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Relative bioavailability of terbutaline to the lungs following inhalation using different methods.
The primary aim was to validate and implement a urinary pharmacokinetic method for terbutaline to determine the relative lung and systemic bioavailability following inhalation and to measure the in-vitro characteristics of the emitted dose by these inhalation methods.
Two new robust, accurate and sensitive high performance liquid chromatography methods for the determination of terbutaline in aqueous and urine samples were validated in accordance with the FDA and ICH guidelines. Terbutaline was extracted using solid phase extraction with salbutamol and bamethane as internal standards. The accuracy, precision, lower limit of detection and recovery for both methods were within recognized limits.
The in-vitro characteristics of terbutaline sulphate inhalers were measured according to standard compendial methodology as well as adaptation of this methodology to simulate routine patient use. The dose emission of terbutaline sulphate from a Bricanyl Turbuhaler was determined using an inhalation volume of 4 L at inhalation flows of 10-60 L min-1. The particle size distribution was measured using an Anderson Cascade Impactor (ACI) with a mixing inlet valve to allow measurement at different flows. A steady increase in total emitted dose (TED) and the fine particle dose (FPD) was observed as the inhalation flow increased thereby highlighting the flow dependent dose emission characteristics of the Turbuhaler.
The in-vitro dose emission characteristics of terbutaline sulphate from Bricanyl MDIs were measured according to the standard compendial methodology at a flow of 28.3 L min-1 using a 4 L inhalation volume. The TED and particle size distribution of terbutaline sulphate from the Bricanyl MDI were determined alone and with different spacers [AeroChamber Max (AMAX), AeroChamber Plus (APLUS), Fisonair and Nebuhaler]. The TED from the MDI alone was significantly higher than all MDI+spacers (p<0.001). The MDI with APLUS resulted in the smallest mass median aerodynamic diameter (MMAD) and the highest fine particle fraction (FPF). The MDI with AMAX resulted in the highest FPD.
The in-vitro characteristics of terbutaline sulphate from Bricanyl respules using the Aeroneb Pro (vibrating mesh) and Sidestream jet nebulisers were determined by the CEN methodology and the Next Generation Impactor (NGI) methodology. The Aeroneb Pro was found to have significantly better aerodynamic properties than the Sidestream. The results from the NGI method were significantly different from the CEN method suggesting further evaluation of both methods. Cooling the NGI decreased the evaporation effect.
Twelve healthy volunteers (6 females) completed in-vivo urinary terbutaline pharmacokinetic studies to determine the relative bioavailability following inhalation. The differences between the amounts excreted 0.5, 1, 2, 4, 6 and 24 hour post inhalation from a Bricanyl MDI (I) and oral (O) dosing of 500 µg terbutaline sulphate and with the co-administration of oral charcoal (IC and OC, respectively) were studied. No terbutaline was found in OC samples. The amount of terbutaline excreted 30 minutes post I and IC were significantly (p<0.001) higher than post O suggesting that the amount of terbutaline excreted 30 minutes post dosing can be used as an index of the lung deposition. The amount of terbutaline excreted 24 hour post I was significantly (p<0.01) higher than post O suggesting that the amount of terbutaline excreted 24 hour post dosing can be used as an index of the relative systemic bioavailability. The dose response relationships and the low inter and intra-subject variability studies confirm the feasibility of this method.
To demonstrate the application of the method the effect of inhalation technique on the lung and systemic bioavailability following inhalation from a dry powder inhaler was evaluated. The effect of different spacers on the dose emitted from the Bricanyl MDI and the effect of different nebulisers on the dose emitted were also studied using twelve healthy volunteers (6 females) for each study.
A fast inhalation flow using the Bricanyl Turbuhaler resulted in significantly higher amounts of terbutaline excreted 0.5 and 24 hour post dosing (2 doses of 500µg terbutaline sulphate from Bricanyl Turbuhaler) than slow inhalation flow (p<0.001). The Bricanyl MDI alone resulted in a significantly higher amount of terbutaline excreted 24 hour post dosing (2 doses of 250µg terbutaline sulphate from Bricanyl MDI) and significantly lower amounts excreted 30 minutes post dosing than the MDI+Spacers. The AMAX provided a greater amount of urinary terbutaline excreted 30 minutes post dosing than the APLUS and Nebuhaler. The Aeroneb Pro resulted in significantly higher amounts of terbutaline excreted 0.5 and 24 hour post dosing (1 dose of 5mg/2ml terbutaline sulphate from Bricanyl respule) than a Sidestream Jet nebuliser (p<0.001).
