Background/Objectives: Tacrine is a centrally active non-competitive reversible acetylcholinesterase inhibitor. It also exerts antagonising activity against N-methyl-D-aspartate receptors. Tacrine was approved for the treatment of Alzheimer's disease in 1993, but was withdrawn from clinical use in 2013 because of its hepatotoxicity and gastrointestinal side effects. Nevertheless, tacrine is currently facing a renewed wave of interest primarily due to several new tacrine-incorporated hybrids and derivates. There were two specific aims for this study: firstly, to explain the mechanisms of the adverse action of tacrine, as a distinctive example of a highly effective acetylcholinesterase inhibitor; and secondly to check whether luminal impedance planimetry is feasible for preclinical testing of possible side effects of compounds potentially toxic to the gastrointestinal tract. Methods: Six experimental pigs were used as the animal model in this study. Five major parameters were evaluated: luminal pressure (mmHg), estimated diameter (mm), cross-sectional area (mm2), distensibility (mm2/mmHg), and zone compliance (mm3/mmHg). All measurements were performed before and 360 min after intragastric administration of 200 mg tacrine (at the porcine tacrine Tmax). Results: This study consistently demonstrated an increase in luminal pressure (a directly measured indicator) for the particular balloon filling volumes used, and inversely a reciprocal decrease in the other parameters after tacrine administration. Conclusions: Endoscopic luminal impedance planimetry is a feasible method to evaluate functional response of the lower oesophageal sphincter to tacrine in experimental pigs. Tacrine did not compromise the function of the lower oesophageal sphincter either toward oesophageal spasms or, in contrast, decreased competence of the lower oesophageal sphincter.

Animal Laboratory Military Faculty of Medicine University of Defence 500 02 Hradec Kralove Czech Republic

Biomedical Research Centre University Hospital Hradec Kralove 500 05 Hradec Kralove Czech Republic

Department of Biological and Medical Sciences Faculty of Pharmacy Charles University 500 03 Hradec Kralove Czech Republic

Department of Data Science Institute for Clinical and Experimental Medicine 140 21 Prague Czech Republic

Department of Gastroenterology St Anne's University Hospital Brno 602 00 Brno Czech Republic

Department of Medicine 1st Faculty of Medicine Charles University Prague and Military University Hospital Prague 169 02 Prague Czech Republic

Department of Toxicology and Military Pharmacy Military Faculty of Medicine University of Defence 500 02 Hradec Kralove Czech Republic

Institute of Gastrointestinal Oncology Military University Hospital Prague 169 02 Prague Czech Republic

Section of Medical Information ANOVA CRO 160 00 Prague Czech Republic

The Royal Marsden NHS Foundation Trust London SW3 6JJ UK

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