anyother reproductive harm.16. OTHER INFORMATIONCopyright 2017 MedChemExpress. The above information is correct to the best of our present knowledge but does not purport to be all inclusive and should be used only as a guide. The product is for research use only and for experienced personnel. It must only be handled by suitably qualified experienced scientists in appropriately equipped and authorized facilities. The burden of safe use of this material rests entirely with the user. MedChemExpress disclaims all liability for any damage resulting from handling or from contact with this product.Caution: Product has not been fully validated for medical applications. For research use only.Tel: 609-228-6898 Fax: 609-228-5909 E-mail: tech@Address: 1 Deer Park Dr, Suite Q, Monmouth Junction, NJ 08852, USA。
盐酸伐昔洛韦的合成路线
Valacyclovir盐酸伐昔洛韦的合成路线制药工程一班刘金贵3010207301Valacyclovir一中文名:维德思,盐酸伐昔洛韦,盐酸万乃洛韦二化学名称为：L-缬氨酸-2-（6-氧代-2-氨基-1，6-二氢- 9H -嘌呤-9-基）甲氧基乙基酯盐酸盐三化学结构式(如下图) 分子式C13-H20-N6-O4 分子量324.342四药代动力学本品口服进入人体后迅速分解为L-缬氨酸和阿昔洛韦，前者在体内参与正常生理生化代谢，后者在被疱疹病毒感染的细胞中，血中阿昔洛韦达峰时间为0.88～1.75小时。
口服生物利用度为67±13%，是阿昔洛韦的3～5倍。
药物进入体内后广泛分布，可分布至多种组织中，其中胃、小肠、肾、肝、淋巴结和皮肤组织中浓度最高，脑组织中的浓度最低。
药物在体内全部转化为阿昔洛韦，代谢物主要从尿中排除，其中阿昔洛韦占46%～59%，8-羟基-9-鸟嘌呤占25%～30%，9-羟基甲氧基鸟嘌呤占11%～12%。
阿昔洛韦原形为单相消除，血消除半衰期（t1/2β）为2.86±0.39小时。
五药理毒理药理作用:伐昔洛韦是一特异性疱疹病毒抑制剂，为阿昔洛韦(嘌呤核苷类似物)的L-缬氨酸酯。
伐昔洛韦在体内可能是通过伐昔洛韦水解酶迅速几乎完全转化为阿昔洛韦和缬氨酸。
阿昔洛韦在体外具有抑制单纯疱疹病毒(HSV)Ⅰ型和Ⅱ型、水痘带状疱疹病毒(VZV)、巨细胞病毒(CMV)、Epstein-Barr病毒(EBV)和人类疱疹病毒6(HHV-6)的作用。
病毒的胸苷激酶使其磷酸化，成为单磷酸化合物，再由细胞激酶磷酸化变成二磷酸和三磷酸化合物。
三磷酸化合物是抗病毒的活性物质，可抑制病毒的DNA聚合酶，终止其DNA合成，显示抗病毒效力。
由于本品是ACV 的氨基酸酯，没有游离羟基提供给磷酸化，因而在未转化为ACV之前，并无抗病毒活性，这一点使其不象其它前体药物如地昔洛韦(desciclovir)等另外增加对细胞的毒性。
抗抑郁药---盐酸维拉佐酮
2014.10.20
前言 • MDD治疗的主要药物种类
• 第一代经典抗抑郁药：主要包括单胺氧化酶抑制剂（maoi）和三环类 抗抑郁药（tca）。
• 第二代新型抗抑郁药：以选择性五羟色胺（5-ht）再摄取抑剂为主。 • 盐酸维拉佐酮（vilazodone hydrochloride）是首个吲哚烷基胺类新 型抗抑郁药。
2014.10.20
药物背景 • 安全性
• 盐酸维拉佐酮在8个临床试验共计2 177例MDD患者的临床研究中显 示具有良好的耐受性和安全性。在与安慰剂，对照的Ⅲ临床研究中， 因不良反应导致盐酸维拉佐酮治疗组中止治疗的患者占7．1％，安慰 剂对照组为3．2％，治疗组导致停药的常见不良反应主耍为恶心(1． 3％)和腹泻(1．2％) 。 • 由于抗抑郁药可增加儿童、青少年和l 8～24岁年轻人服药初期自杀想 法和自杀行为的风险，因此以上患者要慎用。 • 维拉唑酮在治疗终止时，尤其突然终止时，会出现戒断症状(烦躁不 安、易怒、眩晕、感觉障碍、意识模糊等症状)。
2014.10.20
报告框架
• 1.药物背景
• 2.专利介绍 • 3.合成路线
Viibryd（盐酸维拉佐酮）
2014.10.20
药物背景
• • • • • • • • • • • • • • • • 通用名称：维拉佐酮（Vilazodone） 商品名：Viibryd 原研公司：德国Merck KGaA 基本专利： DE19934333254 优先权：1993 年9 月30 日 相关中国专利： CN94116585 类别：抑郁症治疗药 化合物类型：新分子实体 5-［4-［4-( 5-cyano-1H-indol-3-yl) butyl］-1（New molecular entity） piperazinyl］-2-benzofurancarboxamide 分子式：C26H27N5O2 ·HCl hydrochloride 相对分子质量：477.99 CAS 号：163521-08-2 适应症：重度抑郁症（MDD） 化学名： 5-［4-［4-( 5-氰基-1H-吲哚-3-基) 丁基］-1-哌嗪基］-2-苯并呋喃草酰胺盐酸 盐; 获批单位：Trovis 制药有限责任公司 批准日期：2011 年1 月21 日
Evaluation of angiotensin I-converting enzyme (ACE) inhibitory
ORIGINAL PAPEREvaluation of angiotensin I-converting enzyme (ACE)inhibitory activities of smooth hound (Mustelus mustelus )muscle protein hydrolysates generated by gastrointestinal proteases:identification of the most potent active peptideAli Bougatef •Rafik Balti •Naı¨ma Nedjar-Arroume •Rozenn Ravallec •Estelle Yaba Adje´•Nabil Souissi •Imen Lassoued •Didier Guillochon •Moncef NasriReceived:27January 2010/Revised:18February 2010/Accepted:27February 2010/Published online:18March 2010ÓSpringer-Verlag 2010Abstract In this study,smooth hound protein hydroly-sates (SHPHs),obtained by treatment with various gas-trointestinal proteases,were analyzed for their angiotensin I-converting enzyme (ACE)inhibitory activities.Protein hydrolysates were obtained by treatment with crude alka-line enzyme extract,low molecular weight (LMW)alkaline protease,trypsin-like protease and pepsin from Mustelus mustelus ,and bovine trypsin.All hydrolysates exhibited inhibitory activity toward ACE.Hydrolysate generated with alkaline protease extract displayed the highest ACE inhibitory activity,and the higher inhibition activity (82.6%at 2mg/mL)was obtained with a hydrolysis degree of 18.8%.This hydrolysate was then fractionated by size exclusion chromatography on a Sephadex G-25into five major fractions (P 1–P 5).ACE inhibitory activities of all fractions were assayed,and P 3was found to display a high ACE inhibitory activity (62.24%at 1mg/mL).P 3was then fractionated by reversed-phase high-performance liquid chromatography (RP-HPLC)and ten fractions of ACE inhibitors were found (F 1–F 10).Sub-fraction F 3showed the strongest ACE inhibitory activity,being able to suppress more than 60%of initial enzyme activity at a concentration of 100l g/mL.The amino acid sequence of peptide F 3was determined by ESI/MS and ESI–MS/MS as Ala-Gly-Ser,and the IC 50value for ACE inhibitory activity was0.13±0.03mg/mL.Further,purified peptide F 3main-tained inhibitory activity even after in vitro digestion with gastrointestinal proteases in order to demonstrate gastro-intestinal stability digestion to enable oral application.These