| 1. |
- Almquist, Joachim, 1980, et al.
(författare)
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Unraveling the Pharmacokinetic Interaction of Ticagrelor and MEDI2452 (Ticagrelor Antidote) by Mathematical Modeling
- 2016
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Ingår i: CPT: Pharmacometrics and Systems Pharmacology. - : Wiley. - 2163-8306. ; 5:6, s. 313-323
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Tidskriftsartikel (refereegranskat)abstract
- The investigational ticagrelor-neutralizing antibody fragment, MEDI2452, is developed to rapidly and specifically reverse the antiplatelet effects of ticagrelor. However, the dynamic interaction of ticagrelor, the ticagrelor active metabolite (TAM), and MEDI2452, makes pharmacokinetic (PK) analysis nontrivial and mathematical modeling becomes essential to unravel the complex behavior of this system. We propose a mechanistic PK model, including a special observation model for post-sampling equilibration, which is validated and refined using mouse in vivo data from four studies of combined ticagrelor-MEDI2452 treatment. Model predictions of free ticagrelor and TAM plasma concentrations are subsequently used to drive a pharmacodynamic (PD) model that successfully describes platelet aggregation data. Furthermore, the model indicates that MEDI2452-bound ticagrelor is primarily eliminated together with MEDI2452 in the kidneys, and not recycled to the plasma, thereby providing a possible scenario for the extrapolation to humans. We anticipate the modeling work to improve PK and PD understanding, experimental design, and translational confidence.
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| 2. |
- Pehrsson, S., et al.
(författare)
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Hemostatic effects of the ticagrelor antidote MEDI2452 in pigs treated with ticagrelor on a background of aspirin
- 2017
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7836 .- 1538-7933. ; 15:6, s. 1213-1222
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Tidskriftsartikel (refereegranskat)abstract
- Background: Ticagrelor, a P2Y12 antagonist, is approved for the prevention of thromboembolic events. However, antiplatelet therapies carry a risk of bleeding. Objective: To explore the hemostatic effects of MEDI2452, an antidote for ticagrelor. Methods: Pigs, pretreated with aspirin, were given an intravenous infusion of ticagrelor or vehicle. At the end of the infusion, a piece of a liver lobe was cut off and a bolus of MEDI2452 or vehicle was administered intravenously. Blood was collected to monitor blood loss, mean arterial blood pressure (MAP) was recorded and survival time was observed over 4 h. Blood samples for drug plasma exposures and platelet aggregation were collected. Results: MEDI2452 eliminated the free concentrations of ticagrelor and its active metabolite AR-C124910XX within 5 min. ADP-induced platelet aggregation was close to normal at 60 min, which was not significantly different from aspirin alone. MEDI2452 numerically reduced ticagrelor-mediated effects: bodyweight- adjusted blood loss in the 15-to 90-min interval, 12 (confidence interval [ CI] 95% 7-28] vs. 17 (CI 95% 5-31) (ticagrelor and aspirin) vs. 5 (CI 95% 3-9) mL kg(-1) (aspirin alone), survival 70% (CI 95% 47-100) vs. 45% (CI 95% 21-92) (ticagrelor and aspirin) vs. 100% (CI 95% 100-100) (aspirin alone), and median survival time, 240 (CI 95% 180-240) vs. 169 (CI 95% 64-240) (ticagrelor and aspirin) vs. 240 (CI 95% 240-240) min (aspirin alone). Finally, MEDI2452 significantly attenuated the decline in MAP, 0.08 (CI 95% 0.07-0.09) vs. 0.141 (CI 95% 0.1350.148) (ticagrelor and aspirin) vs. 0.04 (CI 95% 0.030.05) mmHg per min (aspirin alone) and maintained MAP at a significantly higher level, 73 (CI 95% 51-95) vs. 48 (CI 95% 25-70) (ticagrelor and aspirin) vs. 115 (CI 95% 94136) mmHg (aspirin alone). Conclusion: MEDI2452 eliminated free ticagrelor and AR-C124910XX within 5 min. This translated into a gradual normalization of ADPinduced platelet aggregation and significant improvement in blood pressure and numerical but non-significant improvements in blood-loss and survival.
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| 4. |
- De Genst, Erwin, et al.
(författare)
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Blocking phospholamban with VHH intrabodies enhances contractility and relaxation in heart failure
- 2022
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Ingår i: Nature Communications. - Stockholm : Karolinska Institutet, Dept of Cell and Molecular Biology. - 2041-1723.
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Tidskriftsartikel (refereegranskat)abstract
- The dysregulated physical interaction between two intracellular membrane proteins, the sarco/endoplasmic reticulum Ca2+ ATPase and its reversible inhibitor phospholamban, induces heart failure by inhibiting calcium cycling. While phospholamban is a bona-fide therapeutic target, approaches to selectively inhibit this protein remain elusive. Here, we report the in vivo application of intracellular acting antibodies (intrabodies), derived from the variable domain of camelid heavy-chain antibodies, to modulate the function of phospholamban. Using a synthetic VHH phage-display library, we identify intrabodies with high affinity and specificity for different conformational states of phospholamban. Rapid phenotypic screening, via modified mRNA transfection of primary cells and tissue, efficiently identifies the intrabody with most desirable features. Adeno-associated virus mediated delivery of this intrabody results in improvement of cardiac performance in a murine heart failure model. Our strategy for generating intrabodies to investigate cardiac disease combined with modified mRNA and adeno-associated virus screening could reveal unique future therapeutic opportunities.
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| 6. |
- Andersson, I, et al.
