| 11. |
- Wagner, Henrik, et al.
(författare)
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Higher body weight patients on clopidogrel maintenance therapy have lower active metabolite concentrations, lower levels of platelet inhibition, and higher rates of poor responders than low body weight patients
- 2014
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Ingår i: Journal of Thrombosis and Thrombolysis. - : Springer Science and Business Media LLC. - 0929-5305 .- 1573-742X. ; 38:2, s. 127-136
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Tidskriftsartikel (refereegranskat)abstract
- Body weight is a predictor of clopidogrel response. However, no prospective studies have compared pharmacodynamic (PD) and pharmacokinetic (PK) data based on body weight. We compared PD and PK effects of clopidogrel 75 mg in low body weight (LBW, <60 kg) and higher body weight (HBW, >= 60 kg) patients with stable coronary artery disease. LBW (n = 34, 56.4 +/- 3.7 kg) and HBW (n = 38, 84.7 +/- 14.9 kg) aspirin-treated patients received clopidogrel 75 mg for 10-14 days. The area under the concentration-time curve of active metabolite (Clop-AM) calculated through the last quantifiable concentration up to 4 h postdose, AUC((0-tlast)), was calculated by non-compartmental methods. Light transmission aggregometry (LTA) (maximum platelet aggregation and inhibition of platelet aggregation to 20 mu M adenosine diphosphate (ADP), and residual platelet aggregation to 5 mu M ADP), VerifyNow (R) P2Y12 reaction units (PRU), and vasodilator-associated stimulated phosphoprotein phosphorylation platelet reactivity index (VASP-PRI) were performed. Mean AUC((0-tlast)) was lower in HBW than LBW patients: 12.8 versus 17.9 ng h/mL. HBW patients had higher platelet reactivity as measured by LTA (all p <= 0.01), PRU (207 +/- 68 vs. 152 +/- 57, p < 0.001), and VASP-PRI (56 +/- 18 vs. 39 +/- 17, p < 0.001). More HBW patients exhibited high on-treatment platelet reactivity (HPR) using PRU (35 vs. 9 %) and VASP-PRI (65 vs. 27 %). Body weight correlated with PRU and VASP-PRI (both p < 0.001), and inversely with log transformed AUC((0-tlast)) (p < 0.001). In conclusion, HBW patients had lower levels of Clop-AM, and higher platelet reactivity and rates of HPR than LBW subjects, contributing to their suboptimal response to clopidogrel.
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| 12. |
- Wagner, Henrik, et al.
(författare)
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Repeated epinephrine doses during prolonged cardiopulmonary resuscitation have limited effects on myocardial blood flow: a randomized porcine study
- 2014
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Ingår i: BMC Cardiovascular Disorders. - : Springer Science and Business Media LLC. - 1471-2261. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Background: In current guidelines, prolonged cardiopulmonary resuscitation (CPR) mandates administration of repeated intravenous epinephrine (EPI) doses. This porcine study simulating a prolonged CPR-situation in the coronary catheterisation laboratory, explores the effect of EPI-administrations on coronary perfusion pressure (CPP), continuous coronary artery flow average peak velocity (APV) and amplitude spectrum area (AMSA). Methods: Thirty-six pigs were randomized 1:1:1 to EPI 0.02 mg/kg/dose, EPI 0.03 mg/kg/dose or saline (control) in an experimental cardiac arrest (CA) model. During 15 minutes of mechanical chest compressions, four EPI/saline-injections were administered, and the effect on CPP, APV and AMSA were recorded. Comparisons were performed between the control and the two EPI-groups and a combination of the two EPI-groups, EPI-all. Result: Compared to the control group, maximum peak of CPP (P-max) after injection 1 and 2 was significantly increased in the EPI-all group (p = 0.022, p = 0.016), in EPI 0.02-group after injection 2 and 3 (p = 0.023, p = 0.027) and in EPI 0.03-group after injection 1 (p = 0.013). At P-max, APV increased only after first injection in both the EPI-all and the EPI 0.03-group compared with the control group (p = 0.011, p = 0.018). There was no statistical difference of AMSA at any P-max. Seven out of 12 animals (58%) in each EPI-group versus 10 out of 12 (83%) achieved spontaneous circulation after CA. Conclusion: In an experimental CA-CPR pig model repeated doses of intravenous EPI results in a significant increase in APV only after the first injection despite increments in CPP also during the following 2 injections indicating inappropriate changes in coronary vascular resistance during subsequent EPI administration.