results indicate that smooth hound protein hydroly-sate possesses potent antihypertensive activity.Keywords Smooth hound muscle ÁM.mustelus ÁIntestine crude extract ÁEnzymatic treatment ÁACE inhibitory activities ÁProtein hydrolysates AbbreviationsSHPH Smooth hound protein hydrolysate ACE Angiotensin-converting enzyme LMW Low molecular weight DH Degree of hydrolysisIntroductionHigh blood pressure has been considered a risk factor for developing cardiovascular diseases (arteriosclerosis,stroke and myocardial infarction)and end-stage renal disease [1].Angiotensin I-converting enzyme (ACE,dipeptidyl car-boxy peptidase,EC 3.4.15.1)plays an important physio-logical role in the regulation of blood pressure by virtue of the rennin angiotensin system [2,3].It is a multifunctional zinc-containing enzyme,located in different tissues.ACE converts the inactive decapeptide,angiotensin I to the potent vasopressor octapeptide,angiotensin II and inacti-vates bradykinin [2].Inhibition of ACE is considered to be a useful thera-peutic approach in the treatment of high blood pressure.A.Bougatef (&)ÁR.Balti ÁN.Souissi Ássoued ÁM.NasriLaboratoire de Ge´nie Enzymatique et de Microbiologie,Ecole Nationale d’Inge´nieurs de Sfax,BP ‘‘1173’’,3038Sfax,Tunisiae-mail:ali.bougatef79@N.Nedjar-Arroume ÁR.Ravallec ÁE.Y.Adje´ÁD.Guillochon Laboratoire de Proce´de ´s Biologiques,Ge ´nie Enzymatique et Microbien,IUT A Lille I,BP 179,59653Villeneuve d’Ascq Cedex,FranceEur Food Res Technol (2010)231:127–135DOI 10.1007/s00217-010-1260-4Several effective oral ACE inhibitors have been developed, namely,captopril,enalapril,and lisinopril and all are cur-rently used as clinical antihypertensive drugs[4].Although synthetic ACE inhibitors are effective as antihypertensive drugs,they cause adverse side effects such as coughing, allergic reactions,taste disturbances,and skin rashes. Therefore,research and development tofind safer,inno-vative,and economical ACE inhibitors is necessary for the prevention and remedy for hypertension.Structure–activity correlation among different peptide inhibitors of ACE indicates that binding to ACE is strongly influenced by the C-terminal tripeptide sequence of the substrate.ACE appears to prefer substrates or competitive inhibitors that mainly have hydrophobic (aromatic or branched side chains)amino acid residues at the three C-terminal positions.ACE inhibition studies with Trp,Tyr,Phe,or Pro residues were most effective in enhancing substrate binding[5].Nevertheless,the structure–activity relationship of ACE inhibitory peptides has not yet been established,and very different hypo-tensive sequences have been derived from a large num-ber of food proteins[6].It is postulated that the mechanism of ACE inhibition involves inhibitor inter-action with an anionic binding site that is distinct from the catalytic site.Since the discovery of ACE inhibitors in snake venom [7],several reports have been published on the ACE inhibitory activity of peptides from food proteins,like casein[8],rapeseed[9],mushroom[10],whey protein[11], porcine muscle[12],bovine skin gelatin[13],soybean [14],sake and sake lees[15],andfish proteins[16,17].Proteases such as pepsin,chymotrypsin,and trypsin are frequently used in hydrolysis to produce ACE inhibitory peptides[18–20].Microbial alkaline proteases are also utilized in the production of ACE inhibitors from food proteins such as sardine(Sardina pilchardus)[21]and rapeseed[9].However,there are a small number of reports on the use of digestive enzymes fromfish in the producing bioactive peptides[22,23].The smooth hound Mustelus mustelus is the most abundant hound shark in the Mediterranean Sea.It is found in the eastern Atlantic from the British Isles to South Africa,including the Mediterranean Sea.This species is found throughout the Tunisian coasts,including Sfax. Smooth hound is relatively important in thefish-catches of Tunisia and is utilized for human consumption. M.mustelus is generally available all year long,and the production was about192tons in2007.In a previous paper,we have shown that digestive pro-teases from smooth hound were very well suited for the generation of hydrolysates enriched in antioxidative pep-tides,from muscle protein of the same species[22].In the present study,we have attempted to isolate and identify inhibitory peptide from smooth hound muscle protein hydrolysate as powerful displaying ACE inhibitory. Materials and methodsSmooth hound sample preparationSmooth hound(M.mustelus)was purchased from thefish market of Sfax City,Tunisia.Muscle and internal organs (stomach and intestines)were separated,rinsed with cold distilled water,then immediately frozen and stored at -20°C until used.Enzymes and chemicalsAngiotensin I-converting enzyme(ACE)from rabbit lung and the ACE synthetic substrate hippuryl-L-histidyl-L-leu-cine(HHL)were purchased from Sigma Chemicals Co(St Louis,MO,USA).Acetonitrile was of HPLC grade. Sephadex G-25was purchased from Pharmacia(Uppsala, Sweden).Water was obtained from a Culligan system;the resistivity was approximately18M X.Other chemicals and reagents used were of analytical grade.The enzymes used for the production of protein hydrol-ysates were the following:pepsin from M.mustelus stomach [24];low molecular weight(LMW)alkaline protease[25], trypsin-like protease[26]and crude enzyme extract from M.mustelus intestines,and bovine trypsin(purchased from Sigma Chemical Co.