Further application of the method was demonstrated by 12 (6 female) COPD non-invasive mechanically ventilated patients. One dose of 2mg in 0.8ml terbutaline sulphate respiratory solution from Aeroneb Pro and one dose of 5mg in 2ml terbutaline sulphate respiratory solution from Sidestream jet nebuliser resulted in a similar amounts of urinary terbutaline excreted 0.5 and 24 hour post dosing. The results were consistent with the results of the ex-vivo study performed on the same patients.
The thesis highlights extension of the urinary pharmacokinetic method following inhalation to terbutaline and its application in volunteer and patient studies.Egyptian Culture Office in UK, Missions Department in Egyp
Customer co-creation in innovations : a protocol for innovating with end users
The transition into the information revolution or age has made it possible for consumers and users to interfere in the conceptualization, design, production and sales processes of firms. Consumers and users can express their needs in more direct way to producing firms, they have access to the way products and services are made, and last but not least, have access to information on competing products and services that even producers don’t know about. Consumers have become more knowledgeable and are therefore capable of designing and producing their own products and services. The success of innovations or new product and service development is highly dependent on whether they take in consideration the needs and demands of potential users and consumers. In other words, a market orientation is essential for the success of an innovation. Firms would therefore welcome the idea of consumers and users expressing their demands and probably appreciate consumers who want to participate in the new product or service development, because they would have immediate feedback on the potential success of the innovation. Question is, however, how to achieve this and how to successfully co-create with customers in the innovation process. This design research addresses customer co-creation in innovations for product and service industries. It addresses how firms should successfully activate customers or users and what process they should follow, i.e. the kind of customers or users to involve, the tools and techniques to apply, and procedures to be followed. It develops the appropriate interventions for this in a Customer Co-Creation in Innovations (3CI) - Protocol. The nature of this research is prescriptive, based on the Design Science principles, aiming to design a solution for firms that are interested in the co-creation role that customers can play in their organizations regarding innovations. The research results in a protocol which organizations that want to co-create with customers in their innovation process, can use or apply, to effectively co-create with these customers. Effectively in this sense means that the customer input will be of added value to the innovation, resulting in the outcome that the organization succeeds in bringing the innovation into the market or in use. This doesn’t necessarily mean that the innovation will be a commercial success, because this success depends on more and other factors than just customer co-creation. But, in this context customer co-creation gives the organization the necessary confirmation that the innovation fits needs and demands in the market, and thus leads to a higher adaptation than one should expect when not co-creating with customers. There is an abundance of literature that argue the benefits of involving customers in the innovation process, while other address the issue of which customers to involve, so, the research focuses itself on best practices, experiments, and such to develop this protocol. This has been accomplished by studying the diverse modes or appearances of customer involvement in product or service development, such as market research, empathic design, user-centered design, co-design, mass customization, user innovation, open source software development, user generated content, crowdsourcing, and customer co-creation. Although there is a lot of overlap and similarities among these modes of involvement, there are also many differences, indicating that customer co-creation in innovations is contingent on many factors and aspects. To reduce the confusion, a construct of customer co-creation in innovations has been developed, which has been defined as the process where product manufacturers and/or service providers actively engage with their end users or customers in (parts or phases of) innovation projects to jointly perform innovation activities and co-create value, with the aim of increasing effectiveness and efficiency of the innovation process. Effectiveness refers to (1) the result of meeting users’ and customers’ needs and demands in a better way; and (2) increasing customer loyalty. Efficiency refers to (1) the reduction of research and development costs; and (2) the reduction of development time. And to analyze differences and similarities so that the appropriate design propositions can stated, a 3CI framework was developed, covering the following topics: (1) how to determine whether a firm can co-create with its customers in innovations, which are the so called context conditions; (2) how to identify, select, and motivate potential customers to participate in customer-open innovations; (3) how to engage and involve these customers in the innovation process in an effective and efficient way, the process, procedures and methods one can follow, the tools one can use to accomplish this. With this framework the practice of customer co-creation was analyzed by means of five case studies, in which two of them, the author was an actor in designing and executing the process of co-creation. The cases, selected for their diversity, reveal the opportunities and challenges of customer-inclusive innovation. Customer involvement was at least a partial success in all cases. At the same time, it was never a ‘silver bullet’ to permanently transform the way the company worked. 