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Conventional Health Technology Assessment (HTA) is usually conducted at a point in time at which the development of the respective technology may no longer be influenced. By this time developers and/or purchasers may have misinvested resources. Thus the demand for Technology Assessment (TA) which incorporates appropriate methods during early development stages of a technology becomes apparent. Against this health political background, the present report describes methods for a development-accompanying assessment of innovative medical technologies. Furthermore, international research programmes set out to identify or apply such methods will be outlined. A systematic literature search as well as an extensive manual literature search are carried out in order to obtain literature and information. The greatest units of the identified methods consist of assessment concepts, decision support methods, modelling approaches and methods focusing on users and their knowledge. Additionally, several general-purpose concepts have been identified. The identified research programmes INNO-HTA and MATCH (Multidisciplinary-Assessment-of-Technology-Centre-for-Healthcare) are to be seen as pilot projects which so far have not been able to generate final results. MATCH focuses almost entirely on the incorporation of the user-perspective regarding the development of non-pharmaceutical technologies, whereas INNO-HTA is basically concerned with the identification and possible advancement of methods for the early, socially-oriented technology assessment. Most references offer only very vague descriptions of the respective method and the application of greatly differing methods seldom exceeds the character of a pilot implementation. A standardisation much less an institutionalisation of development-accompanying assessment cannot be recognized. It must be noted that there is no singular method with which development-accompanying assessment should be carried out. Instead, a technology and evaluation specific method selection seem to be necessary as medical innovations are diverse and none of the methods are exhaustive. Because of a variety of issues (e. g. ideal time of evaluation, lack of data and uncertainty of data) a development-accompanying assessment should not replace a comprehensive HTA, but rather form a possible preceding step in a multi-staged HTA-process. A final appraisal of the methods for development-accompanying assessment cannot be made based on the available sources. However, the present review may serve as a starting point for further development and application of these methods as well as further examination of the concept of development-accompanying assessment. There is a substantial need for further research concerning the application, validation and comparison of the various methods for development-accompanying assessment., GMS Health Technology Assessment; 5:Doc15; ISSN 1861-8863

Konventionelles Health Technology Assessment (HTA) erfolgt in der Regel zu einem Zeitpunkt, an dem die Entwicklung der Technologie nicht mehr direkt beeinflussbar ist. Möglicherweise sind dann Ressourcen von Seiten der Entwickler und/oder Kostenträger fehl investiert worden. Der Bedarf eines Technology Assessment (TA) mit entsprechenden Methoden in frühen Entwicklungsstadien der Technologien wird daher deutlich. Vor diesem gesundheitspolitischem Hintergrund beschreibt der vorliegende Bericht Methoden zur entwicklungsbegleitenden Bewertung von innovativen medizinischen Technologien und stellt internationale Forschungsprogramme zur Identifizierung oder Anwendung dieser Methoden dar. Zur Gewinnung von Literatur und Informationen werden eine systematische Literaturrecherche und eine ausgedehnte Handsuche durchgeführt. Die größten Untergruppen an identifizierten Methoden bilden dabei Bewertungskonzepte, Entscheidungsunterstützungsmethoden, Modellierungsansätze und Methoden, die Nutzer und deren Wissen in den Mittelpunkt stellen. Weiter wurden einige allgemein gefasste Konzepte zur entwicklungsbegleitenden Bewertung identifiziert. Die beiden identifizierten Forschungsprogramme INNO-HTA und MATCH (Multidisciplinary-Assessment-of-Technology-Centre-for-Healthcare) sind als Pilotprojekte zu sehen und haben bisher auch noch keine abschließenden Ergebnisse liefern können. MATCH fokussiert nahezu ausschließlich auf die Einbeziehung der Nutzerperspektive bei der Entwicklung von nichtmedikamentösen Technologien, während INNO-HTA sich vom Grundsatz her mit der Identifizierung und ggf. Weiterentwicklung von Methoden zur frühzeitigen - gesellschaftlich orientierten - Technologiebewertung beschäftigt. Die Methodenbeschreibungen in den Quellen sind meistens sehr vage und die Anwendung der sehr unterschiedlichen Methoden kommt selten über den Charakter einer Pilotanwendung hinaus. Eine Standardisierung geschweige denn eine Institutionalisierung von entwicklungsbegleitender Bewertung lässt sich nicht erkennen. Festzuhalten ist, dass es nicht die eine Methode gibt, mit der eine entwicklungsbegleitende Bewertung erfolgen sollte. Stattdessen scheint eine technologie- und bewertungsspezifische Methodenauswahl sinnvoll, da auch die medizinischen Innovationen verschieden