ABSTRACT
Camostat mesylate, an oral serine protease inhibitor, is used to treat chronic pancreatitis and reflux esophagitis. Recently, camostat mesylate and its active metabolite 4-(4-guanidinobenzoyloxy)phenylacetic acid (GBPA) were reported to inhibit the infection of cells by severe acute respiratory syndrome coronavirus 2 by inhibiting type II transmembrane serine protease. We conducted a phase I study to investigate high-dose camostat mesylate as a treatment for coronavirus disease 2019. Camostat mesylate was orally administered to healthy adults at 600 mg 4 times daily under either of the following conditions: fasted state, after a meal, 30 min before a meal, or 1 h before a meal, and the pharmacokinetics and safety profiles were evaluated. In addition, the time of plasma GBPA concentration exceeding the effective concentration was estimated as the time above half-maximal effective concentration (EC50 ) by using pharmacokinetic/pharmacodynamic modeling and simulation. Camostat mesylate was safe and tolerated at all dosages. Compared with the fasted state, the exposure of GBPA after a meal and 30 min before a meal was significantly lower; however, no significant difference was observed at 1 h before a meal. The time above EC50 was 11.5 h when camostat mesylate 600 mg was administered 4 times daily in the fasted state or 1 h before a meal. Based on the results of this phase I study, we are currently conducting a phase III study.
Subject(s)
COVID-19 Drug Treatment , Drug Repositioning , Esters/adverse effects , Guanidines/adverse effects , Serine Proteinase Inhibitors/administration & dosage , Administration, Oral , Adolescent , Adult , Computer Simulation , Dose-Response Relationship, Drug , Drug Administration Schedule , Esters/administration & dosage , Esters/pharmacokinetics , Food-Drug Interactions , Guanidines/administration & dosage , Guanidines/pharmacokinetics , Healthy Volunteers , Humans , Male , Middle Aged , Models, Biological , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/adverse effects , Young AdultABSTRACT
Imidacloprid is widely used for exterminating harmful insects; however, information regarding its distribution in insects is limited. Herein, we developed a visualization method for imidacloprid in Drosophila melanogaster, by using matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS). IMS requires sample cryosections; however, certain challenges prevail in retaining fly morphology in sections owing to their small size and heterogeneous components. Therefore, the section preparation method was optimized first, followed by imidacloprid distribution visualized using MALDI-IMS. Using 10% gelatin as an embedding material and 70% ethanol for pretreatment, the gaps between embedding material and D. melanogaster body surface were reduced. The tight adhesion between embedding media and D. melanogaster retains fly morphology in sections. Furthermore, the imidacloprid standard was analyzed separately via MALDI and electrospray ionization (ESI), and imidacloprid was converted to guanidine-imidacloprid via laser irradiation. Consequently, the imidacloprid distribution in D. melanogaster was successfully visualized using guanidine-imidacloprid as the target peak.