(St.Louis,MO,USA)).Preparation of crude protease extract from smooth hound intestinesIntestines from M.mustelus(150g)were homogenized for 1min with300mL of extraction buffer(10mM Tris–HCl, pH8.0).The homogenate was centrifuged at8,500g for 30min at4°C.The pellet was discarded and the supernatant was collected and referred to as crude alkaline protease extract(Fig.1).Alkaline protease activity in the crude extract was measured by the method of Kembhavi et al.[27] using casein as a substrate.One unit of protease activity was defined as the amount of enzyme required to liberate1l g of tyrosine per min under the experimental conditions used. Pepsin,low molecular weight protease,and trypsin-like protease were purified as reported by Bougatef et al.[24–26]. Production of smooth hound muscle protein hydrolysates(SHPHs)using various proteasesThe production of protein hydrolysates was carried out as reported by Bougatef et al.[22].The scheme for the pro-duction of protein hydrolysates is given in Fig.1.The degree of hydrolysis(DH)was determined as reported by Adler-Nilsen[28].For the hydrolysate pro-duced by pepsin treatment,DH was determined as descri-bed by Hoyle and Merritt[29].Determination of the ACE inhibition activityThe ACE inhibition activity was assayed as reported by Nakamura et al.[30].For each assay,80l L of SHPH at different concentrations was added to200l L of5mM hippuryl-L-histidyl-L-leucine(HHL),and then pre-incu-bated for3min at37°C.SHPH and HHL were prepared in100mM borate buffer,pH8.3,containing300mM NaCl.The reaction was then initiated by adding20l L of 0.1U/mL ACE from rabbit lung prepared in the same buffer and incubated for30min at37°C.The enzyme reaction was stopped by the addition of250l L of0.1M HCl.The released hippuric acid(HA)was quantified by RP-HPLC on a Vydac C18column connected to a system composed of a Waters TM600automated gradient con-troller pump module,a WaterWisp717automatic sam-pling device,and a Waters996photodiode array detector. The sample was then eluted using an acetonitrile gradient from0to28%and from28to47%in0.1%trifluoro-acetic acid(TFA)(v/v)for50and20min,respectively. The elution profile was monitored at228nm.Spectral and chromatographic data were stored on a NEC lennium software was used to acquire,analyze,and plot chromatographic data.The average value from three determinations at each concen-tration was used to calculate the ACE inhibition rate as follows:ACE inhibitionð%Þ¼BÀABÀC!Â100where A is the absorbance of HA generated in the presence of ACE inhibitor component,B is the absorbance of HA generated without ACE inhibitors,and C is the absorbance of HA generated without ACE(corresponding to HHL autolysis in the course of enzymatic assay).The IC50value was defined as the concentration of hydrolysate(mg/mL)required to reduce the hippuric acid peak by50%(indicating50%inhibition of ACE).Fractionation of SHPH obtained by treatmentwith crude alkaline proteases by Sephadex G-25gelfiltrationThe freeze-dried hydrolysate(1g),with a DH of18.8%, was suspended in20mL of distilled water,then loaded onto a Sephadex G-25gelfiltration(5cm954cm),pre-equilibrated and eluted with distilled water.Fractions (5mL each)were collected at aflow rate of60mL/h,and the absorbance was measured at226nm.Fractionsassociated with each peak showing ACE inhibitory activity were pooled and freeze-dried.Reversed-phase high-performance liquid chromatography(RP-HPLC)The fraction P3from Sephadex G-25,which exhibited the highest ACE inhibitory activity,was further separated by RP-HPLC on a Vydac C18column(10mm9250mm) (Grace-Vydac,USA).The liquid chromatographic system consisted of a Waters600E automated gradient controller pump module,a Waters Wisp717automatic sampling device,and a Waters996photodiode array detector. Spectral and chromatographic data were stored on a NEC lennium software was used to plot,acquire,and analyze chromatographic data.The mobile phase was water/trifluoroacetic acid(1000:1,v/v) as eluent A and acetonitrile/trifluoroacetic acid(1000:1,v/v) as eluent B.Samples werefiltered through0.22l mfilters, and then applied on the C18column and eluted by eluent A for15min then with a linear