| 1. |
|
|
| 2. |
- Karlsson, Lars O, 1975, et al.
(author)
-
Cyclosporine A, 2.5 mg/kg, Does Not Reduce Myocardial Infarct Size in a Porcine Model of Ischemia and Reperfusion
- 2012
-
In: Journal of cardiovascular pharmacology and therapeutics. - : SAGE Publications. - 1940-4034 .- 1074-2484. ; 17:2, s. 159-63
-
Journal article (peer-reviewed)abstract
- BACKGROUND: In recent years, cyclosporine A (CsA) has emerged as a promising therapy to limit myocardial ischemic-reperfusion injury, presumably by inhibiting the opening of the mitochondrial permeability transition pore. Results from different large animal models are conflicting, however, with failure to prove beneficial effects of 10 mg/kg CsA administered at reperfusion. Recently, a small clinical study using a bolus of 2.5 mg/kg CsA showed promising but not unequivocal results. The aim of the present study was to estimate the magnitude of a possible infarct reduction with the use of the latter regimen in a closed-chest porcine model for ischemia and reperfusion. Materials and METHODS: Pigs underwent catheterization with balloon occlusion of the left descending coronary artery for 40 minutes, followed by reperfusion for 4 hours. They were randomized to receive an intravenous bolus 7 minutes before reperfusion of either 2.5 mg/kg CsA (n = 12) or saline (control, n = 11). Hearts were stained to quantify area at risk and infarct size. RESULTS: Throughout the experiment, there were no differences between the groups in baseline characteristics or hemodynamic variables. CsA treatment did not reduce infarct size as a proportion of area at risk compared with control (51% +/- 6% and 54% +/- 6%, respectively, P = .75). CONCLUSION: In a closed-chest porcine model for myocardial ischemia and reperfusion injury, 2.5 mg/kg CsA administered before reperfusion did not reduce infarct size.
|
|
| 3. |
- Karlsson, Lars O., et al.
(author)
-
Cyclosporine does not reduce myocardial infarct size in a porcine ischemia-reperfusion model.
- 2010
-
In: Journal of Cardiovascular Pharmacology and Therapeutics. - : Sage Publications. - 1074-2484 .- 1940-4034. ; 15:2, s. 182-9
-
Journal article (peer-reviewed)abstract
- Cyclosporine A (CsA) has been shown to protect against myocardial ischemia and reperfusion (I/R) injury in small animal models. The aim of the current study was to evaluate the effects of CsA on myocardial I/R injury in a porcine model. Pigs were randomized between CsA (10mg/kg; n = 12) or placebo (n = 15) and anesthetized with either isoflurane (phase I) or pentobarbital (phase II). By catheterization, the left descending coronary artery was occluded for 45 minutes, followed by reperfusion for 2 hours. Hearts were stained to quantify area at risk (AAR) and infarct size (IS). Myocardial biopsies were obtained for terminal dUTP nick end labeling and immunoblot analysis of proapoptotic proteins (apoptosis-inducing factor [AIF], BCL2/adenovirus E1B 19-kd interacting protein 3 [BNIP-3], and active caspase-3). Cyclosporine A did not reduce IS/AAR compared with placebo (49% vs 41%, respectively; P = .21). Pigs anesthetized with isoflurane had lower IS/AAR than pigs anesthetized with pentobarbital (39% vs 51%, respectively; P = .03). This reduction in IS/AAR seemed to be attenuated by CsA. Apoptosis-inducing factor protein expression was higher after CsA administration than after placebo (P = .02). Thus, CsA did not protect against I/R injury in this porcine model. The data suggest a possible deleterious interaction of CsA and isoflurane.
|
|
| 4. |
- Karlsson, Lars O, 1975, et al.