sind und keine der Methoden erschöpfend ist. Eine entwicklungsbegleitende Bewertung sollte aufgrund einer Vielzahl von Problemen (z. B. optimaler Zeitpunkt der Evaluation, Datenmangel und unsichere Daten) ein umfassendes HTA nicht ersetzen, sondern ggf. in einem mehrstufigen HTA-Prozess eine vorgeschaltete Stufe darstellen. Eine abschließende Bewertung der Methoden zur entwicklungsbegleitenden Bewertung ist anhand der verfügbaren Quellen nicht möglich, allerdings mag die vorliegende Übersicht als Ausgangsbasis für weitere Methodenentwicklungen bzw. -anwendungen sowie für eine weiterführende Auseinandersetzung mit dem Konzept der frühzeitigen Bewertung dienen. Es besteht erheblicher Forschungsbedarf zu der Anwendung, der Validierung und dem Vergleich der verschiedenen Methoden zur entwicklungsbegleitenden Bewertung., Schriftenreihe Health Technology Assessment (HTA) in der Bundesrepublik Deutschland; 94; ISSN 1864-9645

Because great interest in an efficient range of effective medicinal innovations and achievements has arisen, many countries have introduced procedures to regulate the adoption of innovative non-medicinal technologies into the benefit catalogue of solidly financed health care insurances. With this as a background, this report will describe procedures for the adoption of innovative non-medicinal technologies by solidly financed health care insurances in Germany, England, Australia and Switzerland. This report was commissioned by the German Agency for Health Technology Assessment at the German Institute for Medical Documentation and Information.In order to find the relevant literature and information, systematic literature research, a hand search and a written survey were carried out. All the selected documents (chosen according to defined criteria for inclusion and exclusion) were qualitatively evaluated, summarized and presented on a chart using a framework developed for this purpose. All the countries in this report require that some innovative non-medicinal technologies undergo evaluation by a central governing body. This evaluation is a prerequisite for adoption into the benefit catalogue. The process of evaluation can differ (e. g. the people and institutions concerned, the division of the synthesis of evidence and overall evaluation, processing the evidence). Similarities do exist, such as the size and composition of the governing bodies or the overreaching criteria according to which institutions must make their recommendations. This is how all the countries examined in this report determine how the benefits and effectiveness of the innovations, as well as their cost-effectiveness, can be chosen as criteria for the evaluation. Furthermore, there are many criteria which differ from country to country (social and ethical aspects, possible effects on the health system, etc.) and which are also relevant to an evaluation. The preferred types of clinical studies for these evaluations are randomized controlled trials. However, all institutions do allow for other types of evidence (e. g. expert opinion) when no other study types of a higher evidence level are available. In addition, all the countries are willing to allow unpublished or confidential information (e. g. from manufacturers) to be included in an evaluation. It is important to remember that the decisions made by the central governing bodies do not necessarily become conditions for the introduction of innovative non-medicinal technologies. There is a host of other requirements which determine how these innovations can be introduced. This means that a large number of non-medicinal technologies make it into the medical care system via these other decision-making processes. Often, these innovations are unevaluated and differ from region to region. Every country has established a system of observation and registration for medicinal products. These systems are meant to document any incidents with the innovations and to confer responsibility on certain organizations. All in all, no country has a central authority which systematically investigates the effects of newly introduced innovative non-medicinal technologies on medical care in general. However, Australia and England both carry out a review of innovations in some areas (e. g. by means of special commissions). In principle, the starting point for improving regulations of innovative non-medicinal technologies lies in the extension of transparency, the shortening of decision-making time (especially the central decision-making processes), the further development of evaluation methods, more flexibility and increased capacity in the governing bodies’ decision-making processes and also, if needed, in the creation of a single authority to act as contact for people who are interested in introducing an innovation into the benefit catalogue. More research is required, especially in the area of decentralized decision-makers and how they actually decide whether or not to introduce innovative technologies into the core care system (methods, criteria, etc.). In view of this, it would also be interesting to see how the application of innovations actually happens in practice once their adoption has been approved by the corresponding governing bodies.