3CI seems to be capable to support both incidental and repeating innovation initiatives of a firm. Another observation is that, whether a B2B or B2C type of firm, a manufacturer or service provider, small or large firms, all seem to be capable of and suited for 3CI. Common in all cases, however, is that the organization’s offerings and markets should be heterogeneous, thereby containing opportunities to either develop line extensions or really novel (radical) offerings. The technology base of the organization, however, does not seem to be a prerequisite. Another theme cutting across the cases is the nature of an ‘innovation community’, where users test, experiment with and modify or enhance existing prototypes and products, paving the roadway to innovation. As for the relationship between innovation type and type of customer, the cases undoubtedly demonstrate that ‘ordinary’ users can provide useful input to develop radical or novel innovations. The cases also demonstrate that nearly all innovation activities can be conducted by co-creating with customers, including needs assessment, ideation, the screening of ideas or concepts, concept testing, design and development, the commercialization of the innovation and even the re-innovation or use stage. So, although one could get the idea of 3CI being of particular interest in the front end of an innovation stage, we see that in all later stages 3CI can be beneficial as well. Typical across all cases is also the contingency of the channel of involvement (online versus face-to-face) with the amount of customers involved, which we have typed as the degree of openness. The more people are involved, the more open (no secrecy) the co-creation is and the more the involvement is obtained through the online channel, either with communities or on an open call. Conversely, the less participants, the more secrecy is needed and the sooner the physical presence or offline participation seems to be imminent in participation. Finally, regarding the use of tools it can be concluded that sophisticated methods for customer co-creation are a complement rather than the sole source of user information. More important seems to be the occurrence of a dialogue between firm and participating customers, implying that the quality of the interaction depends on mutual trust, appreciation, commitment and equality. Tools that support this dialogue, such as the ZMET¿, OBR, or similar techniques, seem to be important to assure effective and efficient contribution from customers. Subsequently, the design process was conducted, first by defining 16 design requirements for the protocol – subdivided in functional and use requirements, and design restrictions and boundary conditions – followed by the development of the design propositions. A grand total of 28 design propositions have been identified, regarding the context of 3CI (10 propositions), the customer requirements (10 propositions) and process (8 propositions). The context propositions reflected the context decisions to be made, i.e. the appropriate strategy, the suitability of the firm’s market, the initiator for the co-creation (firm or customer), and the type of innovation (incremental vs. radical, open vs. closed mode). Wherever appropriate we have also reviewed the appropriate methods, tools and techniques for the best implementation of the interventions. These are the first decisions the firm has to make when undertaking the 3CI Journey. Only when these decisions are made a next step, i.e. determining which customer requirements are appropriate, can be made. It has been argued that any organization can co-create with its customers in innovations, provided that they adopt and maintain a market oriented strategy, along with the necessary tools, space, freedom and transparency for customers to participate. Customer co-creation leads to at least effective incremental innovations, but when the organization applies Customer Knowledge Methods it increases the chance for an effective radical innovation. If secrecy is required, a closed mode approach of co-creation can be followed, entailing that a minimum amount and diversity of external participants are involved, provided that there is a clear scope of innovation objectives and the market it is intended for. Finally, organizations can either rely on customer-initiated ideas or initiate an innovation itself. In the first approach the organization is recommended to create and maintain a customer community, which can be observed and interacted with to elicit the customers’ ideas. The 10 customer design propositions deal with the type of customers to co-create with in innovations and the available interventions to engage with and maintain involvement from the selected participants. We have argued that all (potential) customers are eligible to participate, as long as they have a certain use experience with the product, service or category of innovation. Only