(author)
-
Dose-dependent cardioprotection of enkephalin analogue Eribis peptide 94 and cardiac expression of opioid receptors in a porcine model of ischaemia and reperfusion
- 2012
-
In: European journal of pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 674:2-3, s. 378-383
-
Journal article (peer-reviewed)abstract
- Opioids confer cardioprotection after myocardial ischaemia and reperfusion. The primary aim of the present study was to evaluate the cardioprotective effect of different doses of enkephalin analogue Eribis peptide 94 (EP 94) in a porcine model of ischaemia and reperfusion. A secondary aim was to analyse the impact of ischaemia and reperfusion on the expression of opioid receptor subtypes in the porcine heart. Thirty-four anesthetised pigs underwent 40 min of balloon occlusion of the left anterior descending coronary artery followed by four hours of reperfusion. Pigs were given either vehicle (0.9% NaCl) or one of four doses of EP 94 (0.2, 1, 5 or 25 ug/kg at each administration, respectively), intravenously after 26, 33 and 40 min of ischaemia. Hearts were stained to quantify area at risk and infarct size. mRNA and protein expressions of the opioid receptor subtypes were detected with RT-PCR, immunoblotting and immunohistochemistry in the control and ischaemic/reperfused areas. There was a significant dose-response relationship between higher doses of EP 94 and reduced infarct size. Expression of kappa- and delta-opioid receptors was detected at both mRNA and protein levels. In ischaemic/reperfused areas, an increased expression of mRNA for both receptors was observed, whereas only protein expression for the delta subtype was up-regulated. The mu-opioid receptor was not detected.
|
|
| 5. |
- Karlsson, Lars O, 1975, et al.
(author)
-
Opioid receptor agonist Eribis peptide 94 reduces infarct size in different porcine models for myocardial ischaemia and reperfusion
- 2011
-
In: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 651:1-3, s. 146-151
-
Journal article (peer-reviewed)abstract
- Eribis peptide 94 (EP 94) is a novel enkephalin analog, thought to interact with the and delta-opioid receptors. The purpose of the present study was to examine the cardioprotective potential of EP 94 in two clinically relevant porcine models of myocardial ischaemia and reperfusion, and to investigate if such an effect is associated with an increased expression of endothelial nitric oxide synthase (eNOS). Forty-one anesthetized pigs underwent 40 min of coronary occlusion followed by 4 h of reperfusion. In Protocol I, balloon occlusion of the left anterior descending artery was performed with concurrent intravenous administration of (A) vehicle (n = 7), (B) EP 94 (1 ug/kg) after 5, 12, 19 and 26 min of ischaemia (n = 4) or (C) EP 94 (1 ug/kg) after 26, 33, 40 min of ischaemia (n = 6). In Protocol II, open-chest pigs were administered (D) vehicle (n = 6) or (E) 0.2 ug/kg/min of EP 94 (n = 6) through an intracoronary infusion into the jeopardized myocardium, started after 30 min of ischaemia and maintained for 15 min. The hearts were stained and the protein content of eNOS measured. EP 94 reduces infarct size when administered both early and late during ischaemia compared with vehicle (infarct size group A 61.6 +/- 2%, group B 50.2 +/- 3% and group C 49.2 +/- 2%, respectively, P < 0.05), as well as when infused intracoronary (infarct size group D 82.2 +/- 3.9% and group E 61.2 +/- 2.5% respectively, P < 0.01). Phosphorylated eNOS Ser(I177) in relation to total eNOS was significantly increased in the group administered EP 94. indicating activation of nitric oxide production.