Stickstoffmonoxid (NO) spielt eine bedeutende Rolle in der Regulation des Blutdruckes, es ist ein starker Vasodilatator. Mäuse mit genetisch inaktivierter endothelialer Stickstoffmonoxidsynthase (eNOS-/-) haben einen Bluthochdruck. Mäuse mit fehlender neuronaler NO-Produktion (nNOS-/-) zeigen einen erniedrigten Blutdruck in Narkose. Im Gegensatz dazu konnte in der Literatur eine Hemmung der Katecholaminfreisetzung durch neuronal gebildetes NO gezeigt werden. Es war deshalb das Ziel dieser Studie, die Kreislaufparameter von eNOS-/- und nNOS-/- Mäusen im wachen Zustand in Ruhe und unter Stress zu untersuchen. Außerdem wurde untersucht, ob nNOS die Expression des Schlüsselenzyms der Katecholaminsynthese, Tyrosinhydroxylase (TH), hemmt und die hämodynamische Antwort auf Stress abschwächt. Acht nNOS-/-, neun eNOS-/- und neun Wildtypkontrollmäuse (WT) erhielten einen Femoralarterienkatheter. Blutdruck und Herzfrequenz sowie die Körperkerntemperatur wurden 24h nach der Operation unter wachen Bedingungen in Ruhe und bei Erhöhung der Umgebungstemperatur aufgezeichnet. Die Tyrosinhydroxylase-mRNA-Expression und -Proteingehalt der Nebennieren wurden mittles RT-PCR und Western Blot bestimmt. In Ruhe zeigten eNOS-/- und nNOS-/- Mäuse einen signifikant erhöhten mittleren und diastolischen Blutdruck im Vergleich zu Wildtypkontrollen. Während des Hitzestresses war der initiale Blutdruckabfall bei den eNOS-/- Mäusen signifikant vermindert. Der stressinduzierte Anstieg von Blutdruck und Herzfrequenz war deutlich verstärkt bei nNOS-/- Mäusen im Vergleich zu WT und eNOS-/- Mäusen. Die TH-mRNA-Expression war zehnfach erhöht bei nNOS-/- Mäusen im Vergleich zu WT. Auch der Proteingehalt der Nebennieren war dreifach erhöht in nNOS-/- im Vergleich zu WT. Diese Ergebnisse zeigen, dass endothelial gebildetes NO hauptsächlich an der thermoregulatorischen Vasodilatation der Hautgefäße beteiligt ist. Weiterhin konnte gezeigt werden, dass neuronal gebildetes NO die TH-Expression hemmt und die sympathisch vermittelte Stressantwort vermindert., Nitric oxide (NO) plays an important role in the circulatory regulation, it is a very potent vasodilator. Mice deficient of a functional endothelial NO synthase (eNOS-/-) exhibit hypertension. Mice lacking a functional neuronal NO production (nNOS-/-) were observed to be hypotensive under anaesthesia. In contrast, evidence from the literature suggests an inhibition of catecholamine release by NO derived from nNOS. Therefore it was the aim of this thesis to evaluate the circulatory parameters in eNOS-/- and nNOS-/- under conscious conditions at rest and in reponse to stress. Additionally, it was tested if nNOS inhibits the expression of the key enzyme of the catecholamine synthesis, tyrosine hydroxylase, and thereby reduces the hemodynamic responses to stressful stimuli. Eight nNOS-/-, nine eNOS-/-, and nine wild type controls (WT) were chronically instrumented with femoral artery catheters. 24h after surgery,resting blood pressure and heart rate were measured and then mice were exposed to an elevated ambient temperature. Arterial blood pressure together with heart rate and core temperature were recorded in conscious animals. Tyrosine hydroxylase mRNA expression and protein content in the adrenal gland were measured by RT-PCR and western blotting, respectively. At rest, eNOS-/- and nNOS-/- exhibited a significantly elevated mean and diastolic blood pressure compared to WT. During heat stress, the initial decrease in blood pressure seen in WT and nNOS-/- was significantly blunted in eNOS-/-. The stress-induced acceleration of heart rate and increase in blood pressure were much stronger in nNOS-/- compared to WT and eNOS-/- . TH mRNA expression was ten times larger in nNOS-/- than in WT. Correspondingly, protein content in the adrenal gland was increased threefold in nNOS-/- compared to WT. The results of this thesis indicate that endothelial derived NO predominantly mediates the thermoregulatory vasodilatation. Furthermore, it shows that neuronally derived NO inhibits TH expression and, therefore, limits the sympathetically-mediated responses to stressful stimuli, such as heat stress.

The invention relates to thiazolylpiperidine derivates of the formula (I), where the symbols A, G, Y, n, R1, R2, R3, R4, and R5 have the meanings given in the description, and to agrochemically active salts thereof, and the use thereof for treating plant pathenogenic fungi, and to the method for producing compounds of the formula (I).