| 1. |
- Artibani, Walter, et al.
(författare)
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EAU Policy on Live Surgery Events.
- 2014
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Ingår i: European Urology. - : Elsevier BV. - 1873-7560 .- 0302-2838. ; 66:1, s. 87-97
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Forskningsöversikt (refereegranskat)abstract
- Live surgery is an important part of surgical education, with an increase in the number of live surgery events (LSEs) at meetings despite controversy about their real educational value, risks to patient safety, and conflicts of interest.
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| 2. |
- Jones, Charles H, et al.
(författare)
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Hybrid biosynthetic gene therapy vector development and dual engineering capacity
- 2014
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 111:34, s. 5-12360
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Tidskriftsartikel (refereegranskat)abstract
- Genetic vaccines offer a treatment opportunity based upon successful gene delivery to specific immune cell modulators. Driving the process is the vector chosen for gene cargo packaging and subsequent delivery to antigen-presenting cells (APCs) capable of triggering an immune cascade. As such, the delivery process must successfully navigate a series of requirements and obstacles associated with the chosen vector and target cell. In this work, we present the development and assessment of a hybrid gene delivery vector containing biological and biomaterial components. Each component was chosen to design and engineer gene delivery separately in a complimentary and fundamentally distinct fashion. A bacterial (Escherichia coli) inner core and a biomaterial [poly(beta-amino ester)]-coated outer surface allowed the simultaneous application of molecular biology and polymer chemistry to address barriers associated with APC gene delivery, which include cellular uptake and internalization, phagosomal escape, and intracellular cargo concentration. The approach combined and synergized normally disparate vector properties and tools, resulting in increased in vitro gene delivery beyond individual vector components or commercially available transfection agents. Furthermore, the hybrid device demonstrated a strong, efficient, and safe in vivo humoral immune response compared with traditional forms of antigen delivery. In summary, the flexibility, diversity, and potential of the hybrid design were developed and featured in this work as a platform for multivariate engineering at the vector and cellular scales for new applications in gene delivery immunotherapy.
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| 3. |
- Kingbäck, Maria, 1981-
(författare)
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Genetic influence on enantiomeric drug disposition : Focus on venlafaxine and citalopram
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A molecule that is not identical to its mirror image is said to be chiral. A racemic mixture, or a racemate, is one that has equal amounts of S- and R-enantiomers of a chiral molecule. Two examples of frequently prescribed racemic drugs are the antidepressants venlafaxine (VEN) and citalopram (CIT). The R-enantiomer of VEN is a potent inhibitor of serotonin and noradrenaline reuptake, while the S-enantiomer is more selective in inhibiting serotonin reuptake. CIT is a selective serotonin reuptake inhibitor and the S-enantiomer is responsible for this effect. The R-enantiomer of CIT is therapeutically inactive, but displays other effects or side-effects. Due to the potential of different pharmacological and toxicological activities of the VEN and CIT enantiomers, it is of great interest to investigate the individual enantiomers of these drugs, concerning both pharmacokinetics and pharmacodynamics. For this purpose, it is necessary to develop stereoselective bioanalytical methods. A major clinical problem in the use of many drugs is the inter-individual variability in drug metabolism and response. Genetic variations contribute to this variability, including e.g. polymorphisms in the cytochrome P450 (CYP) enzymes. Approximately 7% of all Caucasians lack the polymorphic isoenzyme CYP2D6 and these individuals are classified as poor metabolisers. Both VEN and CIT are partly metabolised by CYP2D6. However, it is not completely known how CYP2D6 deficiency may influence the in vivo pharmacokinetics of these drugs, especially regarding the enantiomeric disposition. The overall aim of this thesis was to study the relationship between pharmacokinetics and pharmacogenetics for VEN and CIT, with emphasis on enantiomeric drug disposition in different biomatrices. In Paper I, a validated liquid chromatography-tandem mass spectrometry (LC/MS/MS) method for enantioselective determination of VEN and its three major metabolites was developed and applied in plasma from patients and whole blood samples from forensic autopsy cases. In Papers II and III, the genetic influence on enantiomeric drug disposition in serum and brain following administration of racemic CIT and VEN to Sprague-Dawley and Dark Agouti rats was studied. The female Sprague-Dawley and Dark Agouti rats are considered the animal counterparts of the human extensive and poor metaboliser CYP2D6 phenotypes, respectively. Significant quantitative strain-related differences in the pharmacokinetics of CIT and VEN, and their metabolites, were observed. The results indicate that the CYP2D enzymes display a significant impact on the stereoselective metabolism of these drugs. The findings also highlight the importance of comparing different rat strains when conducting experimental pharmacokinetic studies. In Paper IV, the relation between CYP2D6 genotype and the disposition of the enantiomers of VEN and its metabolites in femoral blood from forensic autopsy cases was studied. A substantial variation in the relationship between the S- and R-enantiomers of VEN, and metabolites, was found. In individuals lacking two functional CYP2D6 alleles, a low enantiomeric S/R VEN ratio was strongly related to a high S/R ratio for the main metabolite O-desmethylvenlafaxine. Hence, by using enantioselective analysis of VEN and O-desmethylvenlafaxine, it is possible to predict if a person is a poor metaboliser genotype/phenotype for CYP2D6.
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| 4. |
- Matic, Maja, et al.
(författare)
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Effect of UGT2B7-900G > A (-842G > A; rs7438135) on morphine glucuronidation in preterm newborns: results from a pilot cohort
- 2014
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Ingår i: Pharmacogenomics. - 1462-2416 .- 1744-8042. ; 15:12, s. 1589-1597
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Assess association between UGT2B7 polymorphism -900G>A (rs7438135, also known as -842G>A) with morphine kinetics in preterm newborns undergoing mechanical ventilation. Materials & methods: Thirty-four infants were enrolled in a randomized clinical trial and allocated to rapid sequence intubation with remifentanil (1 mu g/kg) or morphine (0.3 mg/kg). The latter group was included in our study. Results: Morphine plasma concentrations at 20 min post intubation were associated with postnatal age (p = 0.017) and UGT2B7 -900G>A (p = 0.036). UGT2B7 -900A allele carriers (n = 13) had lower morphine levels compared with UGT2B7 -900G/G patients (n = 2). Morphine-3-glucuronide and morphine-6-glucuronide plasma concentrations were only found to be associated with gestational and postnatal age. However, -900A allele carriers had a higher morphine-3-glucuronide: morphine metabolic ratio compared with patients genotyped as -900G/G (p = 0.005), as determined by linear regression. Conclusion: Our small pilot study illustrates that in addition to gestational and postnatal age, the UGT2B7 -900G>A polymorphism significantly alters morphine pharmacokinetics in preterm infants.
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