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| 2. |
- Chaurasia, Chandra S., et al.
(författare)
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AAPS-FDA workshop white paper : microdialysis principles, application and regulatory perspectives
- 2007
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Ingår i: Pharmaceutical research. - : Springer Science and Business Media LLC. - 0724-8741 .- 1573-904X. ; 24:5, s. 1014-1025
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Tidskriftsartikel (refereegranskat)abstract
- Many decisions in drug development and medical practice are based on measuring blood concentrations of endogenous and exogenous molecules. Yet most biochemical and pharmacological events take place in the tissues. Also, most drugs with few notable exceptions exert their effects not within the bloodstream, but in defined target tissues into which drugs have to distribute from the central compartment. Assessing tissue drug chemistry has, thus, for long been viewed as a more rational way to provide clinically meaningful data rather than gaining information from blood samples. More specifically, it is often the extracellular (interstitial) tissue space that is most closely related to the site of action (biophase) of the drug. Currently microdialysis (microD) is the only tool available that explicitly provides data on the extracellular space. Although microD as a preclinical and clinical tool has been available for two decades, there is still uncertainty about the use of microD in drug research and development, both from a methodological and a regulatory point of view. In an attempt to reduce this uncertainty and to provide an overview of the principles and applications of microD in preclinical and clinical settings, an AAPS-FDA workshop took place in November 2005 in Nashville, TN, USA. Stakeholders from academia, industry and regulatory agencies presented their views on microD as a tool in drug research and development.
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| 3. |
- Chaurasia, Chandra S., et al.
(författare)
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AAPS-FDA Workshop White Paper : microdialysis principles, application, and regulatory perspectives
- 2007
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Ingår i: Journal of clinical pharmacology. - : Wiley. - 0091-2700 .- 1552-4604. ; 47:5, s. 589-603
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Tidskriftsartikel (refereegranskat)abstract
- Many decisions in drug development and medical practice are based on measuring blood concentrations of endogenous and exogenous molecules. Yet most biochemical and pharmacological events take place in the tissues. Also, most drugs with few notable exceptions exert their effects not within the bloodstream, but in defined target tissues into which drugs have to distribute from the central compartment. Assessing tissue drug chemistry has, thus, for long been viewed as a more rational way to provide clinically meaningful data rather than gaining information from blood samples. More specifically, it is often the extracellular (interstitial) tissue space that is most closely related to the site of action (biophase) of the drug. Currently microdialysis (μD) is the only tool available that explicitly provides data on the extracellular space. Although μD as a preclinical and clinical tool has been available for two decades, there is still uncertainty about the use of μD in drug research and development, both from a methodological and a regulatory point of view. In an attempt to reduce this uncertainty and to provide an overview of the principles and applications of μD in preclinical and clinical settings, an AAPS-FDA workshop took place in November 2005 in Nashville, TN, USA. Stakeholders from academia, industry and regulatory agencies presented their views on μD as a tool in drug research and development.
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| 5. |
- Mouton, Johan W., et al.
(författare)
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Tissue concentrations : do we ever learn?
- 2008
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Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press (OUP). - 0305-7453 .- 1460-2091. ; 61:2, s. 235-237
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Tidskriftsartikel (refereegranskat)abstract
- Over the last decades, numerous papers have appeared--and still are appearing--that describe concentrations in tissues in an effort to predict the efficacy of an antimicrobial agent based on these concentrations and MICs for microorganisms. A common method is to use measurements of concentrations in tissue homogenates, comparing these with values derived from the corresponding blood samples and on that basis draw conclusions with respect to the potential clinical use of the drug. This approach is not justifiable for a number of reasons that includes both pharmacokinetic as well as pharmacodynamic causes. This way of presenting data with the derived conclusions is often misleading and may ultimately be harmful in patient care.
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| 6. |
- Viberg, Anders, 1974-
(författare)
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Using Pharmacokinetic and Pharmacodynamic Principles to Evaluate Individualisation of Antibiotic Dosing – Emphasis on Cefuroxime
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cefuroxime is a renally eliminated antibiotic used against a variety of different bacterial infections. The pharmacokinetics (PK) for cefuroxime was studied in 97 hospitalized patients using population analysis. To be able to measure cefuroxime in human serum a new sensitive analytical method was developed using mass spectrometry detection. The method was validated and shown to be sensitive and selective. Cystatin C was found to be a better covariate for cefuroxime clearance compared to the traditionally used creatinine clearance (CLcr). This relation might be useful when designing dosing strategies for cefuroxime and other renally eliminated drugs. The time-courses of the biomarkers C-reactive protein (CRP), serum amyloid A (SAA), interleukin-6 (IL-6) and body temperature were studied for the first 72 hours of cefuroxime treatment and was related to the duration of illness previous treatment with cefuroxime and to time to step-down of treatment. When duration of illness was short, CRP and SAA were showed increasing levels. None of the biomarkers could be used to differentiate between early or late step-down of therapy. By use of known PK and pharmacodynamic (PD) principles, dosing strategies based on CLcr for cefuroxime were estimated using minimization of a risk function. The risk function was constructed with the aim to expose patients to cefuroxime concentration above minimum inhibitory concentration (MIC) for 50 % of the dosing interval and to minimize the amount of drug administered in excess to reach the aim. Based on evaluation using wild type MIC distributions for Escherichia coli and Streptococcus pneumoniae improved dosing strategies were selected. In vitro experiments were performed exposing Streptococcus pyogenes to constant concentration of benzylpenicillin, cefuroxime, erythromycin, moxifloxacin or vancomycin. A semi-mechanistic PK/PD model characterizing the time-course of the antibacterial effect was developed using all data simultaneously. Internal validation showed the model being predictive and robust.
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