Exact Renormalization Group and Running Newtonian Coupling in Higher Derivative Gravity

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Approved by the Secretary General and published under his authorityLine OperationsSafety Audit (LOSA)First Edition — 2002Doc 9803AN/761AMENDMENTSThe issue of amendments is announced regularly in the ICAO Journal and in the monthly Supplement to the Catalogue of ICAO Publications and Audio-visual Training Aids, which holders of this publication should consult. The space below is provided to keep a record of such amendments.RECORD OF AMENDMENTS AND CORRIGENDA AMENDMENTS CORRIGENDANo.DateapplicableDateenteredEnteredby No.Dateof issueDateenteredEnteredbyTABLE OF CONTENTSPage PageForeword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .(v) Acronyms and Abbreviations . . . . . . . . . . . . . . . . .(vi) Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .(vii) Chapter 1.Basic error management concepts. .1-11.1Introduction . . . . . . . . . . . . . . . . . . . . . . . . .1-11.2Background . . . . . . . . . . . . . . . . . . . . . . . . .1-2Reactive strategies. . . . . . . . . . . . . . . . . .1-2Combined reactive/proactive strategies. .1-2Proactive strategies . . . . . . . . . . . . . . . . .1-41.3 A contemporary approach to operationalhuman performance and error. . . . . . . . . . .1-51.4The role of the organizational culture . . . .1-71.5Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . .1-7 Chapter2.Implementing LOSA . . . . . . . . . . . . .2-12.1History of LOSA. . . . . . . . . . . . . . . . . . . . .2-12.2The Threat and Error Management Model.2-1Threats and errors defined. . . . . . . . . . . .2-1Definitions of crew error response . . . . .2-4Definitions of error outcomes. . . . . . . . .2-4Undesired Aircraft States . . . . . . . . . . . .2-42.3LOSA operating characteristics . . . . . . . . .2-5Observer assignment . . . . . . . . . . . . . . . .2-7Flight crew participation. . . . . . . . . . . . .2-72.4How to determine the scope of a LOSA . .2-72.5Once the data is collected. . . . . . . . . . . . . .2-82.6Writing the report . . . . . . . . . . . . . . . . . . . .2-82.7Success factors for LOSA. . . . . . . . . . . . . .2-8Chapter3.LOSA and the safety changeprocess (SCP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3-13.1Introduction . . . . . . . . . . . . . . . . . . . . . . . . .3-13.2 A constantly changing scene. . . . . . . . . . . .3-13.3One operator’s example of an SCP . . . . . .3-2 Chapter4.How to set up a LOSA —US Airways experience . . . . . . . . . . . . . . . . . . . . . .4-14.1Gathering information. . . . . . . . . . . . . . . . .4-14.2Interdepartmental support . . . . . . . . . . . . . .4-14.3LOSA steering committee. . . . . . . . . . . . . .4-1Safety department . . . . . . . . . . . . . . . . . .4-1Flight operations and trainingdepartments . . . . . . . . . . . . . . . . . . . . . . .4-2Pilots union . . . . . . . . . . . . . . . . . . . . . . .4-24.4The key steps of a LOSA. . . . . . . . . . . . . .4-2Goals . . . . . . . . . . . . . . . . . . . . . . . . . . . .4-2Action plan . . . . . . . . . . . . . . . . . . . . . . .4-24.5The keys to an effective LOSA . . . . . . . . .4-4Confidentiality and no-jeopardy. . . . . . .4-4The role of the observer . . . . . . . . . . . . .4-54.6Promoting LOSA for flight crews . . . . . . .4-5 Appendix A — Examples of the various forms utilized by LOSA . . . . . . . . . . . . . . . . . . . . . . . . . . .A-1 Appendix B — Example of an introductory letterby an airline to its flight crews. . . . . . . . . . . . . . . .B-1 Appendix C — List of recommended readingand reference material. . . . . . . . . . . . . . . . . . . . . . .C-1FOREWORDThe safety of civil aviation is the major objective of the International Civil Aviation Organization (ICAO). Consider-able progress has been made in increasing safety, but additional improvements are needed and can be achieved. It has long been known that the majority of aviation accidents and incidents result from less than optimum human per-formance, indicating that any advance in this field can be expected to have a significant impact on the improvement of aviation safety.This was recognized by the ICAO Assembly, which in 1986 adopted Resolution A26-9 on Flight Safety and Human Factors. As a follow-up to the Assembly Resolution, the Air Navigation Commission formulated the following objective for the task:“To improve safety in aviation by making States more aware and responsive to the importance of Human Factors in civil aviation operations through the provision of practical Human Factors materials and measures, developed on the basis of experience in States, and by developing and recommending appropriate amendments to existing material in Annexes and other documents with regard to the role of Human Factors in the present and future operational environments. Special emphasis will be directed to the Human Factors issues that may influence the design, transition and in-service use of the future ICAO CNS/A TM systems.”One of the methods chosen to implement Assembly Resolution A26-9 is the publication of guidance materials, including manuals and a series of digests, that address various aspects of Human Factors and its impact on aviation safety. These documents are intended primarily for use by States to increase the awareness of their personnel of the influence of human performance on safety.The target audience of Human Factors manuals and digests are the managers of both civil aviation administrations and the airline industry, including airline safety, training and operational managers. The target audience also includes regulatory bodies, safety and investigation agencies and training establishments, as well as senior and middle non-operational airline management.This manual is an introduction to the latest information available to the international civil aviation community on the control of human error and the development of counter-measures to error in operational environments. Its target audience includes senior safety, training and operational personnel in industry and regulatory bodies.This manual is intended as a living document and will be kept up to date by periodic amendments. Subsequent editions will be published as new research results in increased knowledge on Human Factors strategies and more experience is gained regarding the control and management of human error in operational environments.ACRONYMS AND ABBREVIATIONS ADS Automatic Dependent SurveillanceA TC Air Traffic ControlCFIT Controlled Flight Into TerrainCNS/A TM Communications, Navigation and Surveillance/Air Traffic Management CPDLC Controller-Pilot Data Link CommunicationsCRM Crew Resource ManagementDFDR Digital Flight Data RecorderETOPS Extended Range Operations by Twin-engined AeroplanesFAA Federal Aviation AdministrationFDA Flight Data AnalysisFMS Flight Management SystemFOQA Flight Operations Quality AssuranceICAO International Civil Aviation OrganizationLOSA Line Operations Safety AuditMCP Mode Control PanelQAR Quick Access RecorderRTO Rejected Take-OffSCP Safety Change ProcessSOPs Standard Operating ProceduresTEM Threat and Error ManagementUTTEM University of Texas Threat and Error ManagementINTRODUCTION1.This manual describes a programme for the management of human error in aviation operations known as Line Operations Safety Audit (LOSA). LOSA is proposed as a critical organizational strategy aimed at developing countermeasures to operational errors. It is an organizational tool used to identify threats to aviation safety, minimize the risks such threats may generate and implement measures to manage human error in operational contexts. LOSA enables operators to assess their level of resilience to systemic threats, operational risks and front-line personnel errors, thus providing a principled, data-driven approach to prioritize and implement actions to enhance safety.2.LOSA uses expert and highly trained observers to collect data about flight crew behaviour and situational factors on “normal” flights. The audits are conducted under strict no-jeopardy conditions; therefore, flight crews are not held accountable for their actions and errors that are observed. During flights that are being audited, observers record and code potential threats to safety; how the threats are addressed; the errors such threats generate; how flight crews manage these errors; and specific behaviours that have been known to be associated with accidents and incidents.3.LOSA is closely linked with Crew Resource Management (CRM) training. Since CRM is essentially error management training for operational personnel, data from LOSA form the basis for contemporary CRM training refocus and/or design known as Threat and Error Man-agement (TEM) training. Data from LOSA also provide a real-time picture of system operations that can guide organizational strategies in regard to safety, training and operations. A particular strength of LOSA is that it identifies examples of superior performance that can be reinforced and used as models for training. In this way, training inter-ventions can be reshaped and reinforced based on successful performance, that is to say, positive feedback. This is indeed a first in aviation, since the industry has traditionally collected information on failed human performance, such as in accidents and incidents. Data collected through LOSA are proactive and can be immediately used to prevent adverse events.4.LOSA is a mature concept, yet a young one. LOSA was first operationally deployed following the First LOSA Week, which was hosted by Cathay Pacific Airways in Cathay City, Hong Kong, from 12 to 14 March 2001. Although initially developed for the flight deck sector, there is no reason why the methodology could not be applied to other aviation operational sectors, including air traffic control, maintenance, cabin crew and dispatch.5.The initial research and project definition was a joint endeavour between The University of Texas at Austin Human Factors Research Project and Continental Airlines, with funding provided by the Federal Aviation Admin-istration (FAA). In 1999, ICAO endorsed LOSA as the primary tool to develop countermeasures to human error in aviation operations, developed an operational partnership with The University of Texas at Austin and Continental Airlines, and made LOSA the central focus of its Flight Safety and Human Factors Programme for the period 2000 to 2004.6.As of February 2002, the LOSA archives contained observations from over 2 000 flights. These observations were conducted within the United States and internationally and involved four United States and four non-United States operators. The number of operators joining LOSA has constantly increased since March 2001 and includes major international operators from different parts of the world and diverse cultures.7.ICAO acts as an enabling partner in the LOSA programme. ICAO’s role includes promoting the importance of LOSA to the international civil aviation community; facilitating research in order to collect necessary data; acting as a cultural mediator in the unavoidably sensitive aspects of data collection; and contributing multicultural obser-vations to the LOSA archives. In line with these objectives, the publication of this manual is a first step at providing information and, therefore, at increasing awareness within the international civil aviation community about LOSA.8.This manual is an introduction to the concept, methodology and tools of LOSA and to the potential remedial actions to be undertaken based on the data collected under LOSA. A very important caveat must be introduced at this point: this manual is not intended to convert readers into instant expert observers and/or LOSA auditors. In fact, it is strongly recommended that LOSA not be attempted without a formal introduction to it for the(viii)Line Operations Safety Audit (LOSA)following reasons. First, the forms presented in Appendix A are for illustration purposes exclusively, since they are periodically amended on the basis of experience gained and feedback obtained from continuing audits. Second, formal training in the methodology, in the use of LOSA tools and, most important, in the handling of the highly sensitive data collected by the audits is absolutely essential. Third, the proper structuring of the data obtained from the audits is of paramount importance.9.Therefore, until extensive airline experience is accumulated, it is highly desirable that LOSA training be coordinated through ICAO or the founding partners of the LOSA project. As the methodology evolves and reaches full maturity and broader industry partnerships are developed, LOSA will be available without restrictions to the international civil aviation community.10.This manual is designed as follows:•Chapter 1 includes an overview on safety, and human error and its management in aviationoperations. It provides the necessary backgroundinformation to understand the rationale for LOSA.•Chapter 2 discusses the LOSA methodology and provides a guide to the implementation of LOSAwithin an airline. It also introduces a model of crewerror management and proposes the error classi-fication utilized by LOSA, which is essentiallyoperational and practical.•Chapter 3 discusses the safety change process that should take place following the implementation ofLOSA.•Chapter 4 introduces the example of one operator’s experience in starting a LOSA.•Appendix A provides examples of the various forms utilized by LOSA.•Appendix B provides an example of an introductory letter by an airline to its flight crews.•Appendix C provides a list of recommended reading and reference material.11.This manual is a companion document to the Human Factors Training Manual (Doc 9683). The cooperation of the following organizations in the production of this manual is acknowledged: The University of Texas at Austin Human Factors Research Project, Continental Airlines, US Airways and ALPA, International. Special recognition is given to Professor Robert L. Helmreich, James Klinect and John Wilhelm of The University of Texas at Austin Human Factors Research Project; Captains Bruce Tesmer and Donald Gunther of Continental Airlines; Captains Ron Thomas and Corkey Romeo of US Airways; and Captain Robert L. Sumwalt III of US Airways and of ALPA, International.Chapter 1BASIC ERROR MANAGEMENT CONCEPTS1.1INTRODUCTION1.1.1Historically, the way the aviation industry has investigated the impact of human performance on aviation safety has been through the retrospective analyses of those actions by operational personnel which led to rare and drastic failures. The conventional investigative approach is for investigators to trace back an event under consideration to a point where they discover particular actions or decisions by operational personnel that did not produce the intended results and, at such point, conclude human error as the cause. The weakness in this approach is that the conclusion is generally formulated with a focus on the outcome, with limited consideration of the processes that led up to it. When analysing accidents and incidents, investigators already know that the actions or decisions by operational personnel were “bad” or “inappropriate”, because the “bad” outcomes are a matter of record. In other words, investigators examining human performance in safety occurrences enjoy the benefit of hindsight. This is, however, a benefit that operational personnel involved in accidents and incidents did not have when they selected what they thought of as “good” or “appropriate” actions or decisions that would lead to “good” outcomes.1.1.2It is inherent to traditional approaches to safety to consider that, in aviation, safety comes first. In line with this, decision making in aviation operations is considered to be 100 per cent safety-oriented. While highly desirable, this is hardly realistic. Human decision making in operational contexts is a compromise between production and safety goals (see Figure 1-1). The optimum decisions to achieve the actual production demands of the operational task at hand may not always be fully compatible with the optimumFigure 1-1.Operational Behaviours — Accomplishing the system’s goals1-2Line Operations Safety Audit (LOSA)decisions to achieve theoretical safety demands. All production systems — and aviation is no exception —generate a migration of behaviours: due to the need for economy and efficiency, people are forced to operate at the limits of the system’s safety space. Human decision making in operational contexts lies at the intersection of production and safety and is therefore a compromise. In fact, it might be argued that the trademark of experts is not years of experience and exposure to aviation operations, but rather how effectively they have mastered the necessary skills to manage the compromise between production and safety. Operational errors are not inherent in a person, although this is what conventional safety knowledge would have the aviation industry believe. Operational errors occur as a result of mismanaging or incorrectly assessing task and/or situ-ational factors in a specific context and thus cause a failed compromise between production and safety goals.1.1.3The compromise between production and safety is a complex and delicate balance. Humans are generally very effective in applying the right mechanisms to successfully achieve this balance, hence the extraordinary safety record of aviation. Humans do, however, occasionally mismanage or incorrectly assess task and/or situational factors and fail in balancing the compromise, thus contributing to safety breakdowns. Successful compromises far outnumber failed ones; therefore, in order to understand human performance in context, the industry needs to systematically capture the mechanisms underlying suc-cessful compromises when operating at the limits of the system, rather than those that failed. It is suggested that understanding the human contribution to successes and failures in aviation can be better achieved by monitoring normal operations, rather than accidents and incidents. The Line Operations Safety Audit (LOSA) is the vehicle endorsed by ICAO to monitor normal operations.1.2BACKGROUNDReactive strategiesAccident investigation1.2.1The tool most often used in aviation to document and understand human performance and define remedial strategies is the investigation of accidents. However, in terms of human performance, accidents yield data that are mostly about actions and decisions that failed to achieve the successful compromise between production and safety discussed earlier in this chapter.1.2.2There are limitations to the lessons learned from accidents that might be applied to remedial strategies vis-à-vis human performance. For example, it might be possible to identify generic accident-inducing scenarios such as Controlled Flight Into Terrain (CFIT), Rejected Take-Off (RTO), runway incursions and approach-and-landing acci-dents. Also, it might be possible to identify the type and frequency of external manifestations of errors in these generic accident-inducing scenarios or discover specific training deficiencies that are particularly related to identified errors. This, however, provides only a tip-of-the-iceberg perspective. Accident investigation, by definition, concen-trates on failures, and in following the rationale advocated by LOSA, it is necessary to better understand the success stories to see if they can be incorporated as part of remedial strategies.1.2.3This is not to say that there is no clear role for accident investigation within the safety process. Accident investigation remains the vehicle to uncover unanticipated failures in technology or bizarre events, rare as they may be. Accident investigation also provides a framework: if only normal operations were monitored, defining unsafe behaviours would be a task without a frame of reference. Therefore, properly focused accident investigation can reveal how specific behaviours can combine with specific circumstances to generate unstable and likely catastrophic scenarios. This requires a contemporary approach to the investigation: should accident investigation be restricted to the retrospective analyses discussed earlier, its contribution in terms of human error would be to increase existing industry databases, but its usefulness in regard to safety would be dubious. In addition, the information could possibly provide the foundations for legal action and the allocation of blame and punishment.Combined reactive/proactive strategies Incident investigation1.2.4 A tool that the aviation industry has increasingly used to obtain information on operational human perform-ance is incident reporting. Incidents tell a more complete story about system safety than accidents do because they signal weaknesses within the overall system before the system breaks down. In addition, it is accepted that incidents are precursors of accidents and that N-number of incidents of one kind take place before an accident of the same kind eventually occurs. The basis for this can be traced back almost 30 years to research on accidents from different industries, and there is ample practical evidence that supports this research. There are, nevertheless, limitationsChapter 1.Basic error management concepts1-3on the value of the information on operational human performance obtained from incident reporting.1.2.5First, reports of incidents are submitted in the jargon of aviation and, therefore, capture only the external manifestations of errors (for example, “misunderstood a frequency”, “busted an altitude”, and “misinterpreted a clearance”). Furthermore, incidents are reported by the individuals involved, and because of biases, the reported processes or mechanisms underlying errors may or may not reflect reality. This means that incident-reporting systems take human error at face value, and, therefore, analysts are left with two tasks. First, they must examine the reported processes or mechanisms leading up to the errors and establish whether such processes or mechanisms did indeed underlie the manifested errors. Then, based on this relatively weak basis, they must evaluate whether the error manage-ment techniques reportedly used by operational personnel did indeed prevent the escalation of errors into a system breakdown.1.2.6Second, and most important, incident reporting is vulnerable to what has been called “normalization of deviance”. Over time, operational personnel develop infor-mal and spontaneous group practices and shortcuts to circumvent deficiencies in equipment design, clumsy pro-cedures or policies that are incompatible with the realities of daily operations, all of which complicate operational tasks. These informal practices are the product of the collective know-how and hands-on expertise of a group, and they eventually become normal practices. This does not, however, negate the fact that they are deviations from procedures that are established and sanctioned by the organization, hence the term “normalization of deviance”. In most cases normalized deviance is effective, at least temporarily. However, it runs counter to the practices upon which system operation is predicated. In this sense, like any shortcut to standard procedures, normalized deviance carries the potential for unanticipated “downsides” that might unexpectedly trigger unsafe situations. However, since they are “normal”, it stands to reason that neither these practices nor their downsides will be recorded in incident reports.1.2.7Normalized deviance is further compounded by the fact that even the most willing reporters may not be able to fully appreciate what are indeed reportable events. If operational personnel are continuously exposed to sub-standard managerial practices, poor working conditions and/or flawed equipment, how could they recognize such factors as reportable problems?1.2.8Thus, incident reporting cannot completely reveal the human contribution to successes or failures in aviation and how remedial strategies can be improved to enhance human performance. Incident reporting systems are certainly better than accident investigations in understanding system performance, but the real challenge lies in taking the next step — understanding the processes underlying human error rather than taking errors at face value. It is essential to move beyond the visible manifestations of error when designing remedial strategies. If the aviation industry is to be successful in modifying system and individual per-formance, errors must be considered as symptoms that suggest where to look further. In order to understand the mechanisms underlying errors in operational environments, flaws in system performance captured through incident reporting should be considered as symptoms of mismatches at deeper layers of the system. These mismatches might be deficiencies in training systems, flawed person/technology interfaces, poorly designed procedures, corporate pressures, poor safety culture, etc. The value of the data generated by incident reporting systems lies in the early warning about areas of concern, but such data do not capture the concerns themselves.Training1.2.9The observation of training behaviours (during flight crew simulator training, for example) is another tool that is highly valued by the aviation industry to understand operational human performance. However, the “production”component of operational decision making does not exist under training conditions. While operational behaviours during line operations are a compromise between production and safety objectives, training behaviours are absolutely biased towards safety. In simpler terms, the compromise between production and safety is not a factor in decision making during training (see Figure 1-2). Training behaviours are “by the book”.1.2.10Therefore, behaviours under monitored conditions, such as during training or line checks, may provide an approximation to the way operational personnel behave when unmonitored. These observations may contribute to flesh out major operational questions such as significant procedural problems. However, it would be incorrect and perhaps risky to assume that observing personnel during training would provide the key to understanding human error and decision making in unmonitored operational contexts.Surveys1.2.11Surveys completed by operational personnel can also provide important diagnostic information about daily operations and, therefore, human error. Surveys1-4Line Operations Safety Audit (LOSA)provide an inexpensive mechanism to obtain significant information regarding many aspects of the organization, including the perceptions and opinions of operational personnel; the relevance of training to line operations; the level of teamwork and cooperation among various employee groups; problem areas or bottlenecks in daily operations; and eventual areas of dissatisfaction. Surveys can also probe the safety culture; for example, do personnel know the proper channels for reporting safety concerns and are they confident that the organization will act on expressed concerns? Finally, surveys can identify areas of dissent or confusion, for example, diversity in beliefs among particular groups from the same organization regarding the appropriate use of procedures or tools. On the minus side, surveys largely reflect perceptions. Surveys can be likened to incident reporting and are therefore subject to the shortcomings inherent to reporting systems in terms of understanding operational human performance and error. Flight data recording1.2.12Digital Flight Data Recorder (DFDR) and Quick Access Recorder (QAR) information from normal flights is also a valuable diagnostic tool. There are, however, some limitations about the data acquired through these systems. DFDR/QAR readouts provide information on the frequency of exceedences and the locations where they occur, but the readouts do not provide information on the human behaviours that were precursors of the events. While DFDR/QAR data track potential systemic problems, pilot reports are still necessary to provide the context within which the problems can be fully diagnosed.1.2.13Nevertheless, DFDR/QAR data hold high cost/efficiency ratio potential. Although probably under-utilized because of cost considerations as well as cultural and legal reasons, DFDR/QAR data can assist in identifying operational contexts within which migration of behaviours towards the limits of the system takes place.Proactive strategiesNormal line operations monitoring1.2.14The approach proposed in this manual to identify the successful human performance mechanisms that contribute to aviation safety and, therefore, to the design of countermeasures against human error focuses on the monitoring of normal line operations.Figure 1-2.Training Behaviours — Accomplishing training goals。