gradient of acetonitrile in 45min.Theflow rate was1mL/min.Online UV absor-bance scans were performed between200and300nm at a rate of one spectrum per second with a resolution of 1.2nm.Chromatographic analyses were completed with Millennium software.Mass spectrometry analysisMS and MS/MS measurements were performed in positive ion mode using Electrospray ionization(ESI)and ESI/MS/ MS,respectively.ESI mass spectrometry was performed using a triple quadrupole instrument Applied Biosystems API3000(PE Sciex,Toronto,Canada).The system is controlled by the Analyst Software1.4,allowing the con-trol of the spectrometer,the analysis and the processing data.Interpretations of spectra MS–MS were made with the Bioanalyst software.The freeze-dried samples were dis-solved in a solvent acetonitrile/water(20/80v/v)contain-ing formic acid0.1%for the positive mode.The solution was injected(nebulized)uninterrupted,using a pump (Model22,Harward Apparatus,South Natick,USA)with a flow rate of5l L/min.The potential of ionization was of 5,000V in positive mode.At the time of the recording of the spectrum,30scans on average were added(MCA mode)for each spectrum.The gases used(nitrogen and air) were pure(up to99%)and produced by a compressor Jun-Air4000-40M and a nitrogen generator Whatman model 75-72(Whatman Inc,Haverhill,MA,USA).The poly-propylene glycol(PPG)was used for the calibration and the optimization of the machine.The peptide sequence was determined from the CID spectrum of the protonated ana-lyze[M?H]?by MS/MS experiments.Digestion stability studyThe stability of the ACE inhibitory activity of the purified peptide from fraction F3against gastrointestinal proteases was assessed in vitro.Samples(2mg/mL)were individu-ally incubated with pepsin(pH2.0),or trypsin(pH8.0)for 3h at37°C.In successive digestion test,the sample was first incubated with trypsin for3h,heat treated for5min in boiling water to inactivate the enzyme,and then incubated 3h at37°C with chymotrypsin.The reactions were then heated for5min in boiling water to terminate the reactions. The digests were used for measuring the ACE inhibitory activities.Determination of ACE inhibition patternTo clarify the inhibitory mechanism of the most potent peptide(Ala-Gly-Ser)on ACE,different concentrations of the ACE inhibitory peptide were added to each reaction mixture according to the method of Wu and Ding[31], with slight modifications.The enzyme activities were measured with different concentrations of the substrate (HHL).ACE inhibitory pattern in the presence of the inhibitor was determined with Lineweaver–Burk plot.Statistical analysisStatistical analyses were performed with Statgraphics ver.5.1,professional edition(Manugistics Corp.,USA)using ANOVA analysis.Differences were considered significant at p\0.05.Results and discussionProduction of SHPH using gastrointestinal proteasesThe hydrolysis of proteins,which is measured in terms of degree of hydrolysis(DH),is an important parameter in determining size dependent functional properties of protein hydrolysates preparations[32].DH affects the size and hence the amino acid composition of the peptides,which can affect the taste of protein hydrolysate by producing bitter peptides at high DH[32].Change in amino acid composition as affected by DH could also modulate the biological activity of the peptides formed during hydrolysis.ACE inhibitory peptides can be produced by solvent extraction,enzyme hydrolysis,and microbial fermentation of food proteins.The most common way to produce ACE inhibitory peptides is through enzymatic hydrolysis of food proteins.The specificity of the proteolytic enzyme and process conditions influence the peptide composition of hydrolysates and thus their ACE inhibitory activities[33].In the present study,intestine crude enzyme extract, LMW alkaline protease,trypsin-like protease and pepsin from smooth hound viscera,and bovine trypsin were used for the production of protein hydrolysates.The crude alkaline protease extract was most efficient,whereas pepsin was least efficient.After4h of hydrolysis,the DH reached about20.3,15.4,12.0,10.1,and9.2%with crude alkaline protease extract,LMW protease,trypsin-like protease, bovine trypsin,and pepsin,respectively[22].ACE inhibitory activities of SHPH obtainedwith various proteasesThe hydrolysates obtained after4-h incubation with gas-trointestinal proteases were then assayed for ACE inhibi-tory activity.All hydrolysates,at2mg/mL,showed ACE inhibitory activities at different level(data not shown).The highest ACE inhibitory activity(67.27%)was observed with intestinal crude enzyme hydrolysate followed byLMW protease hydrolysate(52.34%).Pepsin hydrolysate exhibited the lowest ACE inhibitory activity(45.12%).The IC50values for ACE inhibition of all hydrolysates varied