Intradermal delivery of modified mRNA encoding VEGF-A in patients with type 2 diabetes.

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.

Initial Clinical Experience with AZD5718, a Novel Once Daily Oral 5-Lipoxygenase Activating Protein Inhibitor.

We evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of AZD5718, a novel 5-lipooxygenase activating protein (FLAP) inhibitor, in a randomized, single-blind, placebo-controlled, first-in-human (FIH) study consisting of single and multiple ascending dosing (SAD and MAD) for 10 days in healthy subjects. Target engagement was measured by ex vivo calcium ionophore stimulated leukotriene B (LTB ) production in whole blood and endogenous leukotriene E (LTE ) in urine. No clinically relevant safety and tolerability findings were observed.

Dipeptidyl Peptidase 1 Inhibitor AZD7986 Induces a Sustained, Exposure-Dependent Reduction in Neutrophil Elastase Activity in Healthy Subjects.

Neutrophil serine proteases (NSPs), such as neutrophil elastase (NE), are activated by dipeptidyl peptidase 1 (DPP1) during neutrophil maturation. High NSP levels can be detrimental, particularly in lung tissue, and inhibition of NSPs is therefore an interesting therapeutic opportunity in multiple lung diseases, including chronic obstructive pulmonary disease (COPD) and bronchiectasis. We conducted a randomized, placebo-controlled, first-in-human study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple oral doses of the DPP1 inhibitor AZD7986 in healthy subjects.

Clinical safety, tolerability, pharmacokinetics and effects on urinary electrolyte excretion of AZD9977, a novel, selective mineralocorticoid receptor modulator.

Aims: AZD9977 is the first mineralocorticoid receptor modulator in clinical development exerting similar organ protection as eplerenone with minimal urinary electrolyte effects in preclinical studies. The aim was to perform the initial clinical assessment of AZD9977.

Methods: A first-in-human trial explored doses from 5 to 1200 mg.

Prospective use of CYP pharmacogenetics and medication analysis to facilitate improved therapy - a pilot study.

Objectives: To assess the efficacy of cytochrome P450 (CYP) pharmacogenetic testing and medication interaction analysis in a controlled environment for reduction of events, stays in hospital, extra care and required extra doctors visits to the patients.

Methods: A prospective cohort study of 28 patients in a geriatric care facility with multimedication and at least one report of an event was performed over a period of 7 months. In the first phase of the study the patients were closely monitored twice a day by the care staff, recording all potential events, regardless of association with the indication or not, requirement for extra care, requirement for an unplanned site visit from a physician and days in hospital.

Pharmacogenomics of asthma.

Patient response to asthma therapy is consistently observed to be heterogeneous. Pharmacogenomics is the study of inherited differences in interindividual drug disposition and effects, with the goal of selecting the optimal drug therapy and dosage for each patient. This review will cover selected examples of gene polymorphisms that influence the outcome of asthma therapy, and whole-genome expression studies using microarray technology that have shown tremendous potential for benefiting asthma pharmacogenomics.

Inhibitors of mitogen-activated protein kinases differentially regulate costimulated T cell cytokine production and mouse airway eosinophilia.

Background: T cells play a dominant role in the pathogenesis of asthma. Costimulation of T cells is necessary to fully activate them. An inducible costimulator (ICOS) of T cells is predominantly expressed on Th2 cells.