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RangCase files Pharmacology,2nd ed.Eugene C. ToyDrug benefits and risks : internationaltextbook of clinical pharmacology， 2nded.Chris J. vanFoye's principles of medicinalchemistry， 6th ed.Thomas L. Lemke Katzung & Trevor's pharmacology, 8th ed.Anthony J. Trevor, Pharmacotherapy principles and practice Marie A. Chisholm-BurnsPrinciples of pharmacology: thepathophysiologic basis of drug therapy,2nd ed.David E. Golan,Symptoms in the Pharmacy: A Guide to theManagement of Common Illness, 6th ed.Blenkinsopp,A Textbook of Clinical Pharmacology andTherapeutics, 5th ed.James M RitterTextbook of receptor pharmacology, 3rded.John C. Foreman,An introduction to medicinal chemistry,4th ed.Graham L. PatrickBasic and clinical pharmacology, 11th ed.Katzung,Introduction to pharmacology，11th ed.Mary Kaye Asperheim.Lippincott's illustrated reviews : pharmacology 4th ed.Richard Finkel, Michelle A. Clark,Pharmacology condensed, 2nd ed.M.M. Dale,Pharmacology and therapeutics :principles to practiceScott A. Waldman,Roach's Introductory ClinicalPharmacology, 9th ed.Susan, M. Ford,Trease and Evans pharmacognosy， 16th ed.William Charles Evans. The Pharmacologic Principles Of MedicalJohn C. Krantz Jr. Practice V.1-2Basic clinical pharmacokinetics,5th ed.Michael E. Winter.Brody's human pharmacology : bmolecularLynn Wecker,to clinical，5th ed.BRS Pharmacology， 5th ed.Gary C. Rosenfeld,Comprehensive pharmacy review practiceAlan H. Mutnickexams, 6th ed.Introduction to clinical pharmacology,Marilyn Winterton Edmunds. 6th ed.Pharmacology, 3rd ed.George M. Brenner,出版社出版年ISBN索书号Churchill Livingstone 2002443055173TQ460/AME/=2(Y0)Oxford2002192632345R453-43/GSDG/ =3(Y0)Wiley2003352730438X1Wiley2003471370320R914/WME /V1/=6(Y 0)Oxford2003184127335X R917/LDC (Y0)Churchill Livingstone 2003443071454R96/RHP/=5(Y0)Wiley20044712147281 LippincottWilliams & Wilkins 2004781734819R931.6/DRF/=11(Y0)LippincottWilliams & Wilkins 2005781746124R944/AHC/=8(Y0)Saunders20051929007604R96-64/RRB(Y 0)Churchill Livingstone 2005443074453R917/WDG/=2(Y0)CRC Press2005415288630R9/GTK(Y 0)CRC, Taylor & Francis 20069.78159E+12R96/HMA-a(Y0)Mosby20069.78032E+121McGraw-Hill200671422803R96/GAG/ =11(Y0)Mosby20069.78032E+12R96/IP/= 3(Y0)LippincottWilliams & Wilkins 2006078175027XR912/MAN/=5(Y0)Anshan Ltd.20069.7819E+12R914/KA( Y0)Oxford2006195104552R914/NT/ =3(Y0)LippincottWilliams & Wilkins 2006781754690R614/SRK-2/=4(Y0)Pharmaceutical Press 2006085369608XR913/FAT/=4(Y0)Academic Press20069.78012E+121LippincottWilliams & Wilkins 2006781746736R9/GAR/=21(Y0)Wiley20079.78047E+12R914/TG/ =2R(Y0)Elsevier/Churchi ll Livingstone 20079.78044E+12R96/WP-1/=3Churchill Livingstone 20079.78044E+12R9/AME/=3(Y0)Churchill Livingstone 20079.78044E+12R96/RHP/=6(Y0)McGraw-Hill20089.78007E+12R969/TEC /=2(Y0)IOS Press20089.78159E+121 LippincottWilliams & Wilkins 20089.78078E+12R914/FWO/=6(Y0)McGraw-Hill20089.78007E+12R96-44/KBG/= 8(Y0)McGraw-Hill20089.78007E+12R453/CMA (Y0)Wolters Kluwer Health 20089.78078E+12R96/PP/=2(Y0)Wiley20089.78141E+12R97-62/BA/=6 (Y0)Oxford20089.78034E+121CRC Press20089.78142E+12R966-43/FJC/= 3(Y0)Oxford20099.7802E+12R914/PGL /=4(Y0)McGraw-Hill20099.78007E+121Saunders/Elsevie r 20099.78142E+12R96/AMK/=11(Y0)LippincottWilliams & Wilkins 20099.78161E+12R96/RF/=4(Y0)Churchill Livingstone 20099.78044E+12R96-62/DMM/=2(Y0)Saunders20099.78142E+12R969/WSA (Y0)LippincottWilliams & Wilkins 20099.78161E+12R969/FSM/=9(Y0)Saunders20099.7807E+12R93/TGE/ =16(Y0)KessingerPublishing20099.7811E+121 Wolters KluwerHealth/Lippincot t Williams & Wilkins Health 20109.78078E+12R969.1/WME/=5(Y0)Mosby20109.78032E+12R96/BTM/ =5(Y0)Wolters Kluwer Health 20109.78078E+12R96-44/RGC/=5(Y0)LippincottWilliams & Wilkins 20109.78158E+12R9-44/MAH/=7(Y0)Mosby/Elsevier2010323028756R969/EMW /=5(Y0)Saunders20109.78142E+12R96/BGM/ =3(Y0)。

211232341_圣草酚通过抑制TGF-β1

doi：10.3969/j.issn.1000-484X.2023.04.004圣草酚通过抑制TGF-β1/Smad3信号通路改善糖尿病肾病大鼠肾纤维化①应勤丽黄月碧②杨秀翠郑琼飞陈焕梅③（重庆市黔江中心医院康复医学科，黔江 409000）中图分类号R285.5 文献标志码 A 文章编号1000-484X（2023）04-0693-05［摘要］目的：探讨圣草酚对糖尿病肾病（DN）肾纤维化的影响及其作用机制。

方法：采用多次小剂量注射链脲佐菌素建立DN大鼠模型，将建模成功的大鼠随机分为模型组、阳性药物组（二甲双胍，0.5 g/kg）及圣草酚低、中、高剂量组（5、10、20 mg/kg），另设置对照组，每组12只。

各给药组给予相应药物灌胃干预，对照组和模型组灌胃等体积生理盐水，1次/d，连续12周。

收集24 h尿液，检测24 h尿蛋白含量；腹主动脉取血，测定空腹血糖（FBG）、血肌酐（Scr）和血尿素氮（BUN）含量；HE染色观察肾脏组织病理学变化；Masson染色观察肾脏组织纤维化程度；qRT-PCR检测肾组织中TGF-β1、CollagenⅠ和Collagen Ⅲ mRNA表达水平；Western blot检测肾脏组织中TGF-β1、p-Smad3、Smad3、α-SMA蛋白表达水平。

结果：与对照组相比，模型组大鼠肾脏出现明显损伤及纤维化，FBG、BUN、Scr和24 h尿蛋白含量均显著升高（P<0.05），肾脏组织中TGF-β1、CollagenⅠ、Collagen Ⅲ 等mRNA表达水平及TGF-β1、p-Smad3和α-SMA等蛋白表达水平均显著提高（P<0.05）；与模型组相比，圣草酚中、高剂量组和阳性药物组大鼠肾损伤明显改善，肾纤维化程度明显降低，FBG、BUN、Scr和24 h尿蛋白含量均显著降低（P< 0.05），肾脏组织中TGF-β1、CollagenⅠ、Collagen Ⅲ mRNA表达水平及TGF-β1、p-Smad3和α-SMA蛋白表达水平均显著降低（P<0.05），而圣草酚低剂量组大鼠以上各指标变化差异无统计学意义（P>0.05）。

米非司酮周期疗法治疗对围绝经期异常子宫出血患者的影响分析

药物与临床China &Foreign Medical Treatment 中外医疗米非司酮周期疗法治疗对围绝经期异常子宫出血患者的影响分析梅娟，戴淑婷，张雪芳漳州招商局经济技术开发区第一医院妇产科，福建漳州 353100［摘要］目的研讨米非司酮周期疗法治疗对围绝经期异常子宫出血（Abnormal Uterine Bleeding, AUB ）患者的影响。

方法随机选取2021年5月—2023年5月漳州招商局经济技术开发区第一医院确诊为AUB 的100例患者为研究对象，依据随机数表法分组，对照组（n =50）接受米非司酮持续口服，观察组（n =50）接受米非司酮周期疗法治疗，比较两组方案疗效、性激素水平、临床相关指标以及用药安全性。

结果观察组经3个周期用药后的疗效（96.00%）高于对照组（80.00%），差异有统计学意义（χ2=6.060，P <0.05）。

用药后，观察组各项性激素指标水平均低于对照组，差异有统计学意义（P 均<0.05）。

观察组用药后血红蛋白值高于对照组，子宫内膜厚度小于对照组，差异有统计学意义（P 均<0.05）。

两组间发生药物不良反应基本相当，差异无统计学意义（P >0.05）。

结论对围绝经期AUB 患者实施米非司酮周期疗法用药，能够明显提升用药效果，调节患者机体性激素水平，提高血红蛋白值，缩小子宫内膜厚度，同时保障用药安全。

［关键词］围绝经期异常子宫出血；米非司酮；周期疗法；性激素；子宫内膜厚度［中图分类号］ R5 ［文献标识码］ A ［文章编号］ 1674-0742（2024）02(a)-0103-04Analysis of the Effect of Mifepristone Cycle Therapy on Perimenopausal Abnormal Uterine Bleeding PatientsMEI Juan, DAI Shuting, ZHANG XuefangDepartment of Obstetrics and Gynecology, Zhangzhou China Merchants Economic and Technological Development Zone First Hospital, Zhangzhou, Fujian Province, 353100 China[Abstract] Objective To study the effect of mifepristone cycle therapy on patients with perimenopausal abnormal uter⁃ine bleeding (AUB). Methods 100 patients diagnosed as perimenopausal AUB by Zhangzhou China Merchants Eco⁃nomic and Technological Development Zone First Hospital from May 2021 to May 2023 were randomly selected as the study objects and the group design was completed based on the random number table method. 50 cases in the control group received continuous oral mifepristone, and 50 cases in the observation group were treated with mifepristonecycle therapy. The efficacy, sex hormone levels, clinical indexes and drug safety of the two groups were compared. Results After 3 cycles of treatment, the therapeutic effect of the regimen in the observation group (96.00%) was higherthan that in the control group (80.00%), and the difference was statistically significant (χ2=6.060, P <0.05). After treat⁃ment, the levels of various sex hormone indexes in the observation group were lower than those in the control group, and the differences were statistically significant (all P <0.05). The hemoglobin value of the observation group was higher than that of the control group, and the endometrial thickness was lower than that of the control group, the differ⁃ences were statistically significant (both P <0.05). The incidence of adverse drug reactions between the two groups wassimilar, and there was no statistical significance difference (P >0.05). Conclusion The implementation of mifepristonecycle therapy for perimenopausal AUB patients can significantly enhance the effect of medication, regulate the level ofsex hormones in the patient's body, increase hemoglobin value, and reduce the thickness of the endometrium, as well DOI ：10.16662/ki.1674-0742.2024.04.103[作者简介] 梅娟（1983-），女，本科，主治医师，研究方向为妇产科临床。