between0.85and3.55mg/mL(Fig.2).The IC50 value of SHPH(0.85±0.02mg/mL)obtained with intestinal crude protease extract was lower than those of hydrolysates from oyster,scallop,codfish skin,and herring skin whose presented an IC50greater than10mg/mL[34], whereas it is higher than those from bonito(IC50= 0.029mg/mL)[35],salmon(IC50=0.038mg/mL)[36], and sardine(IC50=0.082mg/mL)[37].This can be attributed to the impact of the enzyme’s specificity which is a key factor influencing both the characteristics of hydrolysates and the nature and composition of peptides produced.Proteolysis can operate either sequentially, releasing one peptide at a time,or through the formation of intermediates that are further hydrolyzed to smaller pep-tides as proteolysis progresses,which is often termed‘‘the zipper mechanisms’’[38].Depending on the specificity of the enzyme,environmental conditions,protein source,and the extent of hydrolysis,a wide variety of peptides size will be generated.Resulting protein hydrolysate will possess peculiar properties according to the new peptides generated.These results indicated that the crude alkaline protease extract from M.mustelus intestines would be effective in producing ACE inhibitory peptides.Effect of the degree of hydrolysis on ACE inhibitory activityThe degree of hydrolysis is a measure of the extent of hydrolysis degradation of a protein,and it is the most widely used indicator for comparison among different protein hydrolysates.During hydrolysis,a wide variety of larger,medium than smaller peptides are generated, depending on enzyme specificity.In order to study the effect of the DH on the generation of ACE inhibitory activity,smooth hound muscle proteins were hydrolyzed by the crude protease extract from the intestines of M.mustelus,and the degree of hydrolysis and the ACE inhibition activity were determined.Figure3shows ACEinhibitory activity of released smooth hound peptides along the enzymatic hydrolysis.This profile shows clearly that hydrolysis was necessary in order to release ACE inhibi-tory peptides.However,undigested smooth hound muscle proteins (DH:0%)exhibited very low ACE inhibitory activity (about 1.5%at 2mg/mL).Further,Fig.3shows that the ACE inhibitory activity was correlated with the DH of hydrolysis.Higher ACE inhibition (p \0.05)activity (82.6%at 2mg/mL)was obtained with a DH of 18.8%(after 120min incubation).Further digestion up to a DH value of 18.8%resulted in a decrease in the ACE inhibitory activity.The obtained results clearly show that hydrolysis was required to release ACE inhibitory peptides from an inactive form within the sequence of smooth hound muscle proteins.Fractionation of the protein hydrolysate obtained by treatment with alkaline proteases from M.mustelus intestines by gel filtration G-25The hydrolysate,with a DH of 18.8%,obtained by treat-ment with crude alkaline protease extract,which displayed the highest ACE inhibitory activity,was then fractionated by gel filtration chromatography on a Sephadex G-25column.Five fractions were separated and designated asP 1–P 5(Fig.4a).Fractions were pooled,freeze-dried,and the inhibition against ACE was determined.All fractions displayed ACE inhibitory activity,as shown in Fig.4b.Fraction P 3exhibited the highest level of ACE inhibitory activity (62.24±2.21%at 1mg/mL)followed by fraction P 2(53.14±1.82%).The IC 50value of P 3was determined with logarithmic linearization [39]to be 0.33mg/mL.These results indi-cated that ACE inhibitory peptides are present in the pared with several reports on various protein hydrolysates,which showed IC 50for ACE inhibitory activities in the range of 0.18–246.70mg/mL [40,41],the SHPH had moderate ACE inhibitory activity.0,15 0,20 0,25 0,30501000,10 0,05 0,0 Table 1Hydrolysis conditions of smooth hound muscle proteins EnzymeSourceOptimum conditions Temperature (°C)pHCrude enzyme extract M.mustelus intestine 508.0LMW protease M.mustelus intestine 408.0Trypsin-like protease M.mustelus intestine 378.0Pepsin M.mustelus stomach 37 2.0Bovine trypsinBovine pancreas378.0Table 2IC 50values of fractions from RP-HPLC Fractions IC 50value (mg/mL)F10.613±0.086F20.754±0.093F30.130±0.030F40.324±0.041F50.257±0.012F60.463±0.022F70.522±0.031F80.613±0.052F90.270±0.061F100.783±0.023RP-HPLC analysis and identification of F 3peptide The active fraction P 3,which displayed the highest level of ACE inhibitory activity,was further purified by RP-HPLC on a C 18column using a linear gradient of acetonitrile.As can be seen from the chromatographic profile at 214nm,given in Fig.5,at least ten major fractions (F 1–F 10)were present in fraction P 3.These fractions were collected,and their ACE inhibitory activities were determined.All frac-tions showed ACE inhibitory activity,and sub-fraction F 3possessed the highest