(författare)
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Long-term oxygen therapy and quality of life in elderly patients hospitalised due to severe exacerbation of COPD. A 1 year follow-up study
- 2002
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Ingår i: Respiratory Medicine. - : Elsevier BV. - 1532-3064 .- 0954-6111. ; 96:11, s. 944-949
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was (1) to evaluate the effects of long-term oxygen treatment (LTOT) in elderly patients with severe exacerbations of chronic obstructive pulmonary disease (COPD) and hypoxaemia, (2) to study the health-related quality of life (QOL) during hospital stay and at follow-up, (3) to study the safety of an oxygen withdrawal test performed a few days after admission to hospital and the possibility to predict the future need for LTOT from that test. Patients > 70 years with COPD-exacerbations with hypoxaemia were included after 5-7 days treatment in hospital. Inclusion was based on results of a standardised oxygen withdrawal test. After 1, 3, 6 and 12 months a new oxygen withdrawal test was performed. Health-related QOL was evaluated with SF-36 and the St George's Respiratory Questionnaire at inclusion and after 3,6 and 12 months. Forty-seven patients were screened for participation and 29 patients, mean age 79 years, participated in the study Only one patient could not tolerate the oxygen withdrawal test. Eighteen patients survived to the follow-up after 12 months, 8/19 women and 2/10 men died. After 1 month LTOT was needed (PaO2 without oxygen was less than or equal to 7.5 kPa) in only 6/20 patients. The effect of LTOT could therefore not be studied. Most components of SF-36 were very low at inclusion, but tended to increase after 3 months and were among the surviving patients after 12 months similar to that of healthy people of the same age for psychic well being and functioning. Especially, the symptom score of the SGRQ improved after 3 months. In conclusion, the future need for LTOT cannot be judged after a few days treatment in hospital due to exacerbations with hypoxaemia in elderly patients with COPD. A standardised oxygen withdrawal test can be safely done. Health-related QOL is low in patients during the stay in hospital, but improves after returning home.
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| 8. |
- Clyne, N, et al.
(författare)
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The intracellular distribution of cobalt in exposed and unexposed rat myocardium
- 1990
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Ingår i: Scandinavian Journal of Clinical and Laboratory Investigation. - 0036-5513 .- 1502-7686. ; 50:6, s. 605-609
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Tidskriftsartikel (refereegranskat)abstract
- The intracellular distribution of cobalt was analysed in the myocardium of exposed and unexposed rats. The exposed rats were given a dietary cobalt supplementation of 40 mg CoS04-7 H20/kg body weight for 8 weeks. The mitochondrial fraction showed the greatest relative increase in cobalt: 0.09 ng/mg protein in the unexposed rats to 8.43 ng/mg protein in the exposed rats. In the exposed rats the submitochondrial particles had the highest levels of cobalt: 19.43 ng/mg protein, followed by the sarcoplasmatic reticulum: 12.3 ng/mg protein. The microsomal 44 000g supernatant also showed an increase, although the levels remained low (0.51 ng/mg protein in the exposed animals). Apparently the calcium-storing organelles had the highest levels of cobalt. This could affect calcium flux in myocardial cells and, secondarily, tension development in cardiac muscle.
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| 13. |
- Hyppönen, Hannele, et al.
(författare)
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Nordic eHealth Indicators: Organisation of research, first results and plan for the future.
- 2013
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Ingår i: Medinfo 2013. - Netherländerna : IOS Press. - 9781614992882 ; , s. 273-277
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Konferensbidrag (refereegranskat)abstract
- eHealth indicator and benchmarking activities are rapidly increasing nationally and internationally. The work is rarely based on a transparent methodology for indicator definition. This article describes first results of testing an indicator methodology for defining eHealth indicators, which was reported at the Medical Informatics Europe conference in 2012. The core elements of the methodology are illustrated, demonstrating validation of each of them in the context of Nordic eHealth Indicator work. Validation proved the importance of conducting each of the steps of the methodology, with several scientific as well as practical outcomes. The article is based on a report to be published by the Nordic Council of Ministers.
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| 15. |
- Lind, Marcus, 1976, et al.
(författare)
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Design and methods of a randomised double-blind trial of adding liraglutide to control HbA1c in patients with type 2 diabetes with impaired glycaemic control treated with multiple daily insulin injections (MDI-Liraglutide trial)
- 2015
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Ingår i: PRIMARY CARE DIABETES. - : Elsevier BV. - 1751-9918 .- 1878-0210. ; 9:1, s. 15-22
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Patients with type 2 diabetes are generally treated in primary care setting and as a final treatment step to obtain good glycaemic control, multiple daily insulin injections (MDI) are generally used. The aim of this study is to evaluate the effect of GLP-1 analogue liraglutide on glycaemic control in patients with type 2 diabetes treated with MDI with inadequate glycaemic control. METHODS: Overweight and obese patients with type 2 diabetes and impaired glycaemic control treated with MDI were randomised to liraglutide or placebo over 24 weeks. Masked continuous glucose monitoring was performed at baseline and during the trial. The primary endpoint was the change in haemoglobin A1c from baseline to week 24. Additional endpoints include changes in weight, fasting glucose, glycaemic variability, treatment satisfaction, insulin dose, hypoglycaemias, blood pressure and blood lipid levels. RESULTS: Recruitment occurred between February 2013 and February 2014. A total of 124 patients were randomised. Study completion is anticipated in August 2014. CONCLUSIONS: It is expected that the results of this study will establish whether adding liraglutide to patients with type 2 diabetes treated with MDI will improve glycaemic control, lower body weight, and influence glycaemic variability.
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