Coordination of Supply Chains with risk-averse agents

Coordination of Supply Chainswith Risk-Averse AgentsXianghua Gan,Suresh P.Sethi,and Houmin YanAbstract The extant supply chain management literature has not addressed the issue of coordination in supply chains involving risk-averse agents.We take up this issue and begin with deﬁning a coordinating contract as one that results in a Pareto-optimal solution acceptable to each agent.Our deﬁnition generalizes the standard one in the risk-neutral case.We then develop coordinating contracts in three speciﬁc cases(1)the supplier is risk neutral and the retailer maximizes his expected proﬁt subject to a downside risk constraint,(2)the supplier and the retailer each maximizes his own mean-variance trade-off,and(3)the supplier and the retailer each maximizes his own expected utility.Moreover,in case(3)we show that our contract yields the Nash Bargaining solution.In each case,we show how we can ﬁnd the set of Pareto-optimal solutions,and then design a contract to achieve the solutions.We also exhibit a case in which we obtain Pareto-optimal sharing rules explicitly,and outline a procedure to obtain Pareto-optimal solutions. Keywords Capacity•Coordination•Nash bargaining•Pareto-optimality•Risk averse•Supply chain managementX.Gan(*)Department of Logistics and Maritime Studies,The Hong Kong Polytechnic University,Hung Hom,Kowloon,Hong Konge-mail:lgtxgan@.hkS.P.SethiSchool of Management,SM30,The University of Texas at Dallas,800W.Campbell Road, Richardson,TX75080-3021,USAe-mail:sethi@H.YanDepartment of Systems Engineering and Engineering Management,The Chinese University of Hong Kong,Shatin,NT,Hong Konge-mail:yan@.hkT.-M.Choi and T.C.Edwin Cheng(eds.),Supply Chain Coordination under Uncertainty,3 International Handbooks on Information Systems,DOI10.1007/978-3-642-19257-9_1,#Springer-Verlag Berlin Heidelberg20114X.Gan et al. 1IntroductionMuch of the research on decision making in a supply chain has assumed that the agents in the supply chain are risk neutral,i.e.,they maximize their respective expected proﬁts.An important focus of this research has been the design of supply contracts that coordinate the supply chain.When each of the agents maximizes his expected proﬁt,the objective of the supply chain considered as a single entity is unambiguously to maximize its total expected proﬁt.This fact alone makes it natural to deﬁne a supply chain to be coordinated if the chain’s expected proﬁt is maximized and each agent’s reservation proﬁt is met.A similar argument holds if each agent’s objective is to minimize his expected cost.In this paper we consider supply chains with risk-averse agents.Simply put,an agent is risk averse if the agent prefers a certain proﬁt p to a risky proﬁt,whose expected value equals p.In the literature,there are many measures of risk aversion; see Szeg€o(2004)for examples.Regardless of the measure used,when one or more agents in the supply chain are risk averse,it is no longer obvious as to what the objective function of the supply chain entity should be.Not surprisingly,the issue of coordination of supply chain consisting of risk-averse agents has not been studied in the supply chain management literature.That is not to say that the literature does not realize the importance of the risk-averse criteria.Indeed,there are a number of papers devoted to the study of inventory decisions of a single risk-averse agent.These include Lau(1980),Bouakiz and Sobel(1992),Eeckhoudt et al. (1995),Chen and Federgruen(2000),Agrawal and Seshadri(2000a),Buzacott et al. (2002),Chen et al.(2007),and Gaur and Seshadri(2005).There also have been a few studies of supply chains consisting of one or more risk-averse u and Lau(1999)and Tsay(2002)consider decision making by a risk-averse supplier and a risk-averse retailer constituting a supply chain.Agrawal and Seshadri(2000b) introduce a risk-neutral intermediary to make ordering decisions for risk-averse retailers,whose respective proﬁts are side payments from the intermediary.Van Mieghem(2003)has reviewed the literature that incorporates risk aversion in capacity investment decisions.While these papers consider risk-averse decision makers by themselves or as agents in a supply chain,they do not deal with the issue of the supply chain coordination involving risk-averse agents.It is this issue of coordination of supply chains consisting of one or more risk-averse agents that is the focus of this paper.That many decision makers are risk-averse has been amply documented in theﬁnance and economics literature;see, for example,Van Neumann and Morgenstern(1944),Markowitz(1959),Jorion (2006),and Szeg€o(2004).We shall therefore develop the concept of what we mean by coordination of a supply chain,and then design explicit contracts that achieve the deﬁned coordination.For this purpose we use the Pareto-optimality criterion,used widely in the group decision theory,to evaluate a supply chain’s performance.We deﬁne each agent’s payoff to be a real-valued function of a random variable representing his proﬁt,and propose that a supply chain can be treated as coordinated if no agent’s payoff can beCoordination of Supply Chains with Risk-Averse Agents5 improved without impairing someone else’s payoff and each agent receives at least his reservation payoff.We consider three speciﬁc cases of a supply chain(1)the supplier is risk neutral and the retailer maximizes his expected proﬁt subject to a downside risk constraint,(2)the supplier and the retailer each maximizes his own mean-variance trade-off,and(3)the supplier and the retailer each maximizes his own expected utility.We show how we can coordinate the supply chain in each case according to our deﬁnition.In each case we do this byﬁnding the set of Pareto-optimal solutions acceptable to each agent,and then constructing aﬂexible contract that can attain any of these solutions.Moreover,the concept we develop and the contracts we obtain generalize the same known for supply chains involving risk-neutral agents.The remainder of the paper is organized as the follows.In Sect.2we review the related literature in supply chain management and group decision theory.In Sect.3 we introduce a deﬁnition of coordination of a supply chain consisting of risk-averse agents.In Sect.4we characterize the Pareto-optimal solutions andﬁnd coordinating contracts for the supply chains listed as theﬁrst two cases.In Sect.5weﬁrst take up the third case using exponential utility functions for the agents,and design coordinating contracts as well as obtain the Nash Bargaining solution.Then we examine a case in which the supplier has an exponential utility followed by a linear utility.Section6provides a discussion of our results.The paper concludes in Sect.7 with suggestions for future research.2Literature ReviewThere is a considerable literature devoted to contracts that coordinate a supply chain involving risk-neutral agents.This literature has been surveyed by Cachon(2003). In addition,the book by Tayur et al.(1999)contains a number of chapters addressing supply contracts.In light of these,we limit ourselves to reviewing papers studying inventory and supply chain decisions by risk-averse agents.First we review papers dealing with a single risk-averse agent’s optimal inventory decision.Then we review articles dealing with decision making by risk-averse agents in a supply chain.Chen and Federgruen(2000)re-visit a number of basic inventory models using a mean-variance approach.They exhibit how a systematic mean-variance trade-off analysis can be carried out efﬁciently,and how the resulting strategies differ from those obtained in the standard analyses.Agrawal and Seshadri(2000a)consider how a risk-averse retailer,whose utility function is increasing and concave in wealth,chooses the order quantity and the selling price in a single-period inventory model.They consider two different ways in which the price affects the distribution of demand.In theﬁrst model,they assume that a change in the price affects the scale of the distribution.In the second model, a change in the price only affects the location of the distribution.They show that in comparison to a risk-neutral retailer,a risk-averse retailer will charge a higher price6X.Gan et al. and order less in theﬁrst model,whereas he will charge a lower price in the second model.Buzacott et al.(2002)model a commitment and option contract for a risk-averse newsvendor with a mean-variance objective.The contract,also known as a take-or-pay contract,belongs to a class of volumeﬂexible contracts,where the newsvendor reserves a capacity with initial information and adjusts the purchase at a later stage when some new information becomes available.They compare the performance of strategies developed for risk-averse and risk-neutral objectives. They conclude that the risk-averse objective can be an effective approach when the quality of information revision is not high.Their study indicates that it is possible to reduce the risk(measured by the variance of the proﬁt)by six-to eightfold,while the loss in the expected proﬁt is almost invisible.On the other hand,the strategy developed for the expected proﬁt objective can only be consid-ered when the quality of information revision is high.They show furthermore that theseﬁndings continue to hold in the expected utility framework.The paper points out a need for modeling approaches that deal with downside risk considerations.Lau and Lau(1999)study a supply chain consisting of a monopolistic supplier and a retailer.The supplier and the retailer employ a return policy,and each of them has a mean-variance objective u and Lau obtain the optimal wholesale price and return credit for the supplier to maximize his utility.However,they do not consider the issue of improving the supply chain’s performance,i.e.,improving both players’utilities.Agrawal and Seshadri(2000b)consider a single-period model in which multiple risk-averse retailers purchase a single product from a common supplier.They introduce a risk neutral intermediary into the channel,who purchases goods from the vendor and sells them to the retailers.They demonstrate that the intermediary, referred to as the distributor,orders the optimal newsvendor quantity from the supplier and offers a menu of mutually beneﬁcial contracts to the retailers.In every contract in the menu,the retailer receives aﬁxed side payment,while the distributor is responsible for the ordering decisions of the retailers and receives all their revenues.The menu of contracts simultaneously(1)induces every risk-averse agent to select a unique contract from it;(2)maximizes the distributor’s proﬁt; and(3)raises the order quantities of the retailers to the expected value maximizing (newsvendor)quantities.Tsay(2002)studies how risk aversion affects both sides of the supplier–retailer relationship under various scenario of relative strategic power,and how these dynamics are altered by the introduction of a return policy.The sequence of play is as follows:ﬁrst the supplier announces a return policy,and then the retailer chooses order quantity without knowing the demand.After observing the demand, the retailer chooses the price and executes on any relevant terms of the distribution policy as appropriate(e.g.,returning any overstock as allowed).Tsay shows that the behavior under risk aversion is qualitatively different from that under risk neutrality.He also show that the penalty for errors in estimating a channel partner’s risk aversion can be substantial.Coordination of Supply Chains with Risk-Averse Agents7 In a companion paper(Gan et al.2005),we examine coordinating contracts for a supply chain consisting of one risk-neutral supplier and one risk-averse retailer. There we design an easy-to-implement risk-sharing contract that accomplishes the coordination as deﬁned in this paper.Among these supply chain papers,Lau and Lau(1999)and Tsay(2002)consider the situation in which both the retailer and the supplier in the channel are risk averse.However,neither considers the issue of the Pareto-optimality of the actions of the agents.The aim of Agrawal and Seshadri(2000b)is to design a contract that increases the channel’s order quantity to the optimal level in the risk-neutral case by having the risk-neutral agent assume all the risk.Once again,they do not mention the Pareto-optimality aspect of the decision they obtain.Finally since our deﬁnition of coordination is based on the concepts used in the group decision theory,we brieﬂy review this stream of literature.From the early ﬁfties to the early eighties,a number of papers and books appeared that deal with situations in which a group faces intertwined external and internal problems.The external problem involves the choice of an action to be taken by the group,and the internal problem involves the distribution of the group payoff among the members. Arrow(1951)conducted one of the earliest studies on the group decision theory, and showed that given an ordering of consequences by a number of individuals,no group ordering of these consequences exists that satisﬁes a set of seemingly reasonable behavioral assumptions.Harsanyi(1955)presented conditions under which the total group utility can be expressed as a linear combination of individuals’cardinal utilities.Wilson(1968)used Pareto-optimality as the decision criterion and constructed a group utility function toﬁnd Pareto-optimal solutions. Raiffa(1970)illustrates the criterion of Pareto-optimality quite lucidly,and discusses how to choose a Pareto-optimal solution in bargaining and arbitration Valle(1978)uses an allocation function to deﬁne Pareto-optimality. Eliashberg and Winkler(1981)investigate properties of sharing rules and the group utility functions in additive and multilinear cases.3Deﬁnition of Coordination of a Supply Chainwith Risk-Neutral or Risk-Averse AgentsIn this section we deﬁne coordination of a supply chain consisting of agents that are risk neutral or risk averse.We use concepts developed in group decision theory that deals with situations in which a group faces intertwined external and internal problems.The external problem involves the choice of an action to be taken by the group,and the internal problem involves the distribution of the group payoff among the members.In group decision problems,a joint action of the group members is said to be Pareto-optimal if there does not exist an alternative action that is at least as acceptable to all and deﬁnitely preferred by some.In other words,a joint action is Pareto-optimal if it is not possible to make one agent better off without makinganother one worse off.We call the collection of all Pareto-optimal actions as the Pareto-optimal set .It would not be reasonable for the group of agents to choose a joint action that is not Pareto-optimal.Raiffa (1970)and LaValle (1978)illustrate this idea quite lucidly with a series of examples.A supply chain problem is obviously a group decision problem.The channel faces an external problem and an internal problem.External problems include decisions regarding order/production quantities,item prices,etc.The internal problem is to allocate proﬁt by setting the wholesale price,deciding the amount of a side payment if any,refund on the returned units,etc.Naturally,we can adopt the Pareto-optimality criterion of the group decision theory for making decisions in a supply chain.Indeed,in the risk-neutral case,the optimal action under a coordinating contract is clearly Pareto-optimal.In general,since the agents in the channel would not choose an action that is not in the Pareto-optimal set,the ﬁrst step to coordinate a channel is to characterize the set.Following the ideas of Raiffa (1970)and LaValle (1978),we formalize below the deﬁnition of Pareto-optimality.Let (O ;F ;P )denote the probability space and N denote the number of agents in the supply chain,N r 2.Let S i be the external action space of agent i ;i ¼1;...;N ,and S ¼S 1ÂÁÁÁÂS N .For any given external joint action s ¼s 1;...;s N ðÞ2S ,the channel’s total proﬁt is a random variable P s ;o ðÞ;o 2O .Let E and V denote the expectation and variance deﬁned on (O ;F ;P ),respectively.Now we deﬁne a sharing rule that governs the splitting of the channel proﬁt among the agents.Let Y be the set of all functions from S ÂO to R N .Deﬁnition 1.A function u ðs ;v Þ2Q is called a sharing rule if P i u i ðs ;v Þ¼1almost surely.Under the sharing rule u ðs ;o Þ,agent i’s proﬁt is represented byP i ðs ;v ;u ðs ;v ÞÞ¼u i ðs ;v ÞP ðs ;v Þ;i ¼1;...;N :Often,when there is no confusion,we write P ðs ;v Þsimply as P ðs Þ,u ðs ;v Þas u ðs Þ,and P i ðs ;v ;u ðs ;v ÞÞas P i ðs ;u ðs ÞÞ.A supply chain’s external problem is to choose an s 2S and its internal problem is to choose a function u ðs Þ2Y .Thus the channel’s total problem is to choose a pair ðs ;u ðs ÞÞ2S ÂY .Now we deﬁne the preferences of the agents over their random proﬁts.Let G denote the space of all random variables deﬁned on O ;F ;P ðÞ.For X ;X 02G ,the agent i ’s preference will be denoted by a real-valued payoff function u i ðÁÞdeﬁned on G .The relation u i ðX Þ>u i ðX 0Þ,u i ðX Þ<u i ðX 0Þand u i ðX Þ¼u i ðX 0Þindicate X is preferred to ,less preferred to ,and equivalent to X 0,respectively.It should be noted that this deﬁnition of payoff function allows for ordinal as well as cardinal utility functions.We provide following examples of payoff functions.Example 1.If agent i wants to maximize his mean-variance trade-off,then his payoff function is u i ðX Þ¼E ðX ÞÀl V ðX Þ;X 2G ,for some l >0.Example 2.Assume that agent i maximizes his expected proﬁt under the constraint that the probability of his proﬁt being less than his target proﬁt level a does not exceed a given level b ;0<b b 1.Then his payoff u i can be represented as8X.Gan et al.u iðXÞ¼EðXÞ;if P X b aðÞb b;À1;if P X b aðÞ>b:&Example3.Suppose agent i has a concave increasing utility function g i:R1!R1 of wealth and wants to maximize his expected utility.Then the agent’s payoff function is u iðXÞ¼E g iðXÞ½ ;X2G.Remark1.In Raiffa(1970)and LaValle(1978),each agent is assumed to have a cardinal utility function of proﬁt,and his objective is to maximize his expected utility.However,some preferences,such as the one in Example2,cannot be represented by a cardinal utility function.A point a2R N is said to be Pareto-inferior to or Pareto-dominated by another point b2R N,if each component of a is no greater than the corresponding compo-nent of b and at least one component of a is less than the corresponding component of b.In other words,we say b is Pareto-superior to a or b Pareto-dominates a.A point is said to be a Pareto-optimal point of a subset of R N,if it is not Pareto-inferior to any other point in the subset.With these concepts,we can now deﬁne Pareto-optimality of a sharing rule uðsÞand an action pairðs;uðsÞÞ.Deﬁnition2.Given an external action s of the supply chain,uÃðsÞis a Pareto-optimal sharing rule,ifðu1ðP1ðs;uÃðsÞÞÞ;ÁÁÁ;u NðP Nðs;uÃðsÞÞÞÞis a Pareto-optimal point of the setfðu1ðP1ðs;uðsÞÞÞ;ÁÁÁ;u NðP Nðs;uðsÞÞÞÞ;u2Y g;where u iðP iðs;uðsÞÞÞis the payoff of the i th agent.Deﬁnition3.ðsÃ;uÃðsÃÞÞis a Pareto-optimal action pair if the agents’payoffsðu1ðP1ðsÃ;uÃðsÃÞÞÞ;ÁÁÁ;u NðP NðsÃ;uÃðsÃÞÞÞÞis a Pareto-optimal point of the setfðu1ðP1ðs;uðsÞÞÞ;ÁÁÁ;u NðP Nðs;uðsÞÞÞÞ;ðs;uðsÞÞ2SÂY g:Clearly ifðsÃ;uÃðsÃÞÞis a Pareto-optimal action pair,then uÃðsÃÞis a Pareto-optimal sharing rule given sÃ.We begin now with an examination of the Pareto-optimal set in a supply chain consisting of risk-neutral agents.If an external action maximizes the supply chain’s expected proﬁt,then it is not possible to make one agent get more expected proﬁt without making another agent get less.More speciﬁcally,we have the following proposition.Coordination of Supply Chains with Risk-Averse Agents9Proposition1.If the agents in a supply chain are all risk neutral,then an action pairðs;uðsÞÞis Pareto-optimal if and only if the channel’s external action s maximizes the channel’s expected proﬁt.Proof.The proof follows from the fact that in the risk-neutral case,for each s,Xu iðP iðs;uðsÞÞÞ¼XE P iðs;uðsÞÞ¼EXP iðs;uðsÞÞ¼E PðsÞ:Thus,everyðsÃ;uðsÃÞÞ2SÂY is Pareto-optimal provided sÃmaximizes E PðsÃÞ.□Since agents in a supply chain maximize their respective objectives,the agents’payoffs might not be Pareto-optimal if their objectives are not aligned properly.In this case,it is possible to improve the chain’s performance,i.e.,achieve Pareto-superior payoffs.The agents can enter into an appropriately designed contract, under which their respective optimizing actions leads to a Pareto-superior payoff.In the supply chain management literature,a contract is deﬁned to coordinate a supply chain consisting of risk-neutral agents if their respective optimizing external actions under the contract maximize the chain’s expected proﬁt.Then,according to Propo-sition1,a coordinating contract is equivalent to a Pareto-optimal action in the risk-neutral case.It is therefore reasonable to use the notion of Pareto-optimality to deﬁne supply chain coordination in the general case.Deﬁnition4.Supply Chain Coordination.A contract agreed upon by the agents of a supply chain is said to coordinate the supply chain if the optimizing actions of the agents under the contract1.Satisfy each agent’s reservation payoff constraint.2.Lead to an action pairðsÃ;uÃðsÃÞÞthat is Pareto-optimal.Besides Pareto-optimality of a contract,we have introduced the individual-rationality or the participation constraints as part of the deﬁnition of coordination. The constraints ensure that each agent is willing to participate in the contract by requiring that each gets at least his reservation payoff.It is clear that each agent’s reservation payoff will not be less than his status-quo payoff,which is deﬁned to be his best payoff in the absence of the contract.Thus,we need consider only the subset of Pareto-optimal actions that satisfy these participating constraints.The reservation payoff of an agent plays an important role in bargaining,as we shall see in the next section.Now we illustrate the introduced concept of coordination by an example. Example4.Consider a supply chain consisting of one supplier and one retailer who faces a newsvendor problem.Before the demand realizes,the supplier decides on his capacityﬁrst,and the retailer then prices the product and chooses an order quantity.The supplier and the retailer may enter into a contract that speciﬁes the retailer’s committed order quantity and the supplier’s refund policy for returned items.In this channel,the external actions are the supplier’s capacity selection and the retailer’s pricing and ordering decisions.These are denoted as s.The internal 10X.Gan et al.Coordination of Supply Chains with Risk-Averse Agents11 actions include decision on the quantity of commitment,the refundable quantity, and the refund credit per item.These internal actions together lead to a sharing rule denoted by uðsÞ.Once the contract parameters are determined,the agents in the supply chain choose their respective external actions that maximize their respective payoffs.Ifðs;uðsÞÞsatisﬁes the agents’reservation payoffs and is Pareto-optimal, then the channel is coordinated by the contract.The deﬁnition of coordination proposed here allows agents to have any kind of preference that can be represented by a payoff function satisfying the complete and transitive axioms speciﬁed earlier.For example,all of the seven kinds of preferences listed in Schweitzer and Cachon(2000),including risk-seeking preferences,are allowed.Since often in practice,an agent is either risk neutral or risk averse,we restrict our attention to only these two types.Remark2.Our deﬁnition applies also to a T-period case.For this,we deﬁne the payoff function of player i asu iðP1iðsÃ;uÃðsÃÞÞ;P2iðsÃ;uÃðsÃÞÞ;ÁÁÁ;P T iðsÃ;uÃðsÃÞÞÞ:G T!R1;where P t iðsÃ;uÃðsÃÞÞis agent i’s proﬁt in period t.4Coordinating Supply ChainsEach Pareto-optimal action pairðs;uðsÞÞresults in a vector of payoffsðu1ðP1ðs;uðsÞÞÞ;ÁÁÁ;u NðP Nðs;uðsÞÞÞÞ;where u iðP iðs;uðsÞÞÞis the payoff of the i th agent.LetC¼fðu1ðP1ðs;uðsÞÞÞ;ÁÁÁ;u NðP Nðs;uðsÞÞÞÞjðs;uðsÞÞis Pareto-optimal;ðs;uðsÞÞ2SÂY g;denote the set of all Pareto-optimal payoffs,and let F&C be the subset of Pareto-optimal payoffs that satisfy all of the participation constraints.We shall refer to F as Pareto-optimal frontier.We will assume that F is not empty.To coordinate a supply chain,theﬁrst step is to obtain the Pareto-optimal frontier F.If F is not a singleton,then agents bargain to arrive at an element in F to which they agree.A coordinating contract is one with a speciﬁc set of parameters that achieves the selected solution.A contract is appealing if it has sufﬁcientﬂexibility.In Cachon(2003),a coordinating contract is said to beﬂexible if the contract,by adjustment of some parameters,allows for any division of the supply chain’s expected proﬁt among the risk-neutral agents.This concept can be extended to the general case as follows.12X.Gan et al. Deﬁnition 5.A coordinating contract isﬂexible if,by adjustment of some parameters,the contract can lead to any point in F:We shall now develop coordinating contracts in supply chains consisting of two agents:a supplier and a retailer.We shall consider three different cases.In each of these cases,we assume that agents have complete information.In Case1,the supplier is risk neutral and the retailer has a payoff function in Example2,i.e.,the retailer maximizes his expected proﬁt subject to a downside constraint.In Case2, the supplier and the retailer are both risk averse and each maximizes his own mean-variance trade-off.In Case3,the supplier and the retailer are both risk averse and each maximizes his own expected concave utility.We consider theﬁrst two cases in this section and the third case in Sect.5.In each case,let us denote the retailer’s and the supplier’s reservation payoffs as p r r0and p s r0,respectively.Weﬁrst obtain F and then design aﬂexible contract that can lead to any point in F by adjusting the parameters of the contract.4.1Case1:Risk Neutral Supplier and Retailer Averseto Downside RiskWe consider the supplier to be risk neutral and the retailer to maximize his expected proﬁt subject to a downside risk constraint.This downside risk constraint requires that the probability of the retailer’s proﬁt to be higher than a speciﬁed level is not too small.The risk neutrality assumption on the part of the supplier is reasonable when he is able to diversify his risk by serving a number of independent retailers,which is quite often the case in practice.When the retailers are independent,the supply chain can be divided into a number of sub-chains,each consisting of one supplier and one retailer.This situation,therefore,could be studied as a supply chain consisting of one risk-neutral supplier and one risk-averse retailer.We say that an action pairðs;uðsÞÞis feasible if the pair satisﬁes the retailer’s downside risk constraint.We do not need to consider a pairðs;uðsÞÞthat is not feasible since under the pair the retailer’s payoff isÀ1and he would not enter the contract.We denote PðsÞ,P rðs;uðsÞÞ,and P sðs;uðsÞÞas the proﬁts of the supply chain,the retailer,and the supplier,respectively.Other quantities of interest will be subscripted in the same way throughout the chapter,i.e.,subscript r will denote the retailer and subscript s will denote the supplier.Then we have the following result.Theorem1.If the supplier is risk neutral and the retailer maximizes his expected proﬁt subject to a downside risk constraint,then a feasible action pairðs;uðsÞÞis Pareto-optimal if and only if the supply chain’s expected proﬁt is maximized over the feasible set.Proof.ONLY IF:It is sufﬁcient to show that if E PðsÞis not maximal over the feasible set,thenðs;uðsÞÞis not Pareto-optimal.。

