Utility of Coproporphyrin-I Determination in First-in-Human Study for Early Evaluation of OATP1B Inhibitory Potential Based on Investigation of Ensitrelvir, an Oral SARS-CoV-2 3C-Like Protease Inhibitor.

Coproporphyrin-I (CP-I) has been investigated as an endogenous biomarker of organic anion transporting polypeptide (OATP) 1B. Here, we determined the CP-I concentrations in a cocktail drug-drug interaction (DDI) study of ensitrelvir to evaluate the OATP1B inhibitory potential because ensitrelvir had increased plasma concentrations of rosuvastatin in this study, raising concerns about breast cancer resistance protein and OATP1B inhibition. Furthermore, CP-I concentrations were compared between active and placebo groups in a first-in-human (FIH) study of ensitrelvir to verify whether the OATP1B inhibitory potential could be estimated at an early drug development stage.

Species difference in brain penetration of P-gp and BCRP substrates among monkey, dog and mouse.

The brain penetration of 19 drugs, including P-glycoprotein (P-gp) and/or breast cancer resistance protein (BCRP) substrates, was compared among mice, cynomolgus monkeys and beagle dogs. The brain-to-plasma concentration ratios (K) of the tested compounds in monkey and dog showed good correlation, whereas species differences were observed between non-rodents (monkey/dog) and rodents (mouse). In particular, the K values of 7 compounds out of 12 P-gp substrates (K ratio in P-gp knockout mice versus wild-type mice ≥3) in monkey and dog were more than three-fold higher than those in mice and a similar trend was observed in the brain-to-plasma unbound concentration ratios (K).

Analysis of water-soluble paper for forensic discrimination.

Water-soluble paper (WSP), which easily dissolves in water, has been found in criminal gang hideouts as evidence in crimes including bank transfer fraud, phone fraud, and grandparent scams, i.e. identity fraud to steal money.

Measurement of Distraction Force in Cleft Lip and Palate Patients During Le Fort I Maxillary Advancement With Rigid External Distraction.

Objective: Maxillary distraction osteogenesis (DO) is a mainstream surgical technique for patients who have severe maxillary hypoplasia associated with craniofacial syndromes and cleft-related deformities. However, limited information about the biomechanical aspects of maxillary DO is available limiting broad utilization and improvements to the procedure. The objective of this study was to analyze force levels during the active distraction process and to investigate the relationship between distraction force and maxillary movement during Le Fort I maxillary DO using a rigid external distraction (RED) system.

Riccardin C derivatives cause cell leakage in Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) is a major problem in clinical settings, and because it is resistant to most antimicrobial agents, MRSA infections are difficult to treat. We previously reported that synthetic macrocyclic bis(bibenzyl) derivatives, which were originally discovered in liverworts, had anti-MRSA activity. However, the action mechanism responsible was unclear.

Anti-MRSA activity of isoplagiochin-type macrocyclic bis(bibenzyl)s is mediated through cell membrane damage.

We synthesized three geometrical isomers of a macrocyclic bis(bibenzyl) based on isoplagiochin, a natural product isolated from bryophytes, and evaluated their antibacterial activity towards methicillin-resistant Staphylococcus aureus (anti-MRSA activity). The isomer containing a 1,4-linked ring (5) showed only weak activity, whereas the isomers containing a 1,3-linked (6) or 1,2-linked (7) C ring showed potent anti-MRSA activity. Molecular dynamics calculations indicated that these differences are probably due to differences in the conformational flexibility of the macrocyclic ring; the active compounds 6 and 7 were more rigid than 5.

Structure-anti-MRSA activity relationship of macrocyclic bis(bibenzyl) derivatives.

We synthesized a series of macrocyclic bis(bibenzyl) derivatives, including riccardin-, isoplagiochin- and marchantin-class structures, and evaluated their antibacterial activity towards methicillin-resistant Staphylococcus aureus (anti-MRSA activity). The structure-activity relationships and the results of molecular dynamics simulations indicated that bis(bibenzyl)s with potent anti-MRSA activity commonly have a 4-hydroxyl group at the D-benzene ring and a 2-hydroxyl group at the C-benzene ring in the hydrophilic part of the molecule, and an unsubstituted phenoxyphenyl group in the hydrophobic part of the molecule containing the A-B-benzene rings. Pharmacological characterization of the bis(bibenzyl) derivatives and 2-phenoxyphenol fragment 25, previously proposed as the minimum structure of riccardin C 1 for anti-MRSA activity, indicated that they have different action mechanisms: the bis(bibenzyl)s are bactericidal, while 25 is bacteriostatic, showing only weak bactericidal activity.

Riccardin C derivatives as anti-MRSA agents: structure-activity relationship of a series of hydroxylated bis(bibenzyl)s.

Members of a series of macrocyclic bis(bibenzyl) riccardin-class derivatives were found to exhibit antibacterial activity towards methicillin-resistant Staphylococcus aureus (anti-MRSA activity). Structure-activity relationship (SAR) studies were conducted, focusing on the number and position of the hydroxyl groups. The minimum essential structure for anti-MRSA activity was also investigated.