Demonstration of the innate electrophilicity of 4-(3-(benzyloxy)phenyl)-2-(ethylsulfinyl)-6trifluoromethyl)pyrimidine (BETP), a small molecule positive allosteric modulator of the glucagon-like peptide-1. Drug Metab. Dispos

ABSTRACT 4-(3-(Benzyloxy)phenyl)-2-(ethylsulfinyl)-6-(trifluoromethyl)pyrimidine (BETP) represents a novel small-molecule activator of the glucagonlike peptide-1 receptor (GLP-1R), and exhibits glucose-dependent insulin secretion in rats following i.v. (but not oral) administration. To explore the quantitative pharmacology associated with GLP-1R agonism in preclinical species, the in vivo pharmacokinetics of BETP were examined in rats after i.v. and oral dosing. Failure to detect BETP in circulation after oral administration of a 10-mg/kg dose in rats was consistent with the lack of an insulinotropic effect of orally administered BETP in this species. Likewise, systemic concentrations of BETP in the rat upon i.v. administration (1 mg/kg) were minimal (and sporadic). In vitro incubations in bovine serum albumin, plasma, and liver microsomes from rodents and humans indicated a facile degradation of BETP. Failure to detect metabolites in plasma and liver microsomal incubations in the absence of NADP was suggestive of a covalent interaction between BETP and a protein amino acid residue(s) in these matrices. Incubations of BETP with glutathione (GSH) in buffer revealed a rapid nucleophilic displacement of the ethylsulfoxide functionality by GSH to yield adduct M1, which indicated that BETP was intrinsically electrophilic. The structure of M1 was unambiguously identified by comparison of its chromatographic and mass spectral properties with an authentic standard. The GSH conjugate of BETP was also characterized in NADPH-and GSH-supplemented liver microsomes and in plasma samples from the pharmacokinetic studies. Unlike BETP, M1 was inactive as an allosteric modulator of the GLP-1R

Updating Biodiversity Studies in Loricate Protists: The Case of the Tintinnids (Alveolata, Ciliophora, Spirotrichea)

Species determination is crucial in biodiversity research. In tintinnids, identification is based almost exclusively on the lorica, despite its frequent intraspecific variability and interspecific similarity. We suggest updated procedures for identification and, depending on the aim of the study, further steps to obtain morphological, molecular, and ecological data. Our goal is to help improving the collection of information ( e. g. species re-/descriptions and DNA barcodes) that is essential for generating a natural tintinnid classification and a reliable reference for environmental surveys. These suggestions are broadly useful for protistologists because they exemplify data integration, quality/ effort compromise, and the need for scientific collaborations

Safety and Clinical Outcomes when Utilizing High-Dose (≥8 mg/kg) Daptomycin Therapy

Background: Daptomycin is approved for the treatment of skin and skin-structure infections (4 mg/kg) and Staphylococcus aureus bacteremia, including right-sided endocarditis (β mg/kg). In vitro and animal studies have reported increased activity with increased daptomycin doses. There are limited clinical data on use of daptomycin at doses greater than 6 mg/kg. Objective: To evaluate the safety and efficacy of higher doses (≥8 mg/kg) of daptomycin when administered for a variety of gram-positive infections. Methods: Data were collected retrospectively as part of an ongoing registry (the Cubicin Outcomes Registry and Experience database) for the 2005–2007 program years. For the purpose of this study, the safety and efficacy of daptomycin were evaluated in patients who received doses of 8 m/kg or higher. Results: Ninety-four (2.6%) of 3617 patients received daptomycin doses of 6 mg/kg or higher; 18 (19%) of those patients received doses of 10 mg/kg or higher. The most common infections were bacteremia (30/94), skin and skin-structure infections (22/94), and endocarditis (15/94). The most common pathogens were Enterococcus spp. (37/94; 57% vancomycin-resistant) and S. aureus (28/94; 68% methicllin-resistant). Fifty-one percent of the patients were male. 39% were aged 66 years or older, 27% had an initial creatinine clearance less than 30 mL/min, and 17% were on dialysis. The median duration of daptomycin therapy was 15 days (minimum 1, maximum 90). Six (6.4%) of the 94 patients experienced 1 or more adverse events or abnormal laboratory value changes possibly related to daptomycin; in 2 (2.1%) of the 94 patients, daptomycin was discontinued due to treatment-related adverse events. Seventy-four (79%) patients were considered evaluable for efficacy. The overall clinical success rate was 89% (bacteremia, 91 %; skm and skin-structure infections. 88%: endocarditis. 67%) Conclusions: Daptomycin was well tolerated and effective at doses of 8 mg/kg or higher in patients with gram-positive infections. Further prospective and comparative studies of daptomycin at doses greater than 6 mg/kg are warranted. </jats:sec