用于治疗和预防急性冠状动脉综合征的药物制剂、方法和给药方案[

专利名称：用于治疗和预防急性冠状动脉综合征的药物制剂、方法和给药方案
专利类型：发明专利
发明人：C·L·贝斯盖尔,W·V·罗德里格斯,N·D·拉勒万尼,D·哈特曼,J·约翰森
申请号：CN200480031007.4
申请日：20041019
公开号：CN1870894A
公开日：
20061129
专利内容由知识产权出版社提供
摘要：本发明提供了用于治疗和预防急性冠状动脉综合征的方法和制剂。

本发明的方法提供了用于降低和稳定动脉粥样硬化斑块的载脂蛋白A－I Milano：磷脂复合体的安全有效剂量。

还提供了Apo A－I Milano：磷脂复合体的药物制剂。

申请人：埃斯普里昂治疗公司
地址：美国密执安
国籍：US
代理机构：中国国际贸易促进委员会专利商标事务所
代理人：唐晓峰
更多信息请下载全文后查看。

右旋糖酐铁联合五维赖氨酸治疗婴儿营养性缺铁性贫血的综合疗效

现代医学Modern Medical Journal2020，Aug ；48（8）：1020-1024［收稿日期］2019-02-22［修回日期］2020-07-28［作者简介］陈杰超（1986－），女，山东临沂人，主治医师。

E -mail ：zzzzqu@163．com［引文格式］陈杰超，赵忠全，邢德强，等．右旋糖酐铁联合五维赖氨酸治疗婴儿营养性缺铁性贫血的综合疗效［J ］．现代医学，2020，48（8）：1020-1024．·论著·右旋糖酐铁联合五维赖氨酸治疗婴儿营养性缺铁性贫血的综合疗效陈杰超1，赵忠全2，邢德强1，蒋妍1，杜瑞1（1．聊城市东昌府区妇幼保健院儿保科，山东聊城252000；2．聊城市第三人民医院骨科，山东聊城252000）［摘要］目的：研究右旋糖酐铁联合五维赖氨酸颗粒对婴儿营养性缺铁性贫血的血红蛋白水平以及发育商的影响。

方法：124例门诊患儿随机分为研究组（63例）和对照组（61例），对照组给予右旋糖酐铁口服液配合口服维生素C 片辅助治疗，研究组在此基础上加用五维赖氨酸颗粒，统一治疗8周。

比较两组间血红蛋白水平和发育商数值的变化。

结果：研究组患儿Hb 增长幅度明显大于对照组（P ＜0．01）；研究组的DQ 数值增幅明显高于对照组（P ＜0．01）；研究组的总有效率（95．24%）大于对照组的总有效率（81．97%），P ＜0.05；研究组的不良反应率（4．76%）小于对照组的不良反应率（16．39%），P ＜0．05。

结论：与单用铁剂相比较，右旋糖酐铁联合五维赖氨酸颗粒治疗婴儿营养性缺铁性贫血，能较快提升血红蛋白水平以及发育商数值，可进一步提高疗效。

［关键词］营养性缺铁性贫血；五维赖氨酸颗粒；血红蛋白；发育商［中图分类号］Ｒ556．3［文献标识码］A［文章编号］1671-7562（2020）08-1020-05doi ：10．3969/j．issn．1671-7562．2020．08．016Comprehensive efficacy of nutritional iron deficiency anemia in infants treated with iron dextran and five －dimensional lysineCHEN Jiechao 1，ZHAO Zhongquan 2，XING Deqiang 1，JIANG Yan 1，DU Ｒui 1（1．Department of Child Protection ，Maternal and Child Health Hospital ，Dongchangfu District ，Liaocheng 252000，China ；2．Department of Orthopedics ，Liaocheng Third People ＇s Hospital ，Liaocheng 252000，China ）［Abstract ］Objective ：To investigate the effects of iron dextran and five -dimensional lysine granules on hemoglo-bin levels and developmental quotients in infants with nutritional iron deficiency anemia．Methods ：124outpatients were randomly divided into study group （63cases ）and control group （61cases ）．The control group was given iron dextran oral solution combined with oral vitamin C tablets for adjuvant treatment ，on top of which ，the study group-was given five -dimensional lysine granules for 8weeks．The changes in hemoglobin levels and developmental quo-tient values were compared between the two groups．Ｒesults ：The growth rate of Hb in the study group was signifi-cantly higher than that in the control group （P ＜0．01）．The DQ value of the study group was significantly higher than that of the control group （P ＜0．01）．The total effective rate of the study group （95．24%）was greater than the total effective rate of the control group （81．97%），P ＜0．05．The adverse reaction rate of the study group （4.76%）was lower than that of the control group （16．39%），P ＜0．05．Conclusion ：Compared with iron alone ，iron dextran combined with five -dimensional lysine granules can improve hemoglobin levels and developmen-·0201·tal quotient values in infants with nutritional iron deficiency anemia．At the same time，this method can further im-prove the curative effect．［Key words］nutritional iron deficiency anemia；five-dimensional lysine granules；hemoglobin；development quo-tient营养性缺铁性贫血（nutritional iron deficiency anemia，NIDA）是常见的贫血类型，发病率最高的群体是6个月 1岁的婴幼儿，具有极大危害。