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| 13. |
- Amisten, Stefan, et al.
(författare)
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ADP mediates inhibition of insulin secretion by activation of P2Y13 receptors in mice.
- 2010
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; Jul 1, s. 1927-1934
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESES: To investigate the effects of extracellular purines on insulin secretion from mouse pancreatic islets. METHODS: Mouse islets and beta cells were isolated and examined with mRNA real-time quantification, cAMP quantification and insulin and glucagon secretion. ATP release was measured in MIN6c4 cells. Insulin and glucagon secretion were measured in vivo after glucose injection. RESULTS: Enzymatic removal of extracellular ATP at low glucose levels increased the secretion of both insulin and glucagon, while at high glucose levels insulin secretion was reduced and glucagon secretion was stimulated, indicating an autocrine effect of purines. In MIN6c4 cells it was shown that glucose does induce release of ATP into the extracellular space. Quantitative real-time PCR demonstrated the expression of the ADP receptors P2Y(1) and P2Y(13) in both intact mouse pancreatic islets and isolated beta cells. The stable ADP analogue 2-MeSADP had no effect on insulin secretion. However, co-incubation with the P2Y(1) antagonist MRS2179 inhibited insulin secretion, while co-incubation with the P2Y(13) antagonist MRS2211 stimulated insulin secretion, indicating that ADP acting via P2Y(1) stimulates insulin secretion, while signalling via P2Y(13) inhibits the secretion of insulin. P2Y(13) antagonism through MRS2211 per se increased the secretion of both insulin and glucagon at intermediate (8.3 mmol/l) and high (20 mmol/l) glucose levels, confirming an autocrine role for ADP. Administration of MRS2211 during glucose injection in vivo resulted in both increased secretion of insulin and reduced glucose levels. CONCLUSIONS/INTERPRETATION: In conclusion, ADP acting on the P2Y(13) receptors inhibits insulin release. An antagonist to P2Y(13) increases insulin release and could be evaluated for the treatment of diabetes.
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| 14. |
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| 15. |
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| 16. |
- Annborn, Martin, et al.
(författare)
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Procalcitonin after cardiac arrest - An indicator of severity of illness, ischemia-reperfusion injury and outcome.
- 2013
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Ingår i: Resuscitation. - : Elsevier BV. - 1873-1570 .- 0300-9572. ; 84:6, s. 782-787
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Tidskriftsartikel (refereegranskat)abstract
- AIM: To investigate serial serum concentrations of procalcitonin (PCT) and C-reactive protein (CRP) in patients treated with mild hypothermia after cardiac arrest, and to study their association to severe infections, post cardiac arrest syndrome (PCAS) and long-term outcome. METHODS: Serum samples from cardiac arrest patients treated with mild hypothermia were collected serially at admission, 2, 6, 12, 24, 36, 48 and 72h after cardiac arrest. PCT and CRP concentrations were determined and tested for association with three definitions of infection, two surrogate markers of PCAS (circulation-SOFA and time to return of spontaneous circulation (ROSC)) and cerebral performance category (CPC) at six months. RESULTS: Eighty-four patients were included. PCT displayed an earlier release pattern than CRP with a significant increase within 2h, increasing further at 6h and onwards in patients with poor outcome. CRP increased later and continued to rise during the study period. PCT was strongly associated with circulation-SOFA and time to ROSC, and predicted a poor neurologic outcome with high accuracy (area under the receiver operating characteristic curve of 0.88, 0.86 and 0.87 at 12, 24 and 48h respectively). No association of PCT or CRP to infection was observed. CONCLUSION: Our results suggest that PCT is released early after resuscitation following cardiac arrest, is associated with markers of PCAS but not with infection, and is an accurate predictor of poor outcome. Validation of these findings in larger studies is warranted.
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| 17. |
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| 18. |
- Atar, Dan, et al.