activity (more than 60%at 100l g/mL)(Table 2).The active fraction F 3was analyzed by ESI/MS and ESI/MS/MS,in order to characterize the peptide in this fraction (Fig.6a,b).The Fig.6a shows that this active fraction contained only one peptide.The accurate relative molec-ular mass of the peptide of one mass unit for the attached proton is 234Da.The Fig.6b shows the CID spectrum of the (M ?H)?ion and displays notation of fragment ions of the peptide according to this CID spectrum.According to the fragmentation of this peptide by ESI/MS/MS (Fig.6b),we determined the sequence of the peptide as Ala-Gly-Ser.This peptide has not yet been found in other protein hydrolysates with ACE inhibitory activity.TheFig.6a ESI/MS spectrum of the active fraction F3.The ion at m/z 234designated as amolecular cation (M ?H)?,Ala-Gly-Ser.b ESI/MS/MSspectrum of the active fraction F3.CID spectrum of (M ?H)?ion of peptide Ala-Gly-Ser.MS and MS/MS measurements were performed in positive ion mode using Electrospray ionization (ESI)and ESI/MS/MS,respectivelyIC50value of the purified peptide was0.13±0.03mg/mL (Table2).According to previous studies on ACE inhibitory pep-tides,hydrophobic amino acids in the N-terminal region of the active peptide plays important roles in binding the ACE active site,and leucine and valine residues are the amino acids most frequently observed in other ACE inhibitory peptides[42,43].More recently,Wu et al.[44]proposed models for ACE inhibitory peptides through computational analysis of published data.According to their proposal,the most favorable tripeptide sequences consists of hydrophobic amino acid residues at the N-terminus,positively charged amino acids at the middle position,and aromatic amino acids at the C-terminus.The ACE inhibitory peptide iden-tified here,Ala-Gly-Ser,differs from the common structural motif.The peptide had Ala at the N-terminal position,which might contribute to ACE binding.However,it contained Ser, a hydrophilic amino acid,at the C-terminal.The structure–activity correlations between the various ACE inhibitory peptides remain ambiguous.An increasing number of sequences reported in recent years have revealed a variety of structures with inhibitory activity,and some common structure patterns have evolved.According to previous reports on the structure–activity relationships between different peptide inhibitors of ACE[45],binding to ACE is strongly influenced by the C-terminal amino acid residue.Gobbetti et al.[46]reported that peptides with Trp, Tyr,Phe,Pro,or hydrophobic amino acids at the C-ter-minal were effective for ACE inhibitory activity.Several identified ACE inhibitory peptides have a proline residue in the C-terminal position,but this is neither sufficient nor essential to confer activity.Further,Cheung et al.[5] indicated that ACE prefers competitive inhibitors that contain hydrophobic amino acid residues such as Pro,Phe, and Tyr at the three positions from the C-terminal.Digestive stability of the purified peptideIn order to exert an antihypertensive effect in vivo,the ACE inhibitory peptides must be absorbed in their intact form from intestine and further be resistant to plasma peptidases degradation to reach their target sites.To investigate the resistance of the purified peptide against gastrointestinal proteases,the digestion stability was eval-uated,by incubating the purified peptide with different proteases and testing the residual ACE inhibitory activity. The ACE inhibitory activity of the peptide was not affected by in vitro incubation with gastrointestinal proteases(data not shown).This result suggests that the purified peptide may be resistant to digestion in the gastrointestinal tract. Thesefindings are in accordance with that reported by Yu et al.[19]showing the stability of globin hydrolysate against gastrointestinal proteases.Determination of ACE inhibition pattern of Ala-Gy-SerThe ACE inhibition pattern of the most potent ACE inhibitory peptide,Ala-Gly-Ser,was investigated by Li-neweaver–Burk plot(Fig.7).The kinetic study revealed that ACE inhibitor Ala-Gly-Ser acts as a non-competitive inhibitor.This indicates that the novel peptide cannot bind to catalytic site of ACE and thus could not be hydrolyzed by the enzyme.Although most of the reported peptides acted as com-petitive inhibitors for ACE,a few peptides inhibited ACE activity in a non-competitive manner have been reported, including the following:Val-Gly-Cys-Tyr-Gly-Pro-Asn-Arg-Pro-Gln-Phe from algae protein waste[47],Val-Val-Tyr-Pro-Trp-Thr-Gln-Arg-Phe from Oyster(Crassostrea talienwhanensis Crosse)proteins[48],Phe-Gly-Ala-Ser-Thr-Arg-Gly-Ala from Alaska Pollack(Theragra chalco-gramma)frame protein[49]and Ile-Phe-Leu and Trp-Leu from fermented soybean food[14].The inhibition site of the non-competitive inhibitor