迈克沃伊和法默的中国体外诊断分销指南说明书

McEvoy and Farmer's Complete Guide to IVD Distribution in Chinahttps:///r/W875106C98AEN.htmlDate: May 2009Pages: 240Price: US$ 3,995.00 (Single User License)ID: W875106C98AENAbstractsWho is Who in Clinical Diagnostics in China, produced jointly with the firm McEvoy & Farmer, is the product of on-the-ground primary research on Chinese labs conducted in fall and winter 2008. Included in this report:Market Size Estimate by Major Category (Chemistry, Critical Care Chemistry, Urine Chemistry, Hematology, Flow Cytometry, Coagulation, Immunochemistry, Molecular Testing, Other IVD)Country Industry OverviewChinese Hospital StatisticsProfiles of 42 International Diagnostic Companies with operations in ChinaProfiles of 130 Domestic Diagnostic CompaniesProfiles of 24 Local Distributors, indicating the companies they distribute forThe Chinese market represents a significant opportunity for IVD diagnostic companies. But actionable information about this emerging market is often difficult to get. Only with an exhaustive, on-the-ground research team can a company truly understand the chinese market. Now, a resource is available that can make on-the-ground research available to all companies at a fraction of the cost.Published jointly with trusted Asian IVD market experts, this Kalorama report is acomplete survey of the IVD market in China today. Market size for major categories of the IVD market, products on the market, important Chinese market trends and intense company profiles are part of this exhaustive study.This country of 1.3 billion people is now America’s sixth largest export market, and China’s economy, while showing some effects of the world recession, has been less impacted than other nations and is showing growth, although not as rapid as in recent years. A number of recent events and trends in the Chinese healthcare environment are making China an increasingly attractive market opportunity for in vitro diagnostics companies. The increasing numbers of private laboratories and expanded reference laboratories are expanding the market for tests of all kinds.Although there are a number of challenges for diagnostic manufacturers to understand and overcome, the market for clinical diagnostics in China (both reagents and instruments) remains one of the most promising emerging markets in the world.ContentsCOUNTRY SUMMARYMarket TotalsWhat is New in ChinaThe Healthcare System in ChinaMedical InsuranceA Brief Guide to the BureaucracyPrivate and Reference LaboratoriesPrivate Medical PracticeProduct RegistrationReimbursementTendersReagent RentalQuality ControlVacuum Tube ConversionSecond hand InstrumentsImported and Domestic Sales INTERNATIONAL MANUFACTURER PROFILESAbbott LaboratoriesABXAcon Biotech/InvernessAdaltisAffymetrixAgilent TechnologiesApplied BiosystemsArkrayAudit DiagnosticsBeckman CoulterBDBioneer TradeBio Rad LaboratoriesbioMérieuxDiaSorinDiaSys Diagnostic SystemsEppendorfEuroimmunFujirebio/CanAg DiagnosticsHitachi High Technologies CorporationHospitexHumanInverness MedicalJei Daniel (JD) BiotechJokohMedicine Devices Company (MDC) Melet Schloesing LaboratoriesMP BiomedicalsOrtho ClinicalDiagnosticsPerkinElmerPromegaQiagenRadiometerRandoxR BiopharmRocheSiemens Healthcare Diagnostics StagoSysmex CorporationThermoFisherVirionSerionYD DiagnosticsDOMESTIC MANUFACTURER PROFILES3V BioengineeringAccuBio TechAddcare Bio TechAi De Diagnostic (IND)AmpllyAntai DiagnosticsAudicom Medical InstrumentAutobio DiagnosticsAVE Science & TechnologyB & E Scientific InstrumentBasoDiagnosticsBeijing Genomics Institute (BGI Healthcare)Biocell InstituteBiocreateBiocup Biotech CompanyBioer TechnologyBiosino BiotechnologyBiote CompanyBioway BiotechnologyBlue Cross Bio MedicalBowlinman Sunshine Science & TechnologyCaihong Analytical InstrumentCaltech GroupCapitalBio CorporationCaretium Medical InstrumentsChang Chun Brother BiotechChangdao BiotechnologyChemClin Bio Tech / China Diagnostics Medical Chemtron BiotechChina Medical/Yuande Bio Medical EngineeringCondor Teco Medical TechnologyCornley Hi TechDa An GeneDecipher BioscienceDirui IndustrialDL Medical BiotechDoubleQ LabDragon MedicalElikan Biological TechnologyFenghua BioengineeringFengHui Medical Science & Technology First Sun ElectronicFosun DiagnosticsGenetel PharmaceuticalsGenius ElectronicsGoldsite DiagnosticsHai Tai BiologicalHaoyuan BiotechnologyHeal Force/Nison InstrumentHealthDigitHongcheng (HC) BiopharmaceuticalHongshi Medical TechnologyHope Industry and TradeHua Sin ScienceHua Tong Medical InstrumentHuaguan Biochip CompanyHuatai Biotechnology IndustrialHuayang Analysis InstrumentHybriBioInTec ProductsJian Ye Medical EquipmentinSangTe Medicine InstrumentKanghua Biotech CompanyKehua Bio EngineeringKinghawk TechnologyLabnovation TechnologiesLandwind International Medical Science LaoLa ElectronicLeadman Biochemistry TechnologyLengguang TechnologyLingyi Medical ScienceLivzon GroupLongx TechnologiesMaker Science TechnologyMaysun TechnologyMaxcom ElectronicMD Pacific TechnologyMeiyilin Electronics InstrumentMerit Choice BioengineeringMindray Medical ElectronicsModern Gold BiotechnologyNanfen Medical Biochemical InstrumentNeusoft Medical SystemsNew MoonNewScen Coast Bio PharmaceuticalOption Science & Technology Development Company Perlong GroupPG Biotech/QiagenPrecil InstrumentProcan ElectronicsRayto Life and Analytical SciencesRich Science IndustryRongsheng Biotech.Runbio Biotech .Sanco InstrumentSan Jose Medical Products..Sciarray BiotechSciendox Bio-Technology CompanySenlong Biotech..Share SunShensuo Medical DiagnosticsShenzhen New Industries Biomedical Engineering (SNIBE) Shining Sun TechnologySinnowa Medical Science & TechnologySTAC Medical Science & TechnologySteellex Scientific InstrumentStrong Biotechnologies...Success Technology DevelopmentSun BiotechSunostik Biomedical TechnologySym-Bio Lifescience.Tecom ScienceTechcompTellgen LifeTiangen Biotech...TianHai Medical Equipment (THME)Tianlong Science and TechnologyTigsun Biotinge Science & TechnologyTZD Technological.Urit Medical ElectronicWanCheng Bio-elect.Wantai BiologicalWasson An-Ze Bio-tech Company..WearmaxWeirikang Biological TechnologyW.H.P.M. 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Quality evaluation of Flos Lonicerae through a simultaneous determination of seven saponins by HPLC with ELSDXing-Yun Chai1, Song-Lin Li2, Ping Li1*1Key Laboratory of Modern Chinese Medicines and Department of Pharmacognosy, China Pharmaceutical University, Nanjing, 210009, People’s Republic of China2Institute of Nanjing Military Command for Drug Control, Nanjing, 210002, People’s Republic of China*Corresponding author: Ping LiKey Laboratory of Modern Chinese Medicines and Department of Pharmacognosy, China Pharmaceutical University, Nanjing 210009, People’s Republic of China.E-mail address: lipingli@Tel.: +86-25-8324-2299; 8539-1244; 135********Fax: +86-25-8532-2747AbstractA new HPLC coupled with evaporative light scattering detection (ELSD) method has been developed for the simultaneous quantitative determination of seven major saponins, namely macranthoidinB (1), macranthoidin A (2), dipsacoside B (3), hederagenin-28-O-β-D-glucopyranosyl(6→1)-O-β-D- glucopyranosyl ester (4), macranthoside B (5), macranthoside A (6), and hederagenin-3-O-α-L-arabinopyranosyl(2→1)-O-α-L-rhamnopyranoside (7)in Flos Lonicerae, a commonly used traditional Chinese medicine (TCM) herb.Simultaneous separation of these seven saponins was achieved on a C18 analytical column with a mixed mobile phase consisting of acetonitrile(A)-water(B)(29:71 v/v) acidified with 0.5% acetic acid. The elution was operated from keeping 29%A for 10min, then gradually to 54%B from 10 to 25 min on linear gradient, and then keep isocratic elution with 54%B from 25 to 30min.The drift tube temperature of ELSD was set at 106℃, and with the nitrogen flow-rate of 2.6 l/min. All calibration curves showed good linear regression (r2 0.9922) within test ranges. This method showed good reproducibility for the quantification of these seven saponins in Flos Lonicerae with intra- and inter-day variations of less than 3.0% and 6.0% respectively. The validated method was successfully applied to quantify seven saponins in five sources of Flos Lonicerae, which provides a new basis of overall assessment on quality of Flos Lonicerae.Keywords: HPLC-ELSD; Flos Lonicerae; Saponins; Quantification1. IntroductionFlos Lonicerae (Jinyinhua in Chinese), the dried buds of several species of the genus Lonicera (Caprifoliaceae), is a commonly used traditional Chinese medicine (TCM) herb. It has been used for centuries in TCM practice for the treatment of sores, carbuncles, furuncles, swelling and affections caused by exopathogenic wind-heat or epidemic febrile diseases at the early stage [1]. Though four species of Lonicera are documented as the sources of Flos Lonicerae in China Pharmacopeia (2000 edition), i.e. L. japonica, L. hypoglauca,L. daystyla and L. confusa, other species such as L. similes and L. macranthoides have also been used on the same purpose in some local areas in China [2]. So it is an important issue to comprehensively evaluate the different sources of Flos Lonicerae, so as to ensure the clinical efficacy of this Chinese herbal drug.Chemical and pharmacological investigations on Flos Lonicerae resulted in discovering several kinds of bioactive components, i.e. chlorogenic acid and its analogues, flavonoids, iridoid glucosides and triterpenoid saponins [3]. Previously, chlorogenic acid has been used as the chemical marker for the quality evaluation of Flos Lonicerae,owing to its antipyretic and antibiotic property as well as its high content in the herb. But this compound is not a characteristic component of Flos Lonicerae, as it has also been used as the chemical marker for other Chinese herbal drugs such as Flos Chrysanthemi and so on[4-5]. Moreover, chlorogenic acid alone could not be responsible for the overall pharmacological activities of Flos Lonicerae[6].On the other hand, many studies revealed that triterpenoidal saponins of Flos Lonicerae possess protection effects on hepatic injury caused by Acetaminophen, Cd, and CCl4, and conspicuous depressant effects on swelling of ear croton oil [7-11]. Therefore, saponins should also be considered as one of the markers for quality control of Flos Lonicerae. Consequently, determinations of all types of components such as chlorogenic acid, flavonoids, iridoid glucosides and triterpenoidal saponins in Flos Lonicerae could be a better strategy for the comprehensive quality evaluation of Flos Lonicerae.Recently an HPLC-ELSD method has been established in our laboratory for qualitative and quantitative determination of iridoid glucosides in Flos Lonicerae [12]. But no method was reported for the determination of triterpenoidal saponins in Flos Lonicera. As a series studies on the comprehensive evaluation of Flos Lonicera, we report here, for the first time, the development of an HPLC-ELSD method for simultaneous determination of seven triterpenoidal saponins in the Chinese herbal drug Flos Lonicerae, i.e.macranthoidin B (1), macranthoidin A (2), dipsacoside B (3), hederagenin-28-O-β-D-glucopyranosyl(6→1)-O-β-D- glucopyranosyl ester (4), macranthoside B (5), macranthoside A (6), and hederagenin-3-O-α-L-arabinopyranosyl(2→1)-O-α-L-rhamnopyranoside (7) (Fig. 1).2. Experimental2.1. Samples, chemicals and reagentsFive samples of Lonicera species,L. japonica from Mi county, HeNan province (LJ1999-07), L. hypoglauca from Jiujang county, JiangXi province (LH2001-06), L. similes from Fei county, ShanDong province (LS2001-07), L. confuse from Xupu county, HuNan province (LC2001-07), and L. macranthoides from Longhu county, HuNan province (LM2000-06) respectively, were collected in China. All samples were authenticated by Dr. Ping Li, professor of department of Pharmacognosy, China Pharmaceutical University, Nanjing, China. The voucher specimens were deposited in the department of Pharmacognosy, China Pharmaceutical University, Nanjing, China. Seven saponin reference compounds: macranthoidin B (1), macranthoidin A (2), dipsacoside B (3), hederagenin-28-O-β-D-glucopyranosyl(6→1)-O-β-D- glucopyranosyl ester (4), macranthoside B (5), macranthoside A (6), and hederagenin-3-O-α-L-arabinopyranosyl(2→1)-O-α-L-rhamnopyranoside (7) were isolated previously from the dried buds of L. confusa by repeated silica gel, sephadex LH-20 and Rp-18 silica gel column chromatography, their structures were elucidated by comparison of their spectral data (UV, IR, MS, 1H- NMR and 13C-NMR) with references [13-15]. The purity of these saponins were determined to be more than 98% by normalization of the peak areas detected by HPLC with ELSD, and showed very stable in methanol solution.HPLC-grade acetonitrile from Merck (Darmstadt, Germany), the deionized water from Robust (Guangzhou, China), were purchased. The other solvents, purchased from Nanjing Chemical Factory (Nanjing, China) were of analytical grade.2.2. Apparatus and chromatographic conditionsAglient1100 series HPLC apparatus was used. Chromatography was carried out on an Aglient Zorbax SB-C18 column（250 4.6mm, 5.0µm）at a column temperature of 25℃.A Rheodyne 7125i sampling valve (Cotati, USA) equipped with a sample loop of 20µl was used for sample injection. The analog signal from Alltech ELSD 2000 (Alltech, Deerfield, IL, USA)was transmitted to a HP Chemstation for processing through an Agilent 35900E (Agilent Technologies, USA).The optimum resolution was obtained by using a linear gradient elution. The mobile phase was composed of acetonitrile(A) and water(B) which acidified with 0.5% acetic acid. The elution was operated from keeping 29%A for 10min, then gradually to 54%B from 10 to 25 min in linear gradient, and back to the isocratic elution of 54%B from 25 to 30 min.The drift tube temperature for ELSD was set at 106℃and the nitrogen flow-rate was of 2.6 l/min. The chromatographic peaks were identified by comparing their retention time with that of each reference compound tried under the same chromatographic conditions with a series of mobile phases. In addition, spiking samples with the reference compounds further confirmed the identities of the peaks.2.3. Calibration curvesMethanol stock solutions containing seven analytes were prepared and diluted to appropriate concentration for the construction of calibration curves. Six concentrationof the seven analytes’ solution were injected in triplicate, and then the calibration curves were constructed by plotting the peak areas versus the concentration of each analyte. The results were demonstrated in Table1.2.4. Limits of detection and quantificationMethanol stock solution containing seven reference compounds were diluted to a series of appropriate concentrations with methanol, and an aliquot of the diluted solutions were injected into HPLC for analysis.The limits of detection (LOD) and quantification (LOQ) under the present chromatographic conditions were determined at a signal-to-noise ratio (S/N) of 3 and 10, respectively. LOD and LOQ for each compound were shown in Table1.2.5. Precision and accuracyIntra- and inter-day variations were chosen to determine the precision of the developed assay. Approximate 2.0g of the pulverized samples of L. macranthoides were weighted, extracted and analyzed as described in 2.6 Sample preparation section. For intra-day variability test, the samples were analyzed in triplicate for three times within one day, while for inter-day variability test, the samples were examined in triplicate for consecutive three days. Variations were expressed by the relative standard deviations. The results were given in Table 2.Recovery test was used to evaluate the accuracy of this method. Accurate amounts of seven saponins were added to approximate 1.0g of L. macranthoides,and then extracted and analyzed as described in 2.6 Sample preparation section. The average recoveries were counted by the formula: recovery (%) = (amount found –original amount)/ amount spiked ×100%, and RSD (%) = (SD/mean) ×100%. The results were given in Table 3.2.6. Sample preparationSamples of Flos Lonicerae were dried at 50℃until constant weight. Approximate 2.0g of the pulverized samples, accurately weighed, was extracted with 60% ethanol in a flask for 4h. The ethanol was evaporated to dryness with a rotary evaporator. Residue was dissolved in water, followed by defatting with 60ml of petroleum ether for 2 times, and then the water solution was evaporated, residue was dissolved with methanol into a 25ml flask. One ml of the methanol solution was drawn and transferred to a 5ml flask, diluted to the mark with methanol. The resultant solution was at last filtrated through a 0.45µm syringe filter (Type Millex-HA, Millipore, USA) and 20µl of the filtrate was injected to HPLC system. The contents of the analytes were determined from the corresponding calibration curves.3. Results and discussionsThe temperature of drift tube and the gas flow-rate are two most important adjustable parameters for ELSD, they play a prominent role to an analyte response. In ourprevious work [12], the temperature of drift tube was optimized at 90°C for the determination of iridoids. As the polarity of saponins are higher than that of iridoids, more water was used in the mobile phase for the separation of saponins, therefore the temperature for saponins determination was optimized systematically from 95°C to 110°C, the flow-rate from 2.2 to 3.0 l/min. Dipsacoside B was selected as the testing saponin for optimizing ELSD conditions, as it was contained in all samples. Eventually, the drift tube temperature of 106℃and a gas flow of 2.6 l/min were optimized to detect the analytes. And these two exact experimental parameters should be strictly controlled in the analytical procedure [16].All calibration curves showed good linear regression (r2 0.9922) within test ranges. Validation studies of this method proved that this assay has good reproducibility. As shown in Table 2, the overall intra- and inter-day variations are less than 6% for all seven analytes. As demonstrated in Table 3, the developed analytical method has good accuracy with the overall recovery of high than 96% for the analytes concerned. The limit of detection (S/N=3) and the limit of quantification (S/N=10) are less than 0.26μg and 0.88μg respectively (Table1), indicating that this HPLC-ELSD method is precise, accurate and se nsitive enough for the quantitative evaluation of major non- chromaphoric saponins in Flos Lonicerae.It has been reported that there are two major types of saponins in Flos Lonicerae, i.e. saponins with hederagenin as aglycone and saponins with oleanolic acid as the aglycone [17]. But hederagenin type saponins of the herb were reported to have distinct activities of liver protection and anti-inflammatory [7-11]. So we adoptedseven hederagenin type saponins as representative markers to establish a quality control method.The newly established HPLC-ELSD method was applied to analyze seven analytes in five plant sources of Flos Lonicerae, i.e. L. japonica,L. hypoglauca,L. confusa,L. similes and L. macranthoides(Table 4). It was found that there were remarkable differences of seven saponins contents between different plant sources of Flos Lonicerae. All seven saponins analyzed could be detected in L. confusa and L. hypoglauca, while only dipsacoside B was detected in L. japonica. Among all seven saponins interested, only dipsacoside B was found in all five plant species of Flos Lonicerae analyzed, and this compound was determined as the major saponin with content of 53.7 mg/g in L. hypoglauca. On the other hand, macranthoidin B was found to be the major saponin with the content higher than 41.0mg/g in L. macranthoides,L. confusa, and L. similis, while the contents of other analytes were much lower.In our previous study [12], overall HPLC profiles of iridoid glucosides was used to qualitatively and quantitatively distinguish different origins of Flos Lonicerae. As shown in Fig.2, the chromatogram profiles of L. confusa, L. japonica and L. similes seem to be similar, resulting in the difficulty of clarifying the origins of Flos Lonicerae solely by HPLC profiles of saponins, in addition to the clear difference of the HPLC profiles of saponins from L. macranthoides and L. hypoglauca.Therefore, in addition to the conventional morphological and histological identification methods, the contents and the HPLC profiles of saponins and iridoids could also be used as accessory chemical evidence toclarify the botanical origin and comprehensive quality evaluation of Flos Lonicerae.4. ConclusionsThis is the first report on validation of an analytical method for qualification and quantification of saponins in Flos Lonicerae. This newly established HPLC-ELSD method can be used to simultaneously quantify seven saponins, i.e. macranthoidin B, macranthoidin A, dipsacoside B, hederagenin-28-O-β-D-glucopyranosyl(6→1)-O-β-D- glucopyranosyl ester, macranthoside B, macranthoside A, and hederagenin-3-O-α-L-arabinopyranosyl(2→1)-O-α-L-rhamnopyranoside in Flos Lonicerae. Together with the HPLC profiles of iridoids, the HPLC-ELSD profiles of saponins could also be used as an accessory chemical evidence to clarify the botanical origin and comprehensive quality evaluation of Flos Lonicerae.AcknowledgementsThis project is financially supported by Fund for Distinguished Chinese Young Scholars of the National Science Foundation of China (30325046) and the National High Tech Program（2003AA2Z2010）.[1]Ministry of Public Health of the People’s Republic of China, Pharmacopoeia ofthe People’s Republic of China, V ol.1, 2000, p. 177.[2]W. Shi, R.B. Shi, Y.R. Lu, Chin. Pharm. J., 34(1999) 724.[3]J.B. Xing, P. Li, D.L. Wen, Chin. Med. Mater., 26(2001) 457.[4]Y.Q. Zhang, L.C. Xu, L.P. Wang, J. Chin. Med. Mater., 21(1996) 204.[5] D. Zhang, Z.W. Li, Y. Jiang, J. Pharm. Anal., 16(1996) 83.[6]T.Z. Wang, Y.M. Li, Huaxiyaoxue Zazhi, 15(2000) 292.[7]J.ZH. Shi, G.T. Liu. Acta Pharm. Sin., 30(1995) 311.[8]Y. P. Liu, J. Liu, X.SH. Jia, et al. Acta Pharmacol. Sin., 13 (1992) 209.[9]Y. P. Liu, J. Liu, X.SH. Jia, et al. Acta Pharmacol. Sin., 13 (1992) 213.[10]J.ZH. Shi, L. Wan, X.F. Chen.ZhongYao YaoLi Yu LinChuang, 6 (1990) 33.[11]J. Liu, L. Xia, X.F. Chen. Acta Pharmacol. Sin., 9 (1988) 395[12]H.J. Li, P. Li, W.C. Ye, J. Chromatogr. A 1008(2003) 167-72.[13]Q. Mao, D. Cao, X.SH. Jia. Acta Pharm. Sin., 28(1993) 273.[14]H. Kizu, S. Hirabayashi, M. Suzuki, et al. Chem. Pharm. Bull., 33(1985) 3473.[15]S. Saito, S. Sumita, N. Tamura, et al. Chem Pharm Bull., 38(1990) 411.[16]Alltech ELSD 2000 Operating Manual, Alltech, 2001, p. 16. In Chinese.[17]J.B. Xing, P. Li, Chin. Med. Mater., 22(1999) 366.Fig. 1 Chemical structures of seven saponins from Lonicera confusa macranthoidin B (1), macranthoidin A (2), dipsacoside B (3), hederagenin-28-O-β-D-glucopyranosyl(6→1)-O-β-D- glucopyranosyl ester (4), macranthoside B (5), macranthoside A (6), and hederagenin-3-O-α-L-arabinopyranosyl(2→1)-O-α-L-rhamnopyranoside (7)Fig. 2Representative HPLC chromatograms of mixed standards and methanol extracts of Flos Lonicerae.Column: Agilent Zorbax SB-C18 column（250 4.6mm, 5.0µm）, temperature of 25℃; Detector: ELSD, drift tube temperature 106℃, nitrogen flow-rate 2.6 l/min.A: Mixed standards, B: L. confusa, C: L. japonica, D: L. macranthoides, E: L. hypoglauca, F: L. similes.Table 1 Calibration curves for seven saponinsAnalytes Calibration curve ar2Test range(μg)LOD(μg)LOQ(μg)1 y=6711.9x－377.6 0.9940 0.56–22.01 0.26 0.882 y=7812.6x－411.9 0.9922 0.54–21.63 0.26 0.843 y=6798.5x－299.0 0.9958 0.46–18.42 0.22 0.724 y=12805x－487.9 0.9961 0.38–15.66 0.10 0.345 y=4143.8x－88.62 0.9989 0.42–16.82 0.18 0.246 y=3946.8x－94.4 0.9977 0.40–16.02 0.16 0.207 y=4287.8x－95.2 0.9982 0.42–16.46 0.12 0.22a y: Peak area; x: concentration (mg/ml)Table 2 Reproducibility of the assayAnalyteIntra-day variability Inter-day variability Content (mg/g) Mean RSD (%) Content (mg/g) Mean RSD (%)1 46.1646.2846.2246.22 0.1346.2245.3647.4226.33 2.232 5.385.385.165.31 2.405.285.345.045.22 3.043 4.374.304.184.28 2.244.284.464.024.255.204 nd1)-- -- nd -- --5 1.761.801.821.79 1.701.801.681.841.77 4.706 1.281.241.221.252.451.241.341.201.26 5.727 tr2)-- -- tr -- -- 1): not detected; 2): trace. RSD (%) = (SD/Mean) ×100%Table 3 Recovery of the seven analytesAnalyteOriginal(mg) Spiked(mg)Found(mg)Recovery(%)Mean(%)RSD(%)1 23.0823.1423.1119.7122.8628.1042.7346.1351.0199.7100.699.399.8 0.722.692.672.582.082.913.164.735.515.7698.197.6100.698.8 1.632.172.152.091.732.182.623.884.404.6598.8103.297.799.9 2.94nd1)1.011.050.980.981.101.0297.0104.8104.1102.0 4.250.880.900.910.700.871.081.561.752.0197.197.7101.898.9 2.660.640.620.610.450.610.751.081.211.3397.796.796.096.8 0.97tr2)1.021.101.081.031.111.07100.9102.799.1100.9 1.81): not detected; 2): trace.a Recovery (%) = (Amount found –Original amount)/ Amount spiked ×100%, RSD (%) = (SD/Mean) ×100%Table 4 Contents of seven saponins in Lonicera spp.Content (mg/g)1 2 3 4 5 6 7 L. confusa45.65±0.32 5.13±0.08 4.45±0.11tr1) 2.04±0.04tr 1.81±0.03 L. japonica nd2)nd 3.44±0.09nd nd nd nd L. macranthoides46.22±0.06 5.31±0.13 4.28±0.10 tr 1.79±0.03 1.25±0.03 tr L. hypoglauca11.17±0.07 nq3)53.78±1.18nd 1.72±0.02 2.23±0.06 2.52±0.04 L. similes41.22±0.25 4.57±0.07 3.79±0.09nd 1.75±0.02tr nd 1): trace; 2): not detected.. 3) not quantified owing to the suspicious purity of the peak.。

Teece(蒂斯)——动态能力与战略管理中译版

Teece动态能力与战略管理*大卫·蒂斯加里·皮萨诺Amy Shuen【作者简介】大卫·蒂斯（David J. Teece）, 坎特伯雷大学文学学士，宾夕法尼亚大学文学硕士，宾夕法尼亚大学经济学博士。