(författare)
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Rationale and Design of the 'MITOCARE' Study: A Phase II, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety and Efficacy of TRO40303 for the Reduction of Reperfusion Injury in Patients Undergoing Percutaneous Coronary Intervention for Acute Myocardial Infarction
- 2012
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Ingår i: Cardiology. - : S. Karger AG. - 1421-9751 .- 0008-6312. ; 123:4, s. 201-207
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Tidskriftsartikel (refereegranskat)abstract
- Treatment of acute ST-elevation myocardial infarction (STEMI) by reperfusion using percutaneous coronary intervention (PCI) or thrombolysis has provided clinical benefits; however, it also induces considerable cell death. This process is called reperfusion injury. The continuing high rates of mortality and heart failure after acute myocardial infarction (AMI) emphasize the need for improved strategies to limit reperfusion injury and improve clinical outcomes. The objective of this study is to assess safety and efficacy of TRO40303 in limiting reperfusion injury in patients treated for STEMI. TRO40303 targets the mitochondrial permeability transition pore, a promising target for the prevention of reperfusion injury. This multicenter, double-blind study will randomize patients with STEMI to TRO40303 or placebo administered just before balloon inflation or thromboaspiration during PCI. The primary outcome measure will be reduction in infarct size (assessed as plasma creatine kinase and troponin I area under the curve over 3 days). The main secondary endpoint will be infarct size normalized to the myocardium at risk (expressed by the myocardial salvage index assessed by cardiac magnetic resonance). The study is being financed under an EU-FP7 grant and conducted under the auspices of the MITOCARE research consortium, which includes experts from clinical and basic research centers, as well as commercial enterprises, throughout Europe. Results from this study will contribute to a better understanding of the complex pathophysiology underlying myocardial injury after STEMI. The present paper describes the rationale, design and the methods of the trial. Copyright (c) 2012 S. Karger AG, Basel
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| 19. |
- Björklund, Fredrik, 1968-
(författare)
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Platelet reactivity and comorbidities in acute coronary syndrome
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background In the event of an acute coronary syndrome (ACS), the risk of death and complications such as stroke and re-infarction is high during the first month. Diabetes, impaired kidney function, elevated markers of systemic inflammation and high level of platelet reactivity have all been associated with worsened prognosis in ACS patients. Impaired kidney function is a condition with high cardiovascular morbidity and there is an established association between level of kidney function and outcome in the event of an ACS. Aims We sought to investigate the level of platelet reactivity during the first days of an ACS and specifically the level of platelet reactivity in patients with different conditions associated with worsened prognosis in the event of an ACS. We also wanted to investigate the prognostic impact of baseline levels of cystatin C as well as the importance of decreasing kidney function during the first days of an ACS. Methods We included 1028 unselected patients with ACS or suspected ACS during the years 2002 and 2003, of which 534 were diagnosed with an acute myocardial infarction (AMI). Blood samples for measuring platelet aggregation, cystatin C levels and other clinically important biomarkers were collected day 1, 2, 3 and 5 following admission. Platelet reactivity was measured using 2 different methods. Platelet aggregation was measured using Pa-200, a particle count method, based on scattering of laser light. PFA 100 is a method of measuring primary hemostasis in whole blood. Results Platelet aggregation and comorbidities. We found an increase in platelet aggregation when an ACS was complicated by an infection and there was an increased frequency of aspirin non-responsiveness in patients suffering from pneumonia during the first days of an ACS. Furthermore, we found an independent association between levels of C-reactive protein and platelet aggregation. During the first 3 days following an acute myocardial infarction, platelet aggregation increased despite treatment with anti-platelet agents. Platelet aggregation was found to be more pronounced in patients with diabetes. Patients with impaired kidney function, showed increased platelet aggregation compared to patients with normal renal function, however, this difference was explained by older age, higher prevalence of DM and levels of inflammatory biomarkers. We found no independent association between chronic kidney disease (CKD) and levels of platelet aggregation. Kidney function and outcome Serum levels of cystatin C on admission had an independent association with outcome following an acute myocardial infarction. With a mean follow-up time of 2.9 years, the adjusted HR for death was 1.62 (95% CI 1.28-2.03; p<0.001) for each unit of increase in cystatin C on admission. The level of dynamic changes in cystatin C during admission for an acute myocardial infarction was independently associated with prognosis in patients with normal or mild impairment of renal function. The adjusted HR for death was 10.1 (95% CI 3.4-29.9; p<0.001). Conclusion In patients suffering from an AMI platelet aggregation increases during the first days, despite anti-platelet treatment. Diabetes, age and biomarkers of inflammation are independently associated with platelet aggregation. Admission levels of cystatin C as well as changes in cystatin C levels during hospitalisation are independently associated with outcome.
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