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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Inflammation research 45 (1996), S. 531-540 
    ISSN: 1420-908X
    Keywords: Antiinflammatory ; Analgesic ; Antipyretic ; pKa ; Octanol-water partition coefficient ; NSAIDs ; Animal models ; Carrageenin ED50
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Objective and Design: Relevance of the preclinical pharmacodynamic, toxicity and pharmacokinetic parameters predicting the clinical potency of nonsteroidal antiinflammatory drugs (NSAIDs) was evaluated. Material: Data for oral potencies of 24 NSAIDs in rats were collected from the literature and from New Drug Applications with respect to the following parameters: antiinflammatory, analgesic, antipyretic, acute ulcerogenic activities, acute toxicity, in vitro inhibition of prostaglandin synthesis, acid dissociation constant (pKa), octanolwater partition coefficient and elimination half-life. Treatment: Data for most of the in vivo parameters in rats were collected following single dose administration with the exception of adjuvant arthritis. Single and daily clinical doses were considered. All of these NSAIDs have been approved for marketing although not all have been sold in the USA. Methods: The preclinical data were compared to human dose (unit or daily doses) using single and multiple stepwise regression analyses. Results: Analyses suggest that NSAIDs are effective in all models of preclinical tests for fever, pain and inflammation, however, carrageenin-induced rat paw edema model is clearly the best predictor of human dose. Rank order of preclinical models for predicting human dose is carrageenin 〉yeast induced fever〉pressure induced pain=adjuvant arthritis in rats. The analysis suggested that the pain and adjuvant arthritis models in rats may also involve a prostaglandin independent mechanism. Of the two physicochemical factors tested, pKa contributed best to the carrageenin model towards predicting the clinical potency of NSAIDs. Mathematical relationships between human dose, carrageenin ED50 and pKa were established that may assist in the future clinical development of NSAIDs. Conclusions: Carrageenin-induced paw edema model in rats is the most robust predictor of the clinical potency of NSAIDs. Acid dissociation constant (pKa) appears to be a secondary contributor to the potency of NSAIDs. The relevance of the data analyses for developing cyclooxygenase-2 (COX-2) selective NSAIDs is discussed.
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Research in engineering design 7 (1995), S. 253-269 
    ISSN: 1435-6066
    Keywords: Conceptual design representation ; Function-form relationship
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Technology
    Notes: Abstract Design representation of parts during conceptual design stage has been a challenging task because of the incompleteness of the information available. Traditional geometric design requires too much information on the geometric attributes, and does not consider the functionality of the part any more than that provided by individual features. Functional design in the form of 〈verb, noun〉 representation does not have adequate correlation with the geometric design. In this article, we propose a new form of the design representation of parts during conceptual design. The representation is calledsketching abstraction. In this representation, the discretionary geometry of the part that has functional relevance is captured using functional features, while the non-discretionary geometry is represented using a linkage mechanism. The functional features are related to the part function using data structures calledfunction-form matrices. The sketching abstraction is annotated with a set of primitives, and a grammar has been developed that parses the sketch to extract a set of canonical relationships between the functional features. These relationships can be used to extract part designs that are functionally similar but geometrically dissimilar. The sketching abstraction has a relationship with the solid model of the part as well. Thus we attempt to bridge the gap between function and form representations and provide the designer with a tool that can be used for generating design alternatives. We illustrate the theory developed in the domain of stamped metal parts.
    Type of Medium: Electronic Resource
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