现为加利福尼亚大学伯克利分校Haas商学院Thomas W. Tusher 全球商务讲座教授，管理、创新与组织研究所所长。

·蒂斯教授的主要研究领域包括：公司战略与公共政策，技术创新，知识管理与知识产权，规制与反托拉斯经济学以及电信、计算机与能源问题等。

·蒂斯教授累计出版和发表的论文与著作超过200篇（部），根据Science Watch杂志的统计，他位列1995到2005十年中经济学和管理学领域文章引用率最高的前十位学者。

他还是Industrial and Corporate Change杂志的编辑与创立者之一。

加里·皮萨诺（Gary Pisano），耶鲁大学文学学士，加利福尼亚大学伯克利分校博士。

现为哈佛大学商学院Harry E. Figgie, Jr.工商管理讲座教授，技术与运作管理系系主任。

皮萨诺教授的研究兴趣主要为生物技术与制药产业的技术战略，产品与过程开发管理，组织学习，垂直整合与外包战略等问题。

皮萨诺教授在国际一流期刊中发表了超过25篇学术论文，已出版的著作有：《研发工厂》，《运作、战略与技术》和《科技企业：生物技术的前景，现实与未来》。

Amy Shuen，耶鲁大学理学学士，哈佛大学MBA，加利福尼亚大学伯克利分校博士。

现为Silicon Valley Strategy Group总裁和CEO。

在此之前，她曾任教于宾夕法尼亚大学沃顿商学院和加利福尼亚大学伯克利分校Haas商学院。

【摘要】动态能力框架分析了在高速技术变迁环境中，企业获取财富和创造财富的根源与方法。

本文认为，这些企业的竞争优势由一些独特的过程（协调和组织方式）所确定。

原发性醛固酮增多症(中英文

Patient no. AVS
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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 3 1045-1050
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37 (6.1) 17 (8.5) 257 (6.6)
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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 3 1045-1050

药明奥测

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2020年10月9日，药明奥测宣布与赛默飞世尔科技（以下简称“赛默飞”）和 Mayo Clinic合作开发的新型冠状病毒抗体检测试剂盒 —— Thermo Scientific OmniPath COVID-19 Total Antibody ELISA，获得美国食品药品监督管理局(FDA)紧急使用授权(EUA)，并于赛默飞的美国和欧洲工厂投入生产。
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上海总部、研发中心、专业检测机构
药明奥测作为苏州市企业技术中心、苏州市企业工程技术研究中心，苏州工业园区上市苗圃企业，总部位于上海，研发人员占比过半。旗下上海药明傲喆医学检验所（以下简称“医检所”）是专业从事临床检验服务的医疗机构，具有医学检验实验室临床体液、血液专业，临床微生物学专业，临床化学检验专业，临床免疫、血清学专业，临床细胞分子遗传学专业及病理科“5+1”学科及平台建设执业资质。医检所面积约3000平米，配备全球先进的诊断设备，引进和转化Mayo Clinic临床检测项目，结合临床特检自主开发能力，打造创新型体外诊断服务赋能平台。医检所应用与国际接轨的自动化信息系统，建立国际标准的质量管理体系，现已获得美国病理学家协会(CAP)实验室认可，相关实验室技术能力和质量管理体系已达到世界先进水准，出具的检验报告符合国际质量标准。
苏州产业化基地
苏州药明泽康生物科技有限公司（简称药明泽康）总面积约 8,000m²，主要从事医疗器械和临床诊断试剂产品的研发、注册、生产和销售以及临床诊断医学技术的开发、转让、咨询及服务。公司拥有资历深厚的研发团队，专业的产品临床实验和注册团队，按照ISO建立生产质量管理体系。目前在质谱、病理和分子等多个技术平台上开发诊断产品，并已有200+ 体外诊断试剂获得药监局批准，助力客户为患者提供精准诊断服务。

国外实验室试剂知名品牌

国外实验室试剂知名品牌转载：huahaixindian 来源：点击数：337 更新时间：2021年07月31日--------------------------------------------------------------------------------一些国外生物技术公司的简介QIAGEN：德国著名的试剂公司，该公司的核酸别离纯化系列基于多项专利技术，纯度高，产量高，快速方便，品种齐全，为世界知名品牌。

其大多数产品以即用型试剂盒形式提供，随产品有非常详细的操作技术手册。

此外，还提供优质的传染系统，RT/PCR反响系统〔包括高特异性的逆转录酶及热启动的Taq酶〕，蛋白及多肽表达、纯化、检测分析系统。

Ambion：该公司始终致力于开发RNA相关产品，在RNA的别离纯化、RACE、RT-PCR方面有许多非常有特色的产品，并提供优质的Northern杂交体系，和高效的体外翻译体系。

如今，其产品在RNA研究领域已经成为研究人员的首选品牌。

Invitrogen：该公司成功地提供了PCR产物快速克隆试剂盒，及与之配套的系列产品，包括高效转染和转化试剂、高效感受态细胞、全面的原核及真核基因表达系统、酵母双杂交系统等多种特色产品。

大大便利了分子克隆的全过程操作。

其成功并购了Gibco/BRL，Novex，Research Genetics等知名公司，产品覆盖更为广泛。

Clontech：现已成为B.D.公司旗下分子生物学主力舰。

该公司的cDNA试剂盒、荧光蛋白报告基因系统、酵母双杂交系统、基因Array产品是独具特色的产品，其中一些试剂盒〔GFP、Tet Off &On等〕获得过屡次大奖。

Clontech公司聚集了一大批优秀的科学家，在分子研究的各个领域开发出了许多设计思路独特，快捷便利的试剂产品，紧跟科学前沿。

Strategene：该公司的特色产品包括：预制基因文库、定制文库、文库构建产品、感受态细胞、高效转染试剂、点突变试剂盒、PCR仪及多种专利产品，在分子生物学研究的多个方面有非凡表现，受到全球实验室的好评，成为迅速崛起的佼佼者。

REVIEW AND ANALYSIS OF REPORTS ON CONTROLLED CLINICAL

A CUPUNCTURE: R EVIEW AND A NALYSIS OF R EPORTS ON C ONTROLLED C LINICAL T RIALSiiAcknowledgementsAcknowledgements The World Health Organization acknowledges its indebtedness to the experts who participated in the WHO Consultation on Acupuncture held in Cervia, Italy in 1996, at which the selection criteria for the data included in this publication were set. Special thanks are due to Dr Zhu-Fan Xie, Honorary Director of the Institute of Integrated Medicines, First Hospital of Beijing Medical University, China, who drafted, revised and updated this report. Further, Dr Xie made numerous Chinese language documents available in English. We also thank Dr Hongguang Dong, Geneva University Hospital, Switzerland for providing additional information.Appreciation is extended to the Norwegian Royal Ministry of Health and Social Affairs for providing the financial support to print this review.iiiivContentsContentsAcknowledgements (iii)Contents (v)Introduction (1)Background (1)Objectives (2)Use of the publication (2)1. General considerations (3)1.1 Definition (3)1.2 Need for evaluation (3)1.3 Evaluation methodology (3)1.4 Safety (5)1.5 Availability and practicability (5)1.6 Studies on therapeutic mechanisms (6)1.7 Selection of clinical trial reports (7)2. Review of clinical trial reports (9)2.1 Pain (9)Head and face (9)Locomotor system (9)Gout (10)Biliary and renal colic (10)Traumatic or postoperative pain (11)Dentistry (11)Childbirth (11)Surgery (11)2.2 Infections (12)2.3 Neurological disorders (12)2.4 Respiratory disorders (14)2.5 Digestive disorders (14)2.6 Blood disorders (15)2.7 Urogenital disorders (15)2.8 Gynaecological and obstetric disorders (16)v2.9 Cardiovascular disorders (17)2.10 Psychiatric disorders and mental disturbances (18)2.11 Paediatric disorders (19)2.12 Disorders of the sense organs (19)2.13 Skin diseases (20)2.14 Cancers (20)2.15 Other reports (21)3. Diseases and disorders that can be treated with acupuncture (23)4. Summary table of controlled clinical trials (27)References (67)viIntroductionIntroductionBackgroundOver its 2500 years of development, a wealth of experience has accumulated inthe practice of acupuncture, attesting to the wide range of diseases andconditions that can be effectively treated with this approach. Unlike many othertraditional methods of treatment, which tend to be specific to their national orcultural context, acupuncture has been used throughout the world, particularlysince the 1970s. In recognition of the increasing worldwide interest in the subject,the World Health Organization (WHO) conducted a symposium on acupuncturein June 1979 in Beijing, China. Physicians practising acupuncture in differentcountries were invited to identify the conditions that might benefit from thistherapy. The participants drew up a list of 43 suitable diseases. However, this listof indications was not based on formal clinical trials conducted in a rigorousscientific manner, and its credibility has been questioned.The past two decades have seen extensive studies on acupuncture, and greatefforts have been made to conduct controlled clinical trials that include the use of“sham” acupuncture or “placebo” acupuncture controls. Although still limited innumber because of the difficulties of carrying out such trials, convincing reports,based on sound research methodology, have been published. In addition,experimental investigations on the mechanism of acupuncture have been carriedout. This research, while aimed chiefly at answering how acupuncture works,may also provide evidence in support of its effectiveness.In 1991, a progress report on traditional medicine and modern health care wassubmitted by the Director-General of WHO to the Forty-fourth World HealthAssembly.1The report pointed out that in countries where acupuncture formspart of the cultural heritage, its use in an integrated approach to modern andtraditional medicine presents no difficulty. However, in countries where modernWestern medicine is the foundation of health care, the ethical use of acupuncturerequires objective evidence of its efficacy under controlled clinical conditions.In 1996, a draft report on the clinical practice of acupuncture was reviewed at theWHO Consultation on Acupuncture held in Cervia, Italy. The participantsrecommended that WHO should revise the report, focusing on data fromcontrolled clinical trials. This publication is the outcome of that process.1Traditional medicine and modern health care. Progress report by the Director-General. Geneva,World Health Organization, 1991 (unpublished document A44/10).1Acupuncture: review and analysis of controlled clinical trials ObjectivesThe objective of this publication is to provide a review and analysis of controlledclinical trials of acupuncture therapy, as reported in the current literature, with aview to strengthening and promoting the appropriate use of acupuncture inhealth care systems throughout the world. Information on the therapeuticmechanisms of acupuncture has also been incorporated.Since the methodology of clinical research on acupuncture is still under debate, itis very difficult to evaluate acupuncture practice by any generally acceptedmeasure. This review is limited to controlled clinical trials that were publishedup to 1998 (and early 1999 for some journals), in the hope that the conclusionswill prove more acceptable. Such trials have only been performed for a limitednumber of diseases or disorders. This should not be taken to mean, however, thatacupuncture treatment of diseases or disorders not mentioned here is excluded. Use of the publicationThis publication is intended to facilitate research on and the evaluation andapplication of acupuncture. It is hoped that it will provide a useful resource forresearchers, health care providers, national health authorities and the generalpublic.It must be emphasized that the list of diseases, symptoms or conditions coveredhere is based on collected reports of clinical trials, using the descriptions given inthose reports. Only national health authorities can determine the diseases,symptoms and conditions for which acupuncture treatment can be recommended.The data in the reports analysed were not always clearly recorded. We havemade every effort to interpret them accurately, in some cases maintaining theoriginal wording in the text and summary table presented here. Research ontraditional medicine, including acupuncture is by no means easy. However,researchers should be encouraged to ensure the highest possible standards ofstudy design and reporting in future research in order to improve the evidencebase in this field.Dr Xiaorui ZhangActing CoordinatorTraditional Medicine (TRM)Department of Essential Drugsand Medicines Policy (EDM)World Health Organization 21. General considerations1. General considerations1.1 DefinitionAcupuncture literally means to puncture with a needle. However, the application of needles is often used in combination with moxibustion—the burning on or over the skin of selected herbs—and may also involve the application of other kinds of stimulation to certain points. In this publication the term “acupuncture” is used in its broad sense to include traditional body needling, moxibustion, electric acupuncture (electro-acupuncture), laser acupuncture (photo-acupuncture), microsystem acupuncture such as ear (auricular), face, hand and scalp acupuncture, and acupressure (the application of pressure at selected sites).1.2 Need for evaluationAcupuncture originated in China many centuries ago and soon spread to Japan, the Korean peninsula and elsewhere in Asia. Acupuncture is widely used in health care systems in the countries of this region; it is officially recognized by governments and well received by the general public.Although acupuncture was introduced to Europe as long ago as the early seventeenth century, scepticism about its effectiveness continues to exist in countries where modern Western medicine is the foundation of health care, especially in those where acupuncture has not yet been widely practised. People question whether acupuncture has a true therapeutic effect, or whether it works merely through the placebo effect, the power of suggestion, or the enthusiasm with which patients wish for a cure. There is therefore a need for scientific studies that evaluate the effectiveness of acupuncture under controlled clinical conditions.This publication reviews selected studies on controlled clinical trials. Some of these studies have provided incontrovertible scientific evidence that acupuncture is more successful than placebo treatments in certain conditions. For example, the proportion of chronic pain relieved by acupuncture is generally in the range 55–85%, which compares favourably with that of potent drugs (morphine helps in 70% of cases) and far outweighs the placebo effect (30–35%) (1–3). In addition, the mechanisms of acupuncture analgesia have been studied extensively since the late 1970s, revealing the role of neural and humoral factors.1.3 Evaluation methodologyUnlike the evaluation of a new drug, controlled clinical trials of acupuncture are extremely difficult to conduct, particularly if they have to be blind in design and the acupuncture has to be compared with a placebo. Various “sham” or “placebo” acupuncture procedures have been designed, but they are not easy to3Acupuncture: review and analysis of controlled clinical trials perform in countries such as China where acupuncture is widely used. In these countries, most patients know a great deal about acupuncture, including the special sensation that should be felt after insertion or during manipulation of the needle. Moreover, acupuncturists consider these procedures unethical because they are already convinced that acupuncture is effective. In fact, most of the placebo-controlled clinical trials have been undertaken in countries where there is scepticism about acupuncture, as well as considerable interest.A more practical way to evaluate the therapeutic effect of acupuncture is tocompare it with the effect of conventional therapy through randomized controlled trials or group studies, provided that the disease conditions before treatment are comparable across the groups, with outcome studies developed for all patients.Because of the difficulty of ruling out the placebo effect, a comparative study with no treatment as the control may not be convincing in the evaluation of acupuncture practice. Retrospective surveys, in which the effect of acupuncture therapy is compared with past treatments, may not be of significance either, particularly if they have not been well designed. Non-comparative studies are certainly of little significance, particularly when acupuncture is used for the treatment of a self-limited disease. However, if rapid improvement can be achieved in the treatment of a long-standing, chronic disease, or if there is definite improvement in a disease that is generally recognized as intractable to conventional treatment, the effect of acupuncture should be viewed in a more favourable light, even when a well-designed, controlled study has not been carried out.Another difficulty in evaluating acupuncture practice is that the therapeutic effect depends greatly on the proficiency of the acupuncturists—their ability and skill in selecting and locating the acupuncture points and in manipulating the needles. This may partly explain the disparities or inconsistencies in the results reported by different authors, even when their studies were carried out on equally sound methodological bases.Evaluating acupuncture practice and arriving at generally accepted conclusions is no easy task, therefore. While effectiveness is doubtless of the utmost importance, other factors, including safety, cost, availability and the condition of local health services must also be considered. Given the same effectiveness, these other factors may lead to different evaluations of acupuncture in different countries and areas. However, conclusions are needed that apply to worldwide use, particularly for countries and areas where proper development of acupuncture practice would bring a great deal of benefit. Evaluations should not therefore be confined to those diseases for which modern conventional treatments are inadequate or ineffective.Because of the success of surgical procedures carried out under acupuncture analgesia, the treatment of pain with acupuncture has been extensively studied.For other conditions often treated with acupuncture, there are fewer reports that have adequate methodology.41. General considerations 1.4 SafetyGenerally speaking, acupuncture treatment is safe if it is performed properly by a well-trained practitioner. Unlike many drugs, it is non-toxic, and adverse reactions are minimal. This is probably one of the chief reasons why acupuncture is so popular in the treatment of chronic pain in many countries. As mentioned previously, acupuncture is comparable with morphine preparations in its effectiveness against chronic pain, but without the adverse effects of morphine, such as dependency.Even if the effect of acupuncture therapy is less potent than that of conventional treatments, acupuncture may still be worth considering because of the toxicity or adverse effects of conventional treatments. For example, there are reports of controlled clinical trials showing that acupuncture is effective in the treatment of rheumatoid arthritis (4–6), although not as potent as corticosteroids. Because, unlike corticosteroids, acupuncture treatment, does not cause serious side-effects, it seems reasonable to use acupuncture for treating this condition, despite the difference in effectiveness.1.5 Availability and practicabilityThe availability and practicability of acupuncture are also important factors to consider. The advantages of acupuncture are that it is simple, convenient and has few contraindications. Although the success rate of acupuncture therapy in treating kidney stones, for example, is confirmed by comparative studies with other therapies (7), it is by no means as high as that of surgical intervention. However, acupuncture treatment of kidney stones is still worth recommending because of its simplicity, which makes it more acceptable to patients.There are also instances where acupuncture is not more practicable than conventional therapy. For example, the effectiveness of acupuncture treatment of acute bacillary dysentery has been shown to be comparable with that of furazolidone (8–10), but this is of rather academic significance because oral administration of furazolidone or other antidysenteric drugs is more convenient. The conditions of the health service in a given country or area should also be considered in evaluating acupuncture practice. In developing countries, where medical personnel and medicines are still lacking, the need for acupuncture may be considerable and urgent; proper use of this simple and economic therapy could benefit a large number of patients. On the other hand, in developed countries, where the health system is well established, with sophisticated technology, adequate personnel and a well-equipped infrastructure, acupuncture might be considered to be of great value in only a limited number of conditions. It could still serve as a valuable alternative treatment for many diseases or conditions for which modern conventional treatments are unsuccessful. It is also valuable in situations where the patient is frightened of the potential risks or adverse effects of modern conventional treatments. In fact, in some developed countries, the diseases for which patients seek help from acupuncturists tend to be beyond the scope of orthodox medicine.Acupuncture: review and analysis of controlled clinical trials 1.6 Studies on therapeutic mechanismsClinical evaluations indicate whether the therapy works; research on the mechanisms involved indicates how it works and can also provide important information on efficacy. Knowing that acupuncture is effective and why makes the practitioner confident in its use, and also allows the technique to be used in a more appropriate way.The clinical evaluation may precede studies on the mechanisms, or vice versa. For acupuncture, in most instances the clinical effect has been tested first. Use of the technique may then be further expanded on the basis of the results of research on the mechanisms. For example, experimental studies of the effect of acupuncture on white blood cells led to a successful trial of the treatment of leukopenia caused by chemotherapy.To date, modern scientific research studies have revealed the following actions of acupuncture:• inducing analgesia• protecting the body against infections• regulating various physiological functions.In reality, the first two actions can also be attributed to the regulation of physiological functions. The therapeutic effects of acupuncture are thus brought about through its regulatory actions on various systems, so that it can be regarded as a nonspecific therapy with a broad spectrum of indications, particularly helpful in functional disorders. Although it is often used as a symptomatic treatment (for pain, for instance), in many cases it actually acts on one of the pathogenic links of a disease.Although different acupuncture points and manipulations may have an effect through different actions, the most important factor that influences the direction of action is the condition of the patient. Numerous examples reveal that the regulatory action of acupuncture is bi-directional. Acupuncture lowers the blood pressure in patients with hypertension and elevates it in patients with hypotension; increases gastric secretion in patients with hypoacidity, and decreases it in patients with hyperacidity; and normalizes intestinal motility under X-ray observation in patients with either spastic colitis or intestinal hypotonia (11). Therefore, acupuncture itself seldom makes the condition worse. In most instances, the main danger of its inappropriate application is neglecting the proper conventional treatment.Since its therapeutic actions are achieved by mobilization of the organism’s own potential, acupuncture does not produce adverse effects, as do many drug therapies. For example, when release of hydrocortisone plays an important role in the production of a therapeutic effect, the doses of this substance released by acupuncture are small and finely regulated, thereby avoiding the side-effects of hydrocortisone chemotherapy (12). On the other hand—and for the same reason—acupuncture has limitations. Even under conditions where acupuncture is indicated, it may not work if the mobilization of the individual’s potential is not adequate for recovery.1. General considerations 1.7 Selection of clinical trial reportsIn recent decades, numerous clinical trials have been reported; however, only formally published articles that meet one of the following criteria are included in this review:• randomized controlled trials (mostly with sham acupuncture or conventional therapy as control) with an adequate number of patients observed;• nonrandomized controlled clinical trials (mostly group comparisons) with an adequate number of patients observed and comparable conditions in the various groups prior to treatment.In many published placebo-controlled trials, sham acupuncture was carried out by needling at incorrect, theoretically irrelevant sites. Such a control really only offers information about the most effective sites of needling, not about the specific effects of acupuncture (13). Positive results from such trials, which revealed that genuine acupuncture is superior to sham acupuncture with statistical significance, provide evidence showing the effectiveness of acupuncture treatment. On the other hand, negative results from such trials, in which both the genuine and sham acupuncture showed considerable therapeutic effects with no significant difference between them, can hardly be taken as evidence negating the effectiveness of acupuncture. In the latter case, especially in treatment of pain, most authors could only draw the conclusion that additional control studies were needed. Therefore, these reports are generally not included in this review.The reports are first reviewed by groups of conditions for which acupuncture therapy is given (section 2). The clinical conditions covered have then been classified into four categories (section 3):1. Diseases, symptoms or conditions for which acupuncture has beenproved—through controlled trials—to be an effective treatment.2. Diseases, symptoms or conditions for which the therapeutic effect ofacupuncture has been shown, but for which further proof is needed.3. Diseases, symptoms or conditions for which there are only individualcontrolled trials reporting some therapeutic effects, but for which acupuncture is worth trying because treatment by conventional and othertherapies is difficult.4. Diseases, symptoms or conditions in which acupuncture may be triedprovided the practitioner has special modern medical knowledge andadequate monitoring equipment.Section 4 provides a tabulated summary of the controlled clinical trials reviewed, giving information on the number of subjects, the study design, the type of acupuncture applied, the controls used and the results obtained.Acupuncture: review and analysis of controlled clinical trials2. Review of clinical trial reports2. Review of clinical trial reports 2.1 PainThe effectiveness of acupuncture analgesia has already been established in controlled clinical studies. As mentioned previously, acupuncture analgesia works better than a placebo for most kinds of pain, and its effective rate in the treatment of chronic pain is comparable with that of morphine. In addition, numerous laboratory studies have provided further evidence of the efficacy of acupuncture’s analgesic action as well as an explanation of the mechanism involved. In fact, the excellent analgesic effects of acupuncture have stimulated research on pain.Because of the side-effects of long-term drug therapy for pain and the risks of dependence, acupuncture analgesia can be regarded as the method of choice for treating many chronically painful conditions.The analgesic effect of acupuncture has also been reported for the relief of eye pain due to subconjunctival injection (14), local pain after extubation in children (15),and pain in thromboangiitis obliterans (16).2.1.1 Head and faceThe use of acupuncture for treating chronic pain of the head and face has been studied extensively. For tension headache, migraine and other kinds of headache due to a variety of causes, acupuncture has performed favourably in trials comparing it with standard therapy, sham acupuncture, or mock transcutaneous electrical nerve stimulation (TENS) (17–27). The results suggest that acupuncture could play a significant role in treating such conditions.Chronic facial pain, including craniomandibular disorders of muscular origin, also responds well to acupuncture treatments (28–31). The effect of acupuncture is comparable with that of stomatognathic treatments for temporomandibular joint pain and dysfunction. Acupuncture may be useful as complementary therapy for this condition, as the two treatments probably have a different basis of action (2, 32).2.1.2 Locomotor systemChronically painful conditions of the locomotor system accompanied by restricted movements of the joints are often treated with acupuncture if surgical intervention is not necessary. Acupuncture not only alleviates pain, it also reduces muscle spasm, thereby increasing mobility. Joint damage often results from muscle malfunction, and many patients complain of arthralgia before anyAcupuncture: review and analysis of controlled clinical trials changes are demonstrable by X-ray. In these cases, acupuncture may bring about a permanent cure. Controlled studies on common diseases and conditions in this category have been reported by different authors, with favourable results for acupuncture treatments compared with standard therapy, delayed-treatment controls, control needling, mock TENS, or other sham acupuncture techniques. The conditions concerned include cervical spondylitis or neck pain due to other causes (33–37), periarthritis of the shoulder (38, 39) fibromyalgia (40), fasciitis (41), epicondylitis (tennis elbow) (42–44), low back pain (45–49), sciatica (50–53), osteoarthritis with knee pain (54–56), and radicular and pseudoradicular pain syndromes (57). In some reports, comparison was made between standard care and acupuncture as an adjunct to standard care. The conclusion from one such randomized controlled trial was that acupuncture is an effective and judicious adjunct to conventional care for patients with osteoarthritis of the knee (58). Rheumatoid arthritis is a systemic disease with extra-articular manifestations in most patients. In this disease, dysfunction of the immune system plays a major role, which explains the extra-articular and articular features. Acupuncture is beneficial in the treatment of rheumatoid arthritis (4–6). While acupuncture may not improve the damage that has been done to the joints, successful pain relief has been verified in the majority of controlled studies (58). The action of acupuncture on inflammation and the dysfunctional immune system is also beneficial (5, 59).2.1.3 GoutIn a randomized controlled trial, blood-pricking acupuncture was compared with conventional medication (allopurinol). The acupuncture group showed greater improvement than the allopurinol group. In addition, a similar reduction of uric acid levels in the blood and urine of both groups was noted (60). Plum-blossom needling (acupuncture using plum-blossom needles), together with cupping (the application to the skin of cups which are then depressurized), has been recommended for treating gouty arthritis (61).2.1.4 Biliary and renal colicAcupuncture is suitable for treating acute pain, provided the relief of pain will not mask the correct diagnosis, for which other treatments may be needed. Biliary and renal colic are two conditions for which acupuncture can be used not only as an analgesic but also as an antispasmodic. In controlled studies on biliary colic (62–64) and renal colic (7, 65, 66), acupuncture appears to have advantages over conventional drug treatments (such as intramuscular injection of atropine, pethidine, anisodamine (a Chinese medicine structurally related to atropine, isolated from Anisodus tanguticus), bucinnazine (also known as bucinperazine) or a metamizole–camylofin combination). It provides a better analgesic effect in a shorter time, without side-effects. In addition, acupuncture is effective for relieving abdominal colic, whether it occurs in acute gastroenteritis or is due to gastrointestinal spasm (67).2. Review of clinical trial reports2.1.5 Traumatic or postoperative painFor traumas such as sprains, acupuncture is not only useful for relieving pain without the risk of drug dependence, but may also hasten recovery by improving local circulation (68–70). Acupuncture analgesia to relieve postoperative pain is well recognized and has been confirmed in controlled studies (71–76). The first successful operation under acupuncture analgesia was a tonsillectomy. This was, in fact, inspired by the success of acupuncture in relieving post-tonsillectomy pain. Post-tonsillectomy acupuncture was re-evaluated in a controlled study in 1990, which not only showed prompt alleviation of throat pain, but also reduction in salivation and promotion of healing in the operative wound (76). 2.1.6 DentistryAcupuncture has been widely used in dentistry. There are reports of randomized controlled trials on the analgesic effect of acupuncture for postoperative pain from various dental procedures, including tooth extraction (77–78), pulp devitalization (79), and acute apical periodontitis (80). According to a systematic review of papers on the use of acupuncture in dentistry published between 1966 and 1996, 11 out of 15 randomized controlled studies with blind controls, appropriate statistics and sufficient follow-up showed standard acupuncture to be more effective than a placebo or sham acupuncture. It was therefore concluded that acupuncture should be considered a reasonable alternative or supplement to current dental practice as an analgesic (81). Its use in the treatment of temporomandibular dysfunction was also supported in these studies.2.1.7 ChildbirthIn childbirth, acupuncture analgesia is useful for relieving labour pain and can significantly reduce the duration of labour (82).In the case of weakened uterine contractions, acupuncture increases the activity of the uterus. Episiotomy and subsequent suturing of the perineum can also be carried out with acupuncture analgesia. In addition, the avoidance of narcotics is advantageous for newborn infants.2.1.8 SurgeryAcupuncture analgesia has the following advantages in surgical operations. It is a very safe procedure compared with drug anaesthesia; no death has ever been reported from acupuncture analgesia. There is no adverse effect on physiological functions, whereas general anaesthesia often interferes with respiration and blood pressure, for example. There are fewer of the postoperative complications that sometimes occur after general anaesthesia, such as nausea, urinary retention, constipation, and respiratory infections. The patient remains conscious and able to talk with the medical team during the operation so that injury of the facial and recurrent laryngeal nerve can be avoided. However, remaining conscious may be a disadvantage if the patient cannot tolerate the emotional stress of the procedure.。