|
|
| 6. |
- Karlsson, Lars O, 1975
(author)
-
Pharmacological interventions against myocardial ischemia and reperfusion injury
- 2011
-
Doctoral thesis (other academic/artistic)abstract
- Background: Ischaemic heart disease is the leading cause of death in the industrialised world. Although the concept of early restoration of coronary blood-flow constitutes an important factor to reduce the injury caused by myocardial ischaemia, reperfusion in itself can aggravate the damage to myocardial tissue, a phenomenon denoted myocardial reperfusion injury. Even though promising cardioprotective strategies have been presented in the pre-clinical setting, experience from the clinic has been largely disappointing. Aims: To investigate whether two different pharmacological interventions, cyclosporine A (CsA) and the novel enkephalin analogue EP 94, could reduce myocardial infarct size in different porcine models of myocardial ischaemia and reperfusion. Furthermore, to examine the distribution of the opioid receptor subtypes in the porcine heart, and to investigate how this expression is affected by ischaemia and reperfusion. Methods: Anesthetised pigs underwent balloon occlusion of the left anterior descending coronary artery, followed by reperfusion. CsA and EP 94 were administered during the end of the ischaemic insult. After the reperfusion period hearts were stained with Evans blue and 2, 3, 5-triphenyltetrazolium chloride to quantify area at risk and infarct size, respectively. mRNA and protein expression of different pro-apoptotic proteins, endothelial NO-synthetase and opioid receptor subtypes was quantified in the control and ischaemic/reperfused areas. Results: Two different dosages of CsA did not confer cardioprotection whereas EP 94 reduced myocardial infarct size in a dose-dependant manner in our different porcine models. Immunoblots revealed a possible mechanism for the cardioprotective effect with up-regulation of phosphorylated eNOS in pigs receiving EP 94. Furthermore, protein expression of the κ- and δ-opioid receptors was detected in the left ventricle, with an up-regulation of the δ subtype after ischemia and reperfusion. The µ-opioid receptor was not detected. Conclusions: CsA did not reduce myocardial infarct size, whereas the novel enkephalin analogue EP 94 conferred cardioprotection in different porcine models. The κ- and δ-opioid receptors were detected in the pig left ventricle. Keywords: myocardial ischemia, reperfusion injury, opioids, cyclosporine A ISBN 978-91-628-8373-7
|
|
| 7. |
- Kågedal, Matts, et al.
(author)
-
A positron emission tomography study in healthy volunteers to estimate mGluR5 receptor occupancy of AZD2066-Estimating occupancy in the absence of a reference region
- 2013
-
In: NeuroImage. - : Elsevier BV. - 1053-8119 .- 1095-9572. ; 82, s. 160-169
-
Journal article (peer-reviewed)abstract
- AZD2066 is a new chemical entity pharmacologically characterized as a selective, negative allosteric modulator of the metabotropic glutamate receptor subtype 5 (mGluR5). Antagonism of mGluR5 has been implicated in relation to various diseases such as anxiety, depression, and pain disorders. To support translation from preclinical results and previous experiences with this target in man, a positron emission tomography study was performed to estimate the relationship between AZD2066 plasma concentrations and receptor occupancy in the human brain, using the mGluR5 radioligand [C-11]-ABP688. The study involved PET scans on 4 occasions in 6 healthy volunteers. The radioligand was given as a tracer dose alone and following oral treatment with different doses of AZD2066. The analysis was based on the total volume of distribution derived fro m each PET-assessment. A non-linear mixed effects model was developed where ten delineated brain regions of interest from all PET scans were included in one simultaneous fit. For comparison the analysis was also performed according to a method described previously by Lassen et al. (1995). The results of the analysis showed that the total volume of distribution decreased with increasing drug concentrations in all regions with an estimated Kipl of 1170 nM. Variability between individuals and occasions in non-displaceable volume of distribution could explain most of the variability in the total volume of distribution. The Lassen approach provided a similar estimate for Kipl, but the variability was exaggerated and difficult to interpret.
|
|
| 8. |
- Yun, Sang Ho, et al.
(author)
-
Multifunctional silicon inspired by a wing of male Papilio ulysse
- 2012
-
In: Applied Physics Letters. - : American Institute of Physics (AIP). - 0003-6951 .- 1077-3118. ; 100:3, s. 033109-
-
Journal article (peer-reviewed)abstract
- Effective entrapment of air and light is a key element for maintaining stable superhydrophobicity and enhancing anti-reflection or absorption. Inspired by a wing of male Papilio ulysse having a unique structure for enabling effective trapping of air and light, we demonstrate that the structure consisting of well-defined multilayer decorated by nanostructures can be obtained on a silicon wafer by a simple microelectromechanical process, consequently resulted in stable superhydrophobocity under static and dynamic conditions, and strong wideband optical absorption.
|
|
| 9. |
- Österlund, Lars, 1967-, et al.
(author)
-
EP patent
- 2013
-
Patent (pop. science, debate, etc.)
|
|