in the case of a radical innovation, the company can choose to add some lead users in order to increase the chance of generating really novel ideas or concepts. To find these lead users, the company can make an appeal on the customer community, since lead users are usually known in communities. In order to benefit in the best way from the participating ordinary and lead users, the company should select them on the basis of their willingness to participate. On top of that, participants should be trained or educated in the tools, techniques and methods that are applied during their involvement. To prevent a decrease of intrinsic motivation with participants, companies have to be very prudent with the promise and administering of financial rewards. Rewards can be given, but preferably unexpected and contingent on task complexity and performance demonstrated by the participant. Depending on the channel of involvement, a minimum of 15 to an undetermined maximum of participants is possible, provided that the company reserves sufficient resources to handle the amount of participants. To our initial 20 design propositions we have added an additional 8 design propositions regarding the process of co-creation. We have seen that all innovation stages are suited to co-create with customers. For the appropriate activities in which these customers can contribute we have developed a table depicting activities and contributions per innovation stage. Co-creation can take place in one, more or all stages; to receive the most benefit, customers should be involved as early as possible in the innovation process. To prevent loss of attention, de-motivation and premature abandonment, we have proposed to change participants with ongoing activities; relying on the same customers in all stages can result in ‘myopic’ results. Both online and offline co-creation are possible, depending on openness, amount of participants and available resources. If participation is online, we recommend applying crowdsourcing methods and techniques, preferably within the customer community. To support an effective communication, we finally proposed to use metaphor or analogy based ‘language’ and to treat the participants as if they were team members. Through scrutinizing and analyzing the 28 design propositions in relation to one another and some pre-defined design requirements, we have identified four main routes – metaphorically named the dreamcatcher, contest, touchstone and employment route – that a company can follow when aiming to co-create with customers in the innovation process. The dreamcatcher route appeals on a user community – existing or yet to be created, preferably online, but with a physical possibility – where existing products, services or platforms are used, reviewed and discussed by customers. The company observes and participates in this discussion through a dialogue, possibly also moderating the community. Opportunities are identified by the company and translated into innovation projects by the company, in which customers again can participate. In the contest route the company can pose users with a specific question or request, a challenge, for which they are expected to think of a solution, of which typically one, or a limited amount of solutions are eligible. The intention is to specifically involve the customer in the front end of the innovation, because the company does not know or is not aware yet of customer needs and wants, or the intended product or service requirements. Customer input is then required in the first stage (Conception), but is not necessary excluded in later stages, where customers can test prototypes, assist in the commercialization and the re-innovation. In the touchstone route the company can decide to co-create with customers in any, arbitrary stage or activity of the innovation process, a sort of a one off. In such a case, the company usually has already identified the opportunities, the innovation project and its goals. Customer co-creation is opportune to verify assumptions, fill in details, and provide additional, not thought of product or service requirements. Of course it is possible to co-create with the customer in more than one activity, but this approach is seen as discrete co-creation activities to support just that particular and specific stage, in which the co-creation is required, usually in the implementation stage and thereafter. Finally, in the employment route the company can integrate one or more (limited amount of) customers in the innovation project, e.g. by temporarily employing them. This approach is of particular interest in idea generation, design and development activities, i.e. the Conception and Implementation stage, but later stages aren’t excluded. We can see this approach applied in customized projects, where it is the intention to create something for a specific set of customers or segment. This can be on request by the customer or because the company has discovered an unfulfilled or unattended set of needs with these customers, e.g. through dreamcatching. To decide which route(s) is or are appropriate we have discussed some premises and considerations – objectives for co-creation, stages and contributions for co-creation, type and openness of innovation – that a company has to assess systematically. Each route was elaborated on, providing preparation steps and do’s and don’ts for an effective and efficient contribution from customers. The four routes are also interrelated and do not exclude