Design and Preclinical Characterization Program toward Asundexian (BAY 2433334), an Oral Factor XIa Inhibitor for the Prevention and Treatment of Thromboembolic Disorders.

Activated coagulation factor XI (FXIa) is a highly attractive antithrombotic target as it contributes to the development and progression of thrombosis but is thought to play only a minor role in hemostasis so that its inhibition may allow for decoupling of antithrombotic efficacy and bleeding time prolongation. Herein, we report our major efforts to identify an orally bioavailable, reversible FXIa inhibitor. Using a protein structure-based de novo design approach, we identified a novel micromolar hit with attractive physicochemical properties. During lead modification, a critical problem was balancing potency and absorption by focusing on the most important interactions of the lead series with FXIa while simultaneously seeking to improve metabolic stability and the cytochrome P450 interaction profile. In clinical trials, the resulting compound from our extensive research program, asundexian (BAY 2433334), proved to possess the desired DMPK properties for once-daily oral dosing, and even more importantly, the initial pharmacological hypothesis was confirmed.

Coffee break has no impact on laparoscopic skills: a randomized double-blinded placebo-controlled parallel-group trial.

BACKGROUND: Coffee is a widely consumed beverage. Surgeons often drink coffee before performing surgery. Caffeine intake leads to tremor which might have a negative effect on surgeons' fine motor skills. METHODS: A double-blinded parallel-group trial was conducted in order to investigate if caffeinated coffee intake has a negative effect on laparoscopic skills and increases tremor, regardless of previous coffee consumption. 118 participants were selected during a congress of the German Society of Surgery. Exclusion criteria were immaturity and no given consent. Participants and investigators were blinded. Participants were randomized with a 1:1 allocation into interventional group receiving caffeinated coffee or placebo group receiving decaffeinated coffee. The motor skills were tested with two validated laparoscopic exercises at a laparoscopy simulator (LapSim®) before and 30 min after coffee intake. Data on influencing factors were recorded in a standardized questionnaire and tested for equal distribution in both groups. In both exercises four parameters were recorded: left and right hand path length and angular path. Their differences and the resulting effect scores were calculated for both groups as primary outcome to test which group showed greater improvement on the second round of exercises. Registration number DRKS00023608, registered retrospectively. RESULTS: Fifty nine subjects were assigned to each the interventional (54 analyzed) and placebo group (53 analyzed) with 11 drop outs. There was no significant difference between the placebo and interventional group in the two exercises in effect score 30 min after coffee intake [mean (SD); 38.58 (10.66) vs. 41.73 (7.40) and 113.09 (28.94) vs. 116.59 (25.63)]. A significant improvement from first to second measurement in the first exercise could be observed for both groups, demonstrating the training effect. CONCLUSION: In our study, we verified that additional caffeinated coffee intake, e.g., during a coffee break, does not lead to deterioration of laparoscopic fine motor skills.

Translational In Vivo Models for Cardiovascular Diseases.

Cardiovascular diseases are still the first leading cause of death and morbidity in developed countries. Experimental cardiology research and preclinical drug development in cardiology call for appropriate and especially clinically relevant in vitro and in vivo studies. The use of animal models has contributed to expand our knowledge and our understanding of the underlying mechanisms and accordingly provided new approaches focused on the improvement of diagnostic and treatment strategies of various cardiac pathologies.Numerous animal models in different species as well as in small and large animals have been developed to address cardiovascular complications, including heart failure, pulmonary hypertension, and thrombotic diseases. However, a perfect model of heart failure or other indications that reproduces every aspect of the natural disease does not exist. The complexity and heterogeneity of cardiac diseases plus the influence of genetic and environmental factors limit to mirror a particular disease with a single experimental model.Thus, drug development in the field of cardiology is not only very challenging but also inspiring; therefore animal models should be selected that reflect as best as possible the disease being investigated. Given the wide range of animal models, reflecting critical features of the human pathophysiology available nowadays increases the likelihood of the translation to the patients. Furthermore, this knowledge and the increase of the predictive value of preclinical models help us to find more efficient and reliable solutions as well as better and innovative treatment strategies for cardiovascular diseases.