on ACE was not specified, and the precise inhibition mechanism of ACE inhibitory peptide is also not yet clear.ConclusionIn this study,hydrolysates from smooth hound muscle protein obtained by treatment with variousproteolyticpreparations were analyzed for their ACE inhibitory activity.The obtained results show that smooth hound muscle is a promising protein source for the production of ACE inhibitory peptides that could be utilized to develop func-tional foods for prevention of hypertension.Further works should be done to characterize potent ACE inhibitory peptides from SHPH and to determine their antihyperten-sive activity in vivo.Acknowledgment This work was funded by Ministry of Higher Education and Scientific Research-Tunisia.References1.Scheidegger KJ,Butler S,Witztum JL(1997)J Biochem Chem272:21609–216152.Ondetti MA,Rubin B,Cushman DW(1982)Annu Rev 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GLP类似物药物进展
G L P-1类似物药物进展-截止胰高血糖素样肽（glucagon-likepeptide，GLP）是小肠表皮细胞在食物刺激情况下分泌的单肽类肠促胰岛素，包括GLP-1、GLP-2两种类型。
其中GLP-2具有促进小肠生长，抑制细胞凋亡，促进胃排空，增加食欲的药理作用，临床上可用于治疗小肠短小综合症；而GLP-1具有促进胰岛素分泌，保护胰岛β细胞，抑制胰高血糖素分泌，抑制胃排空，降低食欲的药理作用，临床可用于二型糖尿病和肥胖症的治疗。
人体内具有生物活性的GLP-1主要是GLP-1（7-36）酰胺和GLP-1（7-37），天然GLP-1可被二肽基肽酶Ⅳ（dipeptidylpeptidase-Ⅳ,DPP-Ⅳ）迅速水解失活（半衰期小于5min），不具有临床使用价值，因此对GLP-1结构修饰，掩盖DPP-Ⅳ的结合位点，延长半衰期并保证疗效是该类药物研发的主要方向。
一、已上市GLP-1类似物目前已上市的5个GLP-1类似物（表1）包括艾塞那肽(Byetta/Bydureon,byAmylin/Lilly)、利拉鲁肽(Victoza/Saxenda,byNovoNordisk)、利司那肽(Lyxumia,bySanofiAventis/Zealand)、阿必鲁肽(Tanzeum,byGSK)及杜拉鲁肽(Trulicity,byLilly)：1.艾塞那肽（Exenatide）艾塞那肽（商品名Byetta）是第一个上市的GLP-1类似物，由Amylin和Lilly公司于1995年开始联合研发，2005年4月获得FDA的批准上市。
艾塞那肽源于从蜥蜴唾液中分离出的GLP-1类似物Exendin-4，与GLP-1大约有53%的同源性。
由于其N端第二位由Gly代替了GLP-1中Ala，不被DPP-Ⅳ降解，而相对天然GLP-1而言具有较长的半衰期和较强的生物活性，临床使用频率为每日2次。
AstraZeneca收购Amylin取得艾塞那肽的全球开发销售权后，开发了其缓释混悬制剂BydureonPen，并于2014年获得FDA批准。
二氟尼柳美国药典
Diflunisal Tablets» Diflunisal Tablets contain not less than 90.0 percent and not more than 110.0 percent of the labeled amount of C13H8F2O3.Packaging and storage— Preserve in well-closed containers.USP Reference standards 11—USP Diflunisal RS.Identification—A: The retention time of the major peak in the chromatogram of the Assay preparation corresponds to that of the Standard preparation, obtained as directed in the Assay.B: Transfer a quantity of finely ground Tablets, equivalent to about 100 mg of diflunisal, to a 10-mL volumetric flask, add 2 mL of water, and sonicate for 5 minutes. Dilute with methanol to volume, sonicate for an additional 5 minutes, mix, and filter. Separately apply 10 µL each of the filtrate and a Standard solution of USP Diflunisal RS in methanol solution (4 in 5) containing 10 mg per mL to a thin-layer chromatographic plate (see Chromatography 62) coated with a 0.25-mm layer of chromatographic silica gel mixture.Develop the chromatogram in a solvent system consisting of n-hexane, glacial acetic acid, and chloroform (17:3:2) until the solvent front has moved aboutthree-fourths of the length of the plate. Remove the plate from the chamber, air-dry, and examine under long-wavelength UV light: the RF value of the principal spot in the chromatogram of the test solution corresponds to that obtained from the Standard solution.Dissolution 71—pH 7.20, 0.1 M Tris buffer— Dissolve 121 g of tris (hydroxymethyl) aminome thane (THAM) in 9 liters of water. Adjust the solution with a 7 in 100 solution of anhydrous citric acid in water to a pH of 7.45, at 25. Dliters, equilibrate to 37, a H of 7.20, if necessary.Medium: pH 7.20, 0.1 M Tris buffer; 900 mL.Apparatus 2: 50 rpm.Time: 30 minutes.Procedure— Determine the amount of C13H8F2O3 dissolved from UV absorbances at the wavelength of maximum absorbance at about 306 nm of filtered portions of the solution under test, suitably diluted with pH 7.20, 0.1 M Tris buffer, in comparison with a Standard solution having a known concentration of USP Diflunisal RS in the same Medium.Tolerances— Not less than 80% (Q) of the labeled amount of C13H8F2O3 is dissolved in 30 minutes.Uniformity of dosage units 90: mProcedure for content uniformity—Transfer 1 finely powdered Tablet to a200-mL volumetric flask, add 50 mL of water, shake by mechanical means for 30 minutes, and sonicate for 2 minutes. Add 100 mL of alcohol to the flask, shake by mechanical means for 15 minutes, and sonicate for 2 minutes. Dilute with alcohol to volume, mix, and centrifuge a portion of the solution. Quantitatively dilute an accurately measured volume of the resultant clear supernatant with alcohol, if necessary, to obtain a test solution containing about 1.25 mg per mL. Transfer about 125 mg of USP Diflunisal RS, accurately weighed, to a 100-mL volumetric flask, add 75 mL of alcohol to dissolve, dilute with water to volume, and mix to obtain the Standard solution. Transfer 3.0 mL each of the Standard solution and