Objective The aim of the present study was to develop a neural network to characterize the effect of aging on the ECG in healthy volunteers. Moreover, the impact of the various ECG features on aging was evaluated. Methods & Results A total of 6228 healthy subjects without structural heart disease were included in this study. A neural network regression model was created to predict age of the subjects based on their ECG; 577 parameters derived from a 12-lead ECG of each subject were used to develop and validate the neural network; A ten fold cross-validation was performed, using 118 subjects for validation eacht fold. Using SHapley Additive exPlanations values the impact of the individual features on the prediction of age was determined. Of 6228 subjects tested, 1808 (29%) were females and mean age was 34 years, range 18 – 75 years. Physiologic age was estimated as a continuous variable with an average error of 6.9±5.6 years (R2= 0.72 ± 0.04) . The correlation was slightly stronger for men (R2= 0.74) than for women (R2= 0.66). The most important features on the prediction of physiologic age were T wave morphology indices in leads V4 and V5, and P wave amplitude in leads AVR and II. Conclusion The application of artificial intelligence to the ECG using a neural network regression model, allows accurate estimation of physiologic cardiac age. This technique could be used to pick up subtle age-related cardiac changes, but also estimate the reversing of these age-associated effects by administered treatments.

There is a need for anti-diabetic agents successfully targeting insulin sensitivity and treating obesity control at the same time. The aim of this first-in-human study was 1) to evaluate safety and tolerability; 2) to evaluate pharmacokinetics and 3) to assess indications of receptor engagement of single ascending doses of KBP-042, a Dual Amylin and Calcitonin Receptor Agonists (DACRA) that has shown promising preclinical data, with superior activity in terms of typical amylin-induced responses including reduction of food intake, weight loss and gluco-regulatory capacities. A randomised double-blind placebo-controlled single ascending dose study was performed with six dose levels of KBP-042 (5, 7.5, 10, 20, 20 evening and 40µg) in healthy male adults. KBP-042 or placebo was administered as a single dose after an overnight fast, followed by a standardized lunch after four hours. KBP-042 was associated with dose-dependent complaints of nausea and vomiting, with a lack of tolerability at doses of 20µg and above. Doses of 5 to 40 μg KBP-042 were behaved according to a linear pharmacokinetic profile. Indications of target receptor engagement were observed at the level of glucose control and lowering of bone resorption, compared to placebo. The results of this study showed that doses up to 40 μg were safe, although tolerability was not present at the highest doses. The study confirmed target receptor engagement at the studied doses.

Aim To evaluate feasibility of intradermal (i.d.) adalimumab administration using hollow microneedles, and to compare a single i.d. dose of adalimumab using a hollow microneedle with a single subcutaneous (s.c.) dose using a conventional needle. Methods In this single-centre double-blind, placebo-controlled, double-dummy clinical trial in 24 healthy adults we compared 40 mg adalimumab (0.4 mL) administered i.d. using a hollow microneedle with a s.c. dose using a conventional needle. Primary parameters were pain, acceptability, and local tolerability; secondary parameters safety, pharmacokinetics and immunogenicity. We explored usability of optical coherence tomography (OCT), clinical photography, thermal imaging, and laser speckle contrast imaging (LSCI) to evaluate skin reaction after i.d. injections. In vitro protein analysis was performed to assess compatibility of adalimumab with the hollow microneedle device. Results While feasible and safe, injection pain of i.d. adalimumab was higher compared to s.c. adalimumab (35.4 vs. 7.9 on a 101-point VAS scale). Initial absorption rate and bioavailability were higher after i.d. adalimumab (Tmax=95h(47-120); F=129%(6.46%)) compared to s.c. adalimumab (Tmax=120h(96-221)). In 50% and 83% of the subjects anti-adalimumab antibodies were detected after i.d. and s.c. adalimumab, respectively. We observed statistically significantly more erythema and skin perfusion after i.d. adalimumab, compared to s.c. adalimumab and placebo injections (p<0.0001). Cytokine secretion after whole blood LPS challenge was comparable between administration routes. Conclusion Intradermal of adalimumab using hollowing microneedles was perceived as more painful, and less accepted than s.c. administration, however, yields a higher bioavailability with similar safety and pharmacodynamic effects.

Aim: To investigate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of the highly selective oral p38α/β MAP-kinase inhibitor Org 48775-0, a first-in-human study was conducted. Methods: In the SAD study part, an oral dose of Org 48775-0 ranging from 0.3 mg to 600 mg was evaluated in healthy males. In the MAD study part, dose levels of 30, 70 and 150 mg were evaluated with dosing for six consecutive days, twice daily. Both studies were performed in a double-blind, randomized, placebo-controlled, cross-over fashion and evaluated pharmacokinetics (PK), pharmacodynamics (PD; inhibition of LPS-induced TNFα release) and routine clinical and laboratory data. Moreover, the effect of a standardized fat meal on PK and PD parameters of Org 48775-0 was evaluated, and PK and PD parameters of Org 48775-0 were compared between healthy males and postmenopausal females. Results: All adverse events observed in the SAD and MAD cohorts were mild, transient and completely reversible without medical intervention. Pharmacokinetics were linear up to single dose s of 400 mg. Org 48775-0 doses equal to and greater than 30 mg significantly inhibited LPS-induced TNFα release (42.3% increase in inhibition, 95% CI=-65.2; -4.3) compared to placebo. In the MAD study, Org 48775-0 treatment inhibited the LPS-induced TNFα release during the entire steady state period. Levels of inhibition amounted 30-75% for 30 mg, 53-80% for 70 mg, and 77-92% for 150 mg Org 48775-0. Conclusion: This study demonstrates that Org 48775-0 has the capacity to significantly inhibit MAP-kinase activity in humans, without raising safety concerns.