one another, but nevertheless provide a company with the optimal approach for 3CI. The 3CI-protocol is therefore a robust, handy guideline for companies to co-create with their customers in innovations. Because of the systematic and rigorous analysis and synthesis of theory and practice, the protocol can be applied in most situations. To test and prove the correctness of this last assertion we validated the design by having it reviewed by some potential users, some experts and some scholars, and to base the conclusion of its validity on the opinions of these reviewers. A total of 25 potential reviewers, both national and international, consisting of product/service developers, co-creation intermediaries, consultants and scholars were approached independently from and ‘blind’ to each other to conduct this review. Ten of them consented in participation; three abandoned the review process prematurely for personal reasons, leaving a total of 7 reviewers that have submitted comments. It was agreed on to enhance the review with a Delphi if responses were very divergent. All reviewers found the protocol useful and helpful for guiding the process of customer co-creation. Comments or critique referred mainly to the readability of the protocol, with the remark that users might lose attention because of the academic reasoning. Some of them provided useful additions to the protocol in order to enhance the readability. Also, suggestions were made to promote the protocol to practice, for instance by publishing it via a community and a management book. The comments did not contain divergent viewpoints on the subject, the design and its content, so the Delphi was left out. Based on these comments and suggestions by the reviewers, we have redesigned the protocol into the 3CI Protocol version 1.0, which can be published as a separate document, detached from this thesis, which all potential users can get hold of and apply without having to acquire a copy of the thesis. We propose to use this protocol to further validate it in practice and giving us feedback on its effectiveness. Our main contribution to research in management and organization has been to develop a comprehensive how-to guideline for practitioners, based on and grounded in a diversity of theory. Therefore, we believe that we have contributed with a design that is applicable in all kind of business and organizational contexts where the interaction with end users is aimed at developing new offerings. However, modesty is also in place, when we observe that this has to be proven, yet. Further research can be aimed at obtaining this proof, while other research could focus on the underlying assumptions, which we named generative mechanisms, of the design
ARMING OR CHARMING: OBSEQUIUM AND DOMESTIC POLITICS IN ROMAN NORTH AFRICA
Scholarship to date has dealt mainly with the legal aspects of Roman marriage and its place within Roman society, most of which tends to focus on the disempowerment of women. This article, while not denying the disadvantages women suffered under these conditions, focusses on the mechanics by which women could achieve their aims within the boundaries of marriage and how the concept of obsequium could have been understood and implemented by both partners to the marriage contract
Informatieanalyse beheerplannen: bijdrage beheerplannen aan de rapportageverplichtingen van LNV
Kort verslag en verantwoording van de werkzaamheden ten behoeve van het programma WOT Informatievoorziening Natuur. De werkzaamheden zijn uitgevoerd in de eerste helft van 2010. De EU lidstaten dienen namelijk verantwoording af te leggen aan de Europese Commissie door middel van rapportage
Welkom in Rotterdam! : een studie naar interculturele ontmoetingen tussen 'oude' en 'nieuwe' Rotterdammers
Maatschappelijke solidariteit tussen verschillende bevolkingsgroepen bestaat nog wel degelijk in de huidige multiculturele samenleving van Rotterdam. Dat concluderen onderzoekers in een studie van de Wetenschapswinkel van Wageningen UR (University & Research centre) naar de effecten van de interculturele ontmoetingen die het project 'Welkom in Rotterdam' organiseert. Zowel ‘oude’ als ‘nieuwe’ Rotterdammers staan open voor contact met elkaar, maar de drempel voor spontane contacten is voor veel mensen te hoog. Hun sociale netwerken zijn gescheiden waardoor de gelegenheid vaak ontbreekt
Natura 2000: veerkrachtige gebieden of significante gevolgen?
De Natuurbeschermingswet 1998 is nu drie jaar van kracht. Sinds de invoering in 2005 brengt deze wet veel verwarring. Heikel punt is de interpretatie van het begrip ‘significante gevolgen’. Te vaak drijft toetsing hieraan bestuurders in de hoek van vermeende juridische zekerheid met bijbehorende administratieve lastendruk voor de initiatiefnemer. In dit artikel stellen de auteurs dat onzekerheid bij het beoordelen van significante gevolgen onvermijdelijk is. Als maatschappij moeten we leren omgaan met onzekerheden in besluitvorming. In plaats van investeren in het verkleinen van de onzekerheid, kan men beter investeren in een veerkrachtige natuur
Impact of energy storage systems on the management of fault current at LV network with high penetration of distributed generation
Linking anti-corruptionism and human rights:A dangerous addition to the development discourse
Trace mineral status of the African Buffalo (Syncerus caffer) in the Kruger National Park
(South African J of Animal Science, 2000, 30, Supplement 1: 38-39
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