the test solution to separate 50-mL volumetric flasks. To each flask add 5.0 mL of a solution containing 1 g of ferric nitrate in 100 mL of 0.08 N nitric acid, dilute with water to volume, and mix. Concomitantly determine the absorbances of the solutions at the wavelength of maximum absorbance at about 550 nm, with a suitable spectrophotometer, using water as the blank. Calculate the quantity, in mg, of C13H8F2O3 in the Tablet by the formula:(TC / D)(AU / AS)in which T is the labeled quantity, in mg, of diflunisal in the Tablet; C is the concentration, in µg per mL, of USP Diflunisal RS in the Standard solution; D is the concentration, in µg per mL, of diflunisal in the test solution, based uponthe labeled quantity per Tablet and the extent of dilution; and AU and AS are the absorbances of the solutions from the test solution and the Standard solution, respectively.Assay—Mobile phase—Prepare a suitable degassed mixture of water, methanol, acetonitrile, and glacial acetic acid (45:40:17:6) such that the retention time of diflunisal is about 8 minutes.Standard preparation— Dissolve a suitable quantity of USP Diflunisal RS in a mixture of acetonitrile and water (60:40) to obtain a solution having a known concentration of about 1.0 mg per mL.Assay preparation—Weigh and finely powder not fewer than 20 Tablets. Transfer an accurately weighed portion of the powder, equivalent to about 100 mg of diflunisal, to a 100-mL volumetric flask containing about 5 mL of water. Sonicate for 5 minutes, add 60.0 mL of acetonitrile, sonicate for an additional 5 minutes, dilute with water to volume, mix, and filter.Chromatographic system (see Chromatography 62)—The liquid chromatograph is equipped with a 254-nm detector and a 3.9-mm × 30-cm column that contains packing L1.The flow rate is about 2.0 mL per minute. Chromatograph the Standard preparation, and record the peak responses as directed for Procedure: the tailing factor for the analyte peak is not more than 2.0, and the relative standard deviation for replicate injections is not more than 2.0%.Procedure— Separately inject equal volumes (about 20 µL) of the Standard preparation and the Assay preparation into the chromatograph, record the chromatograms, and measure the responses for the major peaks. Calculate the quantity, in mg, of diflunisal (C13H8F2O3) in the portion of Tablets taken by the formula:100C(rU / rS)in which C is the concentration, in mg per mL, of USP Diflunisal RS in the Standard preparation; and rU and rS are the peak responses obtained from the Assay preparation and the Standard preparation, respectively.。
不同浓度的葛根多糖对小鼠肠道菌群的影响
不同浓度的葛根多糖对小鼠肠道菌群的影响陈融，刘博，陈凯，杨锐乐，王米*（中国农业科学院上海兽医研究所，农业农村部兽用化学药物及制剂学重点实验室，上海 200241）摘 要：为探究不同浓度的葛根多糖对小鼠肠道菌群的影响，本试验选取30只体重为（17.00±1.00）g的雄性昆明小鼠，按照体重被随机分为3组，每组10只，包括对照组（生理盐水）、低浓度组（12.5 mg/kg体重）、高浓度（100 mg/kg体重）组，葛根多糖连续灌服14 d后，颈椎脱臼法处死小鼠，称取胸腺、心脏、肝脏、脾脏、肺脏、肾脏和睾丸重量；收集盲肠内容物，通过GC-MS法测定肠道内短链脂肪酸浓度，并结合Illumina Miseq高通量测序技术对肠道菌群的多样性进行分析。
结果显示：2种浓度葛根多糖对于小鼠脏器指数无显著影响；与对照组相比，低浓度葛根多糖能显著降低盲肠内异丁酸和异戊酸含量，而高浓度葛根多糖仅显著降低异戊酸含量；低浓度葛根多糖能够显著提高粪球菌属（Coprococcus）、厌氧棍状菌属（Anaerotruncus）、颤螺旋菌属（Oscillospira）的相对丰度，显著降低棒状杆菌属（Corynebacterium）、葡萄球菌属（Staphylococcus）、丁酸弧菌属（Anaerostipes）、产碱菌属（Alcaligenes）的相对丰度；高浓度葛根多糖能够显著提高粪球菌属的相对丰度，使产碱杆菌属的相对丰度显著降低。
结果表明，低浓度葛根多糖能显著提高肠道菌群多样性，并改善肠道菌群结构，对机体产生有益影响。
关键词：多糖；脏器指数；短链脂肪酸；肠道菌群中图分类号：S816.7 文献标识码：A DOI编号：10.19556/j.0258-7033.20200629-01肠道菌群是肠道微环境的重要组成部分，数量与人体细胞比例接近1:1，对于宿主维持肠道免疫稳态，增强免疫应答具有重要意义[1-2]。
研究表明，与宿主基因相比，日粮对于肠道菌群组成的影响更大，通过饮食干预能够影响到菌群结构，具有疾病预防和治疗的作用[3-6]，这为功能性食品及添加剂等产品的研究开发提供了更多思路。
Ag(Ⅲ)配合物-鲁米诺化学发光体系用于文拉法辛的测定
Ag(Ⅲ)配合物-鲁米诺化学发光体系用于文拉法辛的测定苑洁;王玮;康维钧;徐向东【摘要】Ag(Ⅲ)配合物在碱性介质中可氧化鲁米诺产生化学发光.实验发现,抗抑郁药物文拉法辛对该化学发光体系有显著的增敏作用.据此,结合流动注射技术,建立了化学发光测定文拉法辛的新方法.在优化条件下,方法的线性范围为0.1～2.0 mg·L-1,检出限(S/N=3)为0.05 mg·L-1,回收率为96％～ 105％,相对标准偏差( RSD,n=11)为0.87％.该方法简单、灵敏、准确、重现性好,已成功用于市售胶囊中文拉法辛含量的测定.%Based on the fact that venlafaxine had remarkable enhancing effect on Ag ( M ) complex -luminol chemiluminescence( CL) system, a novel method for the determination of venlafaxine was established by CL method with flow-injection analysis. Under the optimum conditions, the calibration curve was linear in the range of 0. 1 -2. 0 mg ? L with detection limit ( S/N - 3 ) of 0. 05 mg ? L . The relative standard deviation ( n = 11 ) for 0. 1 mg ? L venlafaxine was 0. 87% , and the recovery ranged from 96% to 105% . This method was simple, sensitive and accurate, and was successfully applied in the determination of venlafaxine in capsules.【期刊名称】《分析测试学报》【年(卷),期】2011(030)012【总页数】4页(P1436-1439)【关键词】文拉法辛;鲁米诺;Ag(Ⅲ)配合物;流动注射;化学发光【作者】苑洁;王玮;康维钧;徐向东【作者单位】河北医科大学公共卫生学院,河北石家庄050017;河北医科大学公共卫生学院,河北石家庄050017;河北医科大学公共卫生学院,河北石家庄050017;河北医科大学公共卫生学院,河北石家庄050017【正文语种】中文【中图分类】O433.4;TQ460.72文拉法辛(Venlafaxine)，又称1-［2-(二甲胺)-1-(4-甲氧苯基)乙基］环己醇，是一种兼具抑制5-羟色胺和去甲肾上腺素重摄取双重作用的新型抗抑郁药物，用于治疗包括伴有焦虑的抑郁症及广泛性焦虑症，现有商品制剂为口服片剂或胶囊。