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- Boström, Emma, 1975-
(författare)
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Pharmacokinetics and Pharmacodynamics of Oxycodone and Morphine with Emphasis on Blood-Brain Barrier Transport
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The pharmacokinetics and pharmacodynamics of oxycodone and morphine was investigated and related to the transport across the blood-brain barrier (BBB) in rats. The influence of a P-glycoprotein (P-gp) inhibitor on the plasma pharmacokinetics and pharmacodynamics of oxycodone was evaluated. Microdialysis experiments were conducted to evaluate the unbound pharmacokinetics, including the rate and extent of transport across the BBB, of oxycodone and morphine. Mathematical models were used to assess the pharmacokinetics and also the relationship between pharmacokinetics and pharmacodynamics of the drugs.Oxycodone clearance, volume of distribution at steady-state, half-life, total brain tissue concentrations and tail-flick latency were all unaffected when a P-gp inhibitor was co-administered with oxycodone as compared to a control group. The lack of differences between the groups indicates that oxycodone BBB transport is not affected by P-gp inhibition. Investigating the unbound concentrations of oxycodone in brain and blood using microdialysis revealed an exciting finding. At steady-state, the unbound concentration in brain was 3 times higher than in blood (i.e. a Kp,uu of 3), indicating that active influx is involved in the BBB transport of oxycodone. In contrast, the Kp,uu of morphine was estimated to 0.56, which is an indication that active efflux mechanisms are involved in the BBB transport of morphine. This means that based on the same unbound concentration in blood, an approximately 6-fold higher unbound concentration of oxycodone compared to morphine will be reached in the brain. Using pharmacokinetic-pharmacodynamic modelling, the unbound brain concentrations of oxycodone and morphine were correlated to the tail-flick latency in vivo. The relative potency of the drugs was found to be concentration dependent with an infliction point of 55 nM.In summary, this thesis emphasise the importance of taking the local brain pharmacokinetics into consideration when investigating the pharmacokinetics and the pharmacokinetic-pharmacodynamic relationships of centrally acting drugs.
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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: 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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| 4. |
- 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. |
- Hammarlund, Dan, et al.
(författare)
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Stable isotope variations in stalagmites from northwestern Sweden document changes in temperature and vegetation during the early Holocene: a comment on Sundqvist et al. 2007a
- 2008
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Ingår i: The Holocene. - : SAGE Publications. - 0959-6836 .- 1477-0911. ; 18:6, s. 1007-1008
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- We offer an alternative palaeoenvironmental interpretation of oxygen-isotope data obtained on two early-Holocene stalagmite records from caves in the Scandes Mountains of northern Sweden (Korallgrottan and Labrintgrottan), and the well-known Soylegrotta (Norway) SG93 record with which they are compared, that differs in several respects from that proposed by the authors. Contrary to viewing these as inverted palaeotemperature records, we suggest that they primarily reflect changes in the delta O-18 of local annual precipitation, modified by secondary temperature-dependent variation in water-calcite oxygen-isotope fractionation, at each of the three sites. This is supported by the striking similarity over the entire Holocene between the SG93 calcite delta O-18 record and the lacustrine carbonate delta O-18 record from Lake Tibetanus (northern Sweden), which implies straightforward transfer of annual precipitation delta O-18 signals into cave drip waters. Recent studies of drip waters in Korallgrottan also support this model. This further enhances the value of cave deposits as palaeoclimate archives in this region and provides additional evidence of the sensitivity of the precipitation 'isotope thermometer' to changes in atmospheric circulation patterns.
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