外企和部分合资制药企业简介

小木虫(金币+1):奖励一下，鼓励发有价值的话题huqiu1953(金币+3):谢谢您的分享~不错的资源，欢迎常来药学专区参与交流~让我们共同进步~ 2010-05-23 13:00:40部分外企介绍：1。

辉瑞（Pfizer Pharmaceuticals Ltd ）——新辉瑞是由老辉瑞公司和法玛西亚普强（也有译为法玛克普强）公司携手创立的一家拥有空前规模、广泛的产品治疗领域和产品系列的全球药业巨擘。

新辉瑞公司包括三个业务领域：医药保健、动物保健、以及消费者保健品。

大家熟知的著名产品枸橼酸西地那非就是常能提起的伟哥（中文商品名：万艾可），干什么用的大家心里明白，我就不说了。

2。

默克（Merck）——确切的说公司的名称应该是MSD,即大家熟知的默沙东（Merck sharp&Dohme），大名鼎鼎的“万络”就是这个公司的产品。

另外德国也有一家叫默克的医药企业德文名称Merck KGaA,建立于1647年，主要生产化工产品，医药产品也有一些。

从年龄上推算一下也知道德国的默克是MSD 的老祖宗。

3。

葛兰素史克（Glaox smithkline）——是一家以研究为中心的公司。

是老牌的制药业巨头Glaox与史克比切姆公司合并而成。

4。

强生（Johnson&Johnson）——一家世界上最大的，最具综合性的医疗保健产品的生产集团，它为消费品、制药业及专业用品市场提供服务。

他的儿子大家肯定特别熟悉，就是杨森。

5。

诺华（Novartis Pharma Ltd）——瑞士的跨国医药集团。

该公司目前在华分别在北京、上海等地建有四家企业。

诺华也是世界上最大的医用营养品提供商之一。

6。

阿斯利康（AstraZeneca Pharmaceutical Co Ltd）——英国的阿斯利康是由阿斯特拉和捷利康合并形成的世界第三大制药公司。

凭借强大的研发后盾，致力于研制、开发、生产和营销优越的产品，在心血管、消化、麻醉、肿瘤、呼吸五大领域处于世界领先地位。

孟鲁司特钠联合西替利嗪、特布他林雾化吸入治疗儿童社区获得性肺炎的效果

- 130 -①中宁县人民医院　宁夏　中宁　755100②宁夏回族自治区中医医院暨中医研究院孟鲁司特钠联合西替利嗪、特布他林雾化吸入治疗儿童社区获得性肺炎的效果田占国①　孙旭①　潘朝云②【摘要】　目的：探究孟鲁司特钠联合西替利嗪、特布他林雾化吸入治疗儿童社区获得性肺炎的效果。

方法：选取2021年1月—2022年1月宁夏回族自治区中宁县人民医院收治的102例社区获得性肺炎患儿作为研究对象。

根据电脑随机数法将其分为联合组和常规组，各51例。

常规组给予西替利嗪、特布他林雾化吸入治疗，联合组在常规组基础上给予孟鲁司特钠治疗。

比较两组临床疗效、时间指标及不良反应。

结果：联合组临床疗效优于常规组，总有效率高于常规组，差异有统计学意义（P <0.05）。

联合组喘息改善时间、咳嗽改善时间及肺部啰音改善时间均早于常规组，差异有统计学意义（P <0.05）。

两组不良反应发生率比较，差异无统计学意义（χ2=0.793，P =0.373）。

结论：孟鲁司特钠联合西替利嗪、特布他林雾化吸入治疗儿童社区获得性肺炎，可有效提高治疗效果，缩短临床症状恢复时间，安全性良好。

【关键词】　孟鲁司特钠　西替利嗪　特布他林　儿童社区获得性肺炎 doi：10.14033/ki.cfmr.2023.33.032 文献标识码　B 文章编号　1674-6805（2023）33-0130-04 Efficacy of Montelukast Sodium Combined with Cetirizine and Terbutaline Atomization Inhalation in the Treatment of Community-acquired Pneumonia in Children/TIAN Zhanguo, SUN Xu, PAN Chaoyun. //Chinese and Foreign Medical Research, 2023, 21(33): 130-133 [Abstract]　Objective: To explore the efficacy of Montelukast Sodium combined with Cetirizine and Terbutaline atomization inhalation in the treatment of community-acquired pneumonia in children. Method: A total of 102 children with community-acquired pneumonia treated in People's Hospital of Zhongning County from January 2021 to January 2022 were selected as the study objects. According to computer random number method, they were divided into combined group and conventional group, 51 cases in each group. The conventional group was given Cetirizine and Terbutaline atomization inhalation treatment, and the combined group was given Montelukast Sodium treatment on the basis of the conventional group. The clinical efficacy, time indexes and adverse reactions were compared between the two groups. Result: The clinical effect of combined group was better than that of conventional group, and the total effective rate was higher than that of conventional group, the differences were statistically significant (P <0.05). The improvement time of wheezing, cough and pulmonary rales in combined group were earlier than those in conventional group, and the differences were statistically significant (P <0.05). There was no significant difference in the incidence of adverse reactions between the two groups (χ2=0.793, P =0.373). Conclusion: Montelukast Sodium combined with Cetirizine and Terbutaline atomization inhalation in the treatment of children with community-acquired pneumonia can effectively improve the therapeutic effect, shorten the recovery time of clinical symptoms, and have good safety. [Key words]　Montelukast Sodium　Cetirizine　Terbutaline　Children with community-acquired pneumonia First-author's address: People's Hospital of Zhongning County, Zhongning 755100, China 儿童社区获得性肺炎的主要症状包括胸闷、气短及呼吸困难等。

尼可地尔注射液药品说明书(英文)

