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- Ericsson, H., et al.
(författare)
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Phase 1 Pharmacokinetic Study of AZD5718 in Healthy Volunteers: Effects of Coadministration With Rosuvastatin, Formulation and Food on Oral Bioavailability
- 2020
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Ingår i: Clinical Pharmacology in Drug Development. - : Wiley. - 2160-7648 .- 2160-763X. ; 9:3, s. 411-421
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Tidskriftsartikel (refereegranskat)abstract
- AZD5718 is a first-in-class small-molecule anti-inflammatory drug with the potential to reduce the residual risk of cardiovascular events after myocardial infarction in patients receiving lipid-lowering statin therapy. Leukotrienes are potent proinflammatory and vasoactive mediators synthesized in leukocytes via 5-lipoxygenase and 5-lipoxygenase-activating protein (FLAP). AZD5718 is a FLAP inhibitor that dose-dependently reduced leukotriene biosynthesis in a first-in-human study. We enrolled 12 healthy men in a randomized, open-label, crossover, single-dose phase 1 pharmacokinetic study of AZD5718 to investigate a potential drug-drug interaction with rosuvastatin, and the effects of formulation and food intake (ClinicalTrials.gov identifier: NCT02963116). Rosuvastatin (10 mg) were absorbed more rapidly when coadministered with AZD5718 (200 mg), probably owing to weak inhibition of hepatic statin uptake, but relative bioavailability was unaffected (geometric least-squares mean ratio [GMR], 100%; 90% confidence interval [CI], 86%-116%). AZD5718 pharmacokinetics were unaffected by coadministration of rosuvastatin. AZD5718 (200 mg) was absorbed less rapidly when formulated as tablets than oral suspension, with reduced relative bioavailability (GMR, 72%; 90%CI, 64%-80%). AZD5718 absorption was slower when 200-mg tablets were taken after a high-fat breakfast than after fasting, but relative bioavailability was unaffected (GMR, 96%; 90%CI, 87%-106%). In post hoc pharmacodynamic simulations, plasma leukotriene B-4 levels were inhibited by >90% throughout the day following once-daily AZD5718, regardless of formulation or administration with food. AZD5718 was well tolerated, with no severe or serious adverse events. These data supported the design of a phase 2a efficacy study of AZD5718 in patients with coronary artery disease.
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| 2. |
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| 3. |
- Anttila, V., et al.
(författare)
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Synthetic mRNA Encoding VEGF-A in Patients Undergoing Coronary Artery Bypass Grafting: Design of a Phase 2a Clinical Trial
- 2020
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Ingår i: Molecular Therapy-Methods & Clinical Development. - : Elsevier BV. - 2329-0501. ; 18, s. 464-472
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Tidskriftsartikel (refereegranskat)abstract
- Therapeutic angiogenesis may improve outcomes in patients with coronary artery disease undergoing surgical revascularization. Angiogenic factors may promote blood vessel growth and regenerate regions of ischemic but viable myocardium. Previous clinical trials of vascular endothelial growth factor A (VEGF-A) gene therapy with DNA or viral vectors demonstrated safety but not efficacy. AZD8601 is VEGF-A(165) mRNA formulated in biocompatible citrate-buffered saline and optimized for high-efficiency VEGF-A expression with minimal innate immune response. EPICCURE is an ongoing randomized, double-blind, placebo-controlled study of the safety of AZD8601 in patients with moderately decreased left ventricular function (ejection fraction 30% 50%) undergoing elective coronary artery bypass surgery. AZD8601 3 mg, 30 mg, or placebo is administered as 30 epicardial injections in a 10-min extension of cardioplegia. Injections are targeted to ischemic but viable myocardial regions in each patient using quantitative O-15-water positron emission tomography (PET) imaging (stress myocardial blood flow < 2.3 mL/g/min; resting myocardial blood flow > 0.6 mL/g/min). Improvement in regional and global myocardial blood flow quantified with O-15-water PET is an exploratory efficacy outcome, together with echocardiographic, clinical, functional, and biomarker measures. EPICCURE combines high-efficiency delivery with quantitative targeting and follow-up for robust assessment of the safety and exploratory efficacy of VEGF-A mRNA angiogenesis (ClinicalTrials.gov: NCT03370887).
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| 6. |
- Arsalani, N., et al.
(författare)
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Iranian nursing staff's self-reported general and mental health related to working conditions and family situation
- 2012
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Ingår i: International Nursing Review. - : Wiley. - 0020-8132 .- 1466-7657. ; 59:3, s. 416-423
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Tidskriftsartikel (refereegranskat)abstract
- Background: There is increasing global evidence that today's work environment results in higher risk of adverse health among nursing staff than among other professions.Aim: To investigate self-reported general and mental health among Iranian nursing staff, and associations with organizational, physical and psychosocial working conditions and family situation.Methods: 520 nursing personnel from 10 university hospitals in Tehran participated in this cross-sectional study. Data were collected using a validated questionnaire in the Persian language, containing the Copenhagen Psychosocial Questionnaire, physical items from the Nurse Early eXit Study and two scales relating to general health and mental health from the Short Form-36. The Chi-square test with P < 0.05 and logistic regression were used to analyse data.Results: Three out of four nursing staff reported overtime work. The self-reported general and mental health rates of participants were poor/fair (38%, 41%), good (44%, 39%) and very good/excellent (18%, 20%), respectively. Family demands were associated with general health but were not associated with mental health. Adverse physical and psychosocial work conditions gave an elevated odds ratio for poor health.Conclusion: Poor general and mental health was associated with adverse working conditions and family demands. Physical and psychosocial working conditions of nursing personnel should be improved. Social facilities such as daycare for children and care for the elderly should be available during work shifts to help Iranian nurses play their family roles.
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| 9. |
- Gan, Li-Ming, 1969, et al.
(författare)
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Intradermal delivery of modified mRNA encoding VEGF-A in patients with type 2 diabetes
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Chemically modified mRNA is an efficient, biocompatible modality for therapeutic protein expression. We report a first-time-in-human study of this modality, aiming to evaluate safety and potential therapeutic effects. Men with type 2 diabetes mellitus (T2DM) received intradermal injections of modified mRNA encoding vascular endothelial growth factor A (VEGF-A) or buffered saline placebo (ethical obligations precluded use of a non-translatable mRNA control) at randomized sites on the forearm. The only causally treatment-related adverse events were mild injection-site reactions. Skin microdialysis revealed elevated VEGF-A protein levels at mRNA-treated sites versus placebo-treated sites from about 4-24 hours post-administration. Enhancements in basal skin blood flow at 4 hours and 7 days post-administration were detected using laser Doppler fluximetry and imaging. Intradermal VEGF-A mRNA was well tolerated and led to local functional VEGF-A protein expression and transient skin blood flow enhancement in men with T2DM. VEGF-A mRNA may have therapeutic potential for regenerative angiogenesis.
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