Revised: March 2010 (10th version)- DRUG FOR TREATMENT OF UNSTABLE ANGINA PECTORIS AND ACUTE HEART FAILURE -SIGMART®Injection 2 mgSIGMART®Injection 12 mgSIGMART®Injection 48 mgINDICATIONSUnstable angina pectorisAcute heart failure (including acute decompensation of chronic heart failure)DOSAGE AND ADMINISTRATIONUnstable angina pectorisSIGMART is dissolved in isotonic sodium chloride solution or 5% glucose injection to prepare a 0.01%-0.03% solution. The usual adult dosage for intravenous drip infusion is 2 mg of nicorandil per hour. The dosage may be adjusted according to symptoms, while not exceeding 6 mg per hour. Acute heart failure (including acute decompensation of chronic heart failure)SIGMART is dissolved in isotonic sodium chloride solution or 5% glucose injection to prepare a 0.04%-0.25% solution. The usual adult dosage is 0.2 mg/kg of nicorandil to be given by intravenous administration over about 5 minutes, followed by 0.2 mg/kg/hr of nicorandil to be given by continuous intravenous infusion. The dosage may be adjusted in the range of 0.05-0.2 mg/kg/hr according to changes in blood pressure and symptoms.PRECAUTIONS1. Careful Administration (SIGMART Injection should beadministered with care in the following patients.)(1) Elderly (see 4, "Use in the Elderly".)(2) Patients with hypotension (Since SIGMART lowersblood pressure, this symptom may be exacerbated.)(3) Patients with hepatic or renal dysfunction (Sincemetabolic and excretory functions are impaired, theblood concentration of SIGMART may become high).(4) Patients with left ventricular outflow stenosis,hypertrophic obstructive cardiomyopathy, or aorticstenosis due to acute heart failure (Difference inpressure may be increased and lead to aggravation ofsymptoms.)2. Important Precautions(1) While SIGMART is being administered, blood pressureand hemodynamics should be monitored frequently.Dosage should be adjusted gradually according topatient's hemodynamics and symptoms.(2) When abnormalities such as hypotension are observedwhile SIGMART is being administered or whenpatients may suffer from hypotension, dosage should bereduced or administration discontinued. If necessary,appropriate measures such as elevation of lowerextremities or administration of vasopressors(catecholamine preparations) should be taken.(3) Since coadministration with drugs withPDE5-inhibiting effect(sildenafil citrate, vardenafilhydrochloride hydrate, or tadalafil) may enhance thehypotensive effect of SIGMART and excessivelydecrease blood pressure, confirmation should be madebefore administering SIGMART that these drugs arenot being used. Moreover, the patient should becautioned against using these drugs during or aftertaking SIGMART.(4) When used in patients with acute heart failure,SIGMART should be administered with sufficientmanagement of the patient’s general conditionincluding blood pressure, heart rate, urinary output,body fluids and electrolytes, as well as pulmonaryarterial wedge pressure, cardiac output and blood gasesif possible.(5) When used in patients with acute heart failure,SIGMART may cause a serious decrease in bloodpressure. Therefore, blood pressure should befrequently measured during treatment with SIGMART.If any abnormality is observed, treatment should bediscontinued and appropriate measures taken.(6) If expected improvement is not achieved followingtreatment with SIGMART in patients with acute heartfailure, appropriate measures such as change oftreatment to another should be taken.(7) In patients with acute heart failure, if hemodynamicsand clinical symptoms improve and the patient’scondition becomes stabilized (recover from the acutestage) following treatment with SIGMART, treatmentshould be switched to another. SIGMART has rarelybeen used for more than 48 hours in patients with acuteheart failure. Therefore, if it is necessary to useSIGMART for more than 48 hours, the drug should beadministered with sufficient management of thepatient’s blood circulation and general condition.3. Drug InteractionsContraindications for coadministration (SIGMART4. Adverse ReactionsUnstable angina pectorisThe following adverse reactions to this drug were reported in 227 patients (6.64%) and 301 events of 3,420 patients analyzable for safety. The major adverse reactions were headache (53 events, 1.55%), hepatic function disorder (37 events, 1.08%), increased ALT (GPT) (29 events, 0.85%), decreased blood pressure (24 events, 0.70%), increased AST (GOT) (19 events, 0.56%), increased Al-P (15 events,0.44%), thrombocytopenia (15 events, 0.44%), increased total bilirubin (13 events, 0.38%), increased LDH (9 events, 0.26%), anemia (9 events, 0.26%), and increased γ-GTP (8 events, 0.23%) (at the end of the reexamination period). Acute heart failure (including acute decompensation of chronic heart failure)The following adverse reactions to this drug were reported in 50 of 193 patients (25.9%, 79 events), who were the subjects of safety analysis. The main adverse reactions were throm-bocytopenia (11 events, 5.7%), headache (10 events, 5.2%), decreased blood pressure (7 events, 3.6%), increased total bilirubin (7 events, 3.6%), decreased serum total protein (5 events, 2.6%), increased AST (GOT) (3 events, 1.6%), increased ALT (GPT) (3 events, 1.6%), increased blood creatinine (3 events, 1.6%), leucocytosis (3 events, 1.6%), urinary protein positive (3 events, 1.6%), increased LDH (2 events, 1.0%), increased CK (CPK) (2 events, 1.0%), ventricular tachycardia (2 events, 1.0%), increased blood potassium (2 events, 1.0%) and decreased HDL cholesterol (2 events, 1.0%) (at the time of approval).(1) Clinically Significant Adverse Reactions1) Hepatic dysfunction and jaundice (incidence unknown):Jaundice may develop. Hepatic dysfunction, with in-creased AST (GOT), ALT (GPT) and γ-GTP may occur.Patients should be carefully monitored, and administra-tion of the drug should be discontinued and appropriatetherapeutic measures taken, if suchabnormalities are observed.2) Thrombocytopenia (incidence unknown): Thrombocy-topenia may occur. If any abnormalities are observed,the drug should be discontinued immediately and ap-propriate therapeutic measures must be taken.(2) Other adverse reactionsIf any of the following adverse reactions are observed,appropriate measures such as dosage reduction orNote 4)In the event of such symptom, administration should be discontinued.5. Use in the ElderlySince the elderly often have reduced physiological function and are more likely to experience adverse reactions,SIGMART should be administered while closely andfrequently monitoring blood pressure and hemodynamics.The dosage should be carefully and gradually adjusted inview of the patient’s hemodynamics and symptoms. (See"Important Precautions".)In particular, caution should be taken for decrease in blood pressure, which is apt to occur in elderly patients with acute heart failure.6. Use during Pregnancy, Delivery or LactationSince the safety of SIGMART in pregnant women has not been established, use of SIGMART in pregnant women or women who may possibly be pregnant is not recommended.7. Pediatric UseThe safety of SIGMART in children has not beenestablished (no clinical experience).8. Precautions concerning UsePreparation methodSIGMART should be dissolved in physiological saline or 5% glucose solution for injection and used within 24 hours of preparation.PHARMACOKINETICS1. Blood concentration(1) Single administration1)To five healthy volunteers, 2 mg of SIGMART Injectionwas administered once over a two minute period Note 5).administrationNote 5) This is different from the approved dosage andadministration of SIGMART. (See "DOSAGE AND ADMINISTRATION”.)(2) Continuous administration 2), 3)To five healthy volunteers, SIGMART Injection was intravenously administered for six hours continuously Note 6)6h completion of continuous intravenous administration(3) Long-term administration (in patients with acute heartfailure) 4)SIGMART Injection was intravenously administered to 14 patients with acute heart failure at a dose of 0.2 mg/kg for 5 minutes, and then at a rate of 0.2 mg/kg/hr for 48 hours continuously. The time course of plasma nicorandil concentration is shown below.Time after the start of administration (hr)Time course of plasma nicorandil concentration in patients with acute heart failure (mean±SE)2. Metabolism and excretion 3), 5)The metabolism and excretion of SIGMART wereinvestigated by intravenously administering 2, 4 or 6 mg/hr of SIGMART Injection (as nicorandil) to five healthy men Note 6)and 6 mg/hr of nicorandil labelled with deuterium to four healthy men for six hours, respectively. Most nicorandil was subjected to a denitration reaction and metabolized to N-(2-hydroxy ethyl) nicotinamide. This metabolite, N-(2-hydroxy ethyl) nicotinamide, wasdetectable in the plasma 0.25-0.5 hours after the start of continuous intravenous administration, and reached aplateau 3 to 9 hours after administration. The cumulative urinary excretion of nicorandil and the metabolite [N-(2-hydroxy ethyl) nicotinamide] 24 hours after administration was 0.2% to 0.4% and 2% to 5%, respectively.Note 6) This is different from the approved dosage andadministration of SIGMART for acute heart failure (including acute decompensation of chronic heart failure).(See "DOSAGE AND ADMINISTRATION".)3. Serum protein binding rate 6)In an in vitro test using human serum, the serum protein binding rate ranged from 34.2% to 41.5% (nicorandil concentration: 1-100 µg/mL)CLINICAL STUDIES1. The usefulness of SIGMART Injection was confirmed by a double-blind comparative study on patients with unstableangina pectoris 7).2. In clinical studies including double-blind study on patients with unstable angina pectoris, overall improvement rates ranged from 68.4% to 75.0%7, 8) in a total of 134 assessable patients.3. In clinical studies including a double-blind study of patients with acute heart failure (including acute decompensation of chronic heart failure, with a pulmonary arterial wedge pressure of 18 mmHg or more), SIGMART Injection was intravenously administered to 54 patients at a dose of 0.2 mg/kg for 5 minutes, and then at a rate of 0.2 mg/kg/hr continuously. As a result, their pulmonary arterial wedge pressure decreased by 21.2%9-11).PHARMACOLOGY1. Pharmacological action(1) Coronary vasodilating activity1) In a canine Langendorff preparation, nicorandil dilated relatively small coronary arteries under normal-pressure perfusion, whereas underlow-pressure perfusion during ischemia, it dilated large coronary arteries. In unanesthetized dogs, intravenous administration of nicorandil dilated large coronary arteries in a dose-dependent manner irrespective of coronary blood flow 12, 13). 2) When SIGMART Injection (2 mg to 6 mg or 0.05-0.1 mg/kg of nicorandil) was administered intravenously once to patients with coronary artery disease Note 7), coronary angiography showed02004006008001000120014001600012243648Time after the start of administration (hr)Time course of plasma nicorandil concentration (mean±SE)Continuous i.v. administrationP l a s m a c o n c e n t r a t i o n (n g /m L )P l a s m a c o n c e n t r a t i o n (n g /m L )significant coronary vasodilation in a dose-dependentmanner. The rate of dilation (in relation to theinternal diameter of non-stenotic vessels) ranged from108% to 127%14-16).(2) Effects on coronary blood flow1) Nicorandil produced a dose-dependent, sustainedincrease in coronary blood flow following intravenousor intraduodenal administration in open-chestedanesthetized dogs. The same responses were shownin conscious dogs, isolated canine heart-lungpreparations, and canine Langendorff'spreparations13,17-20).2) SIGMART Injection (0.1 mg/kg of nicorandil) wasadministered intravenously once Note 7) to patients withangina pectoris having no significant stenosis or anorganic stenosis of 75% or greater in the left coronaryartery and to people with no significant stenosis.The great cardiac vein flow was then measured threeto five minutes after administration (continuousthermal dilution method). In the non-stenosis group(n=5), the average volume increased from 115 to 187mL/min., and in the stenosis group (n=4), it increasedfrom 38 to 69 mL/min., thus confirming significantincreases in coronary blood flow16).(3) Coronary vasospasmolytic activity1) In dogs with partially constricted coronary arteries,nicorandil inhibited cyclical reductions of coronaryblood flow and ST elevations in ECG. Coronaryvasoconstriction induced by the intracoronaryinjection of methacholine or norepinephrine inminiature pigs was also suppressed by nicorandil21,22).2) In 10 patients with coronary spastic angina pectoris,0.1 mg/kg of nicorandil was administeredintravenously to treat coronary spasms induced byergonovine load test or naturally occuring coronaryspasms Note 7). The results showed that nicorandilattenuated coronary spasms 23).(4) Effects on cardio-hemodynamics1) Nicorandil slightly decreased systemic blood pressuredose-dependently when injected intravenously inopen chest dogs under general anesthesia. Therewere no appreciable effects on heart rate, myocardialcontractility, myocardial oxygen consumption andatrioventricular conduction time at doses causing asignificant decrease in coronary vascular resistance17,18, 24).2) When SIGMART Injection (2 to 6 mg or0.05-0.1 mg/kg of nicorandil) was administeredintravenously once to patients with coronary anginapectoris at rest Note 7), heart rate increased, and BPdynamics index (e.g., systolic aortic pressure),systemic vascular resistance, and pressure-rateproduct decreased in a dose-dependent manner.However, the range of these fluctuations were slightto mild14-16). While right intraventricular pacing wasutilized, SIGMART Injection (0.05mg/kg ofnicorandil) was administered intravenously once Note7)to eight patients with angina pectoris with 75% orgreater stenosis. In terms of left ventricular function,nicorandil suppressed increases in the left ventricularend-diastolic pressure and increased the cardiacindex25).Note 7) This is different from the approved dosageand administration of SIGMART. (See"DOSAGE AND ADMINISTRATION”.) (5) Effects on heart failure1) In a canine model of acute heart failure, treatment withnicorandil decreased right atrial pressure and leftventricular pressure in the late diastolic phase (adecrease in the preload), with a concurrent decrease inthe total peripheral vascular resistance (a decrease inthe afterload). Consequently, by improving the leftventricular contractility and increasing the cardiacoutput, the treatment improved the hemodynamics inheart failure26).2) Patients with acute heart failure (including acutedecompensation of chronic heart failure) receivedintravenous administration of SIGMART at a dose of0.2 mg/kg/5 min followed by a 2-hour continuousintravenous infusion at a rate of 0.2 mg/kg/hr. As aresult, a significant decrease was found in thepulmonary arterial wedge pressure, diastolic pressure,systolic pulmonary arterial pressure, diastolicpulmonary arterial pressure, and total peripheralvascular resistance, while a significant increase wasseen in the cardiac index, cardiac output, output perstroke, and output index per stroke. No significantchange was found in the heart rate, systolic bloodpressure, mean right atrial pressure, or pressure-rateProduct11).3) In patients with congestive heart failure who receiveda long-term continuous intravenous infusion ofSIGMART, a decrease in the pulmonary arterialwedge pressure was maintained, which suggested thatdrug resistance would hardly occur27).2. Vasodilating effect and its mechanismThe vasohypotonic effect of nicorandil on extracted blood vessels is suppressed by ATP-sensitive K channel inhibitors or guanylate cyclase inhibitors28). Moreover, in a caninemodel of acute heart failure, the cardiachemodynamics-improving effect of the drug (e.g. effect of increasing the aortic blood flow) was suppressed byATP-sensitive K channel inhibitors29). Furthermore, the drug caused an increase in the cGMP content in extracted blood vessels30). These facts suggest that the vasodilating effect of the drug is related to the effect of opening the ATP-sensitive K channel, as well as to the effect of increasing production of cGMP.PHYSICOCHEMISTRYNonproprietary name:Nicorandil (JAN)Chemical name:N-[2-(Nitrooxy) ethyl] pyridine-3-carboxamide Structural formula:Molecular formula: C 8H 9N 3O 4Molecular weight: 211.17 Description:Nicorandil occurs as white crystals.It is freely soluble in methanol, ethanol (99.5), acetic acid (100); soluble in acetic anhydride; sparingly soluble in water.Melting point:About 92° C (to be decomposed)PACKAGING2 mg InjectionBoxes of 10 vials. 12 mg InjectionBoxes of 10 vials. 48 mg InjectionBoxes of 10 vials.REFERENCES1) Azuma J. et. al.: Yakuri To Chiryo (Jpn. Pharmacol. & Ther.), 15 (11), 4779, 19872) Azuma J. et. al.: Yakuri To Chiryo (Jpn. Pharmacol. & Ther.), 18 (9), 3479, 19903) Internal document: Azuma J. et al.: Pharmacokinetics following intravenous continuous administration of nicorandil in healthy adults (1990)4) Internal document: Phase III study in patients with acute heart failure (long-term administration)5) Internal document: Ishitani H. et al.: Investigation on urinary metabolites following continuous intravenous administration of nicorandil in healthy adults (1990) 6) Internal document: Ida S. et al.: in vivo and in vitro serum protein binging of nicorandil (1991)7) Kato K. et al.: Rinsho Iyaku (J. of Clinical Ther. & Medicines), 7 (9), 2031, 19918) Kato K. et al.: Rinsho To Kenkyu (Jpn. J. of Clinical and Experi. Medicine), 68 (11), 3480, 19919) Internal document: Early phase II study in patients with acute heart failure (single + continuous administration) 10) Internal document: Late phase II study in patients with acute heart failure11) Internal document: Phase III study in patients with acute heart failure (placebo-controlled)12) Yamada A. et al.: Arzneim. -Forsch. (Drug Res.), 37 (11), 1252, 198713) Nakagawa Y. et al.: Jpn. Heart J., 20 (6), 881, 1979 14) Hata N. et al.: Myakkangaku (Vessels), 31 (4), 333, 199115) Gomyo Y. et al.: Therapeutic Research, 10 (4), 1615, 198916) Motohara S. et al.: Therapeutic Research, 10(4), 1307, 198917) Uchida Y. et al.: Jpn. Heart J., 19 (1), 112, 197818) Satoh K. et al.: Shinzo (Heart), 12 (4), 371, 1980 19) Mizukami M. et al.: Arzneim-Forsch. (Drug Res.), 31 (2), 1244, 198120) Sakanashi M. et al.: Oyo Yakuri (Pharmacotrics), 15 (3), 385, 197821) Uchida Y. et al.: Jpn. Heart J., 19 (6), 904, 197822) Sakai K. et al.: J. Pharmacol. Exp. Ther., 227 (1), 220, 198323) Matsumura Y. et al.: Therapeutic Research, 11 (5), 1448, 199024) Sakai K. et al.: J. Cardiovasc. Pharmacol., 3 (1), 139, 198125) Kambara H. et al.: Am. J. Cardiol., 63, 56J, 1989 26) Kamijo, T. et al.: J. Cardiovasc. Pharmacol., 33: 93 (1999)27) Larsen, A. I. et al.: Am. Heart J., 134: 435 (1997) 28) Internal document: Fukazawa M. et al.:Pharmacological study using extracted blood vessels of rats (2001)29) Kamijo, T. et al.: Asia Pac. J. Pharmacol., 11: 141 (1996)30) Internal document: Imagawa J. et al.: Influence on cAMP and cGMP in aortas of rats (2000)REQUEST FOR LITERATURE SHOULD BE MADE TO:Requests for any of the internal documents listed in the“REFERENCES” section can also be made to the following: Drug Information CenterChugai Pharmaceutical Co., Ltd.1-1 Nihonbashi-Muromachi 2-chome, Chuo-ku, Tokyo 103-8324, Japan TEL: 0120-189706 FAX: 0120-189705http://www.chugai-pharm.co.jpManufactured and Distributed by:Chugai Pharmaceutical Co., Ltd., Roche Group.1-1 Nihonbashi-Muromachi 2-chome, Chuo-ku, Tokyo 103-8324, JapanBRAND NAMES IN OTHER COUNTRIESSigmart Injection (Korea)。

上海CMC培训美国仿制药申报和当前的挑战从研发到注册上市

Acceptance is taking longer, up to 6 months Brand has 45 days to respond to the certification of non-infringement
Applicant has 30 months from date of filing to receive Tentative Approval Otherwise FDA will deem the applicant’s exclusivity forfeited

New strengths New products Orphan Drug 505b(2)
FTF Categories
2005 NCE ER & DR Combination product New strength New Product New Dosage Form 505b2 8 8 8 0 4 1 1 30 2006 10 7 13 0 2 1 0 33 2007 8 6 6 0 1 0 2 23 2008 8 7 3 1 1 2 2 24 2009 16 7 7 0 3 1 2 36 2010 5 5 2 0 6 4 2 24 55 40 39 1 17 9 9 170 32% 24% 23% 1% 10% 5% 5% 100%
Pre-formulation
Formulation
Development Phases
(continued)
1. Granulation optimization 2. Fluid bed parameters
Process Optimization
3. Blending effects (BU, CU)