PA-457 [3-O-(3′,3′-dimethylsuccinyl)-betulinic acid] represents a new class of anti-HIV drug candidates termed maturation inhibitors. After oral administration to rats, PA-457 was metabolized to several glucuronide conjugates and mainly eliminated into rat bile. Liquid chromatography-electrospray ionization-mass spectrometry analysis showed that the glucuronidation products of PA-457 were acyl glucuronides including one di-glucuronide, di-PA-457G, and two mono-glucuronides, referred to as mono-PA-457G (I) and mono-PA-457G (II), respectively. In-source fragmentation of MS spectra supported the conclusion that mono-PA-457G (I) was glucuronidated at the C-28 carboxyl of PA-457, whereas mono-PA-457G (II) was conjugated at the dimethylsuccinic acid side chain of the C-3 position. Quantification demonstrated that the predominant glucuronide of PA-457 in rat bile was mono-PA-457G (I) with lower amounts of mono-PA-457G (II) and di-PA-457G. In vitro stability indicated that the mono-acyl glucuronides of PA-457 were not degraded after incubation with 0.1 M phosphate buffer (pH 4, 7.4 and 9), plasma (human, rat, and mouse), and UDP-glucuronosyltransferase reaction media (without uridine 5′-diphosphoglucuronic acid) with microsomes (human, rat, and mouse liver microsomes), respectively, whereas the minor diglucuronide was unstable in rodent liver microsomes. All glucuronides of PA-457 could be hydrolyzed both by β-glucuronidase and alkaline (1 M NaOH). Minor putative acyl migration products were slowly formed at pH 9, suggesting that the acyl glucuronides of PA-457 have relatively high in vitro stability.
Curcumin inhibits UDP-glucuronyltransferases, a primary metabolic pathway for cancer chemotherapeutic agents like irinotecan. Concurrent administration of both agents may exacerbate irinotecan toxicity. We conducted this phase I study to determine the safety of concurrent curcumin and irinotecan administration. Ten participants with advanced solid tumors received one of four doses (1, 2, 3, and 4 g) of a curcumin phosphatidylcholine complex (PC) orally daily, and 200 mg/m
Pregnancy increases the clearance of CYP3A4 substrate drugs and pregnancy-related hormones (PRHs) induce hepatic CYP3A4 expression and metabolism. However, it remains unclear to what extent the magnitude of PRH-evoked changes in hepatic CYP3A metabolism varies across multiple substrates. This study quantified the impact of PRHs on CYP3A protein concentrations and buprenorphine metabolism in human hepatocytes, and compared the magnitude of these effects to nifedipine and midazolam metabolism.
Quantitative characterization of UDP-glucuronosyltransferase (UGT) enzymes is valuable in glucuronidation reaction phenotyping, predicting metabolic clearance and drug-drug interactions using extrapolation exercises based on pharmacokinetic modeling. Different quantitative proteomic workflows have been employed to quantify UGT enzymes in various systems, with reports indicating large variability in expression, which cannot be explained by interindividual variability alone. To evaluate the effect of methodological differences on end-point UGT abundance quantification, eight UGT enzymes were quantified in 24 matched liver microsomal samples by two laboratories using stable isotope-labeled (SIL) peptides or quantitative concatemer (QconCAT) standard, and measurements were assessed against catalytic activity in seven enzymes (n = 59). There was little agreement between individual abundance levels reported by the two methods; only UGT1A1 showed strong correlation [Spearman rank order correlation (Rs) = 0.73, P < 0.0001; R2 = 0.30; n = 24]. SIL-based abundance measurements correlated well with enzyme activities, with correlations ranging from moderate for UGTs 1A6, 1A9, and 2B15 (Rs = 0.52–0.59, P < 0.0001; R2 = 0.34–0.58; n = 59) to strong correlations for UGTs 1A1, 1A3, 1A4, and 2B7 (Rs = 0.79–0.90, P < 0.0001; R2 = 0.69–0.79). QconCAT-based data revealed generally poor correlation with activity, whereas moderate correlations were shown for UGTs 1A1, 1A3, and 2B7. Spurious abundance-activity correlations were identified in the cases of UGT1A4/2B4 and UGT2B7/2B15, which could be explained by correlations of protein expression between these enzymes. Consistent correlation of UGT abundance with catalytic activity, demonstrated by the SIL-based dataset, suggests that quantitative proteomic data should be validated against catalytic activity whenever possible. In addition, metabolic reaction phenotyping exercises should consider spurious abundance-activity correlations to avoid misleading conclusions.
Abstract What attitudes do preservice teachers have regarding ESL (English as a Second Language) students, and do these attitudes change by taking an introductory ESL course? A survey was conducted with university students enrolled in an introductory ESL course to answer this question. The survey was administered as a pre- and post-course questionnaire to a total of 164 students. The post-course survey contained an additional section that asked the participants to rate how much they felt their perceptions had changed and what they felt had contributed to that change. The results indicate that an ESL introductory course, and particularly the field experience connected to it, can contribute to preservice teachers' confidence in being able to help ESL students, and help overcome the fear of having them as students in their mainstream classrooms. Introduction Present demographic trends in the United States indicate that by the year 2026, one in every four children in our public schools will be an English language learner (Garcia, 1999). This increases the demand for mainstream teachers to be skilled in educating ESL students in their mainstream classes. The purpose of this study is to examine the effect of an introductory ESL methods course on the attitudes of preservice teachers regarding ESL students. The following questions are addressed: (1) What impact does an initial ESL education class have on preservice teachers' attitudes regarding ESL students? (2) What attitudes change the most? and (3) What factors contribute to preservice teachers' attitudes regarding ESL students? Review of Literature Teachers' attitudes play an important part in the over-all learning process (Bloom, 1976; Diaz-Rico & Weed, 2002; Garcia, 1999; and Krashen, 1981). Second Language Acquisition (SLA) theory informs us of the importance of providing a good learning environment for all ESL students. The teacher's attitudes have a direct effect on the students' motivation, self-esteem, and anxiety level (Krashen, 1981; and Garcia, 1999). Studies have been conducted regarding preservice teachers' expectations for ESL students (Terrill & Mark, 2000), attitudes toward diversity (Agnello & Mittag, 1999), attitudes toward urban schools (Mason, 1999), and zone of concern and comfort with multiculturalism (Montecinos et al., 1999). Several studies and articles have been written about teachers' attitudes toward ESL students (Byrnes et al., 1996; Clair, 1995; Layzer, 2000; Markham et al., 1996; Terrill & Mark, 2000; and Youngs & Youngs, 2001), but no studies known to the investigator have examined the effect that ESL courses have on preservice teachers' attitudes toward ESL students. The importance of teachers' attitudes is emphasized in the Professional Standards for the Accreditation of Schools, Colleges, and Departments of Education by NCATE (National Council for Accreditation of Teacher Education). This document not only recognizes that knowledge and skills is valued in teachers, but dispositions as well (Standard 1: Candidate's knowledge, skills, and dispositions). This inclusion reflects the growing awareness nationally of the importance of attitudes and beliefs for beginning teachers (NCATE, 2001). Method This study was conducted with university students enrolled in an introductory ESL course. For many of these preservice teachers, this course is the first time they worked with, or even thought about ESL students. This course gives participants an over-view of ESL policies and practices, cultural awareness, SLA (second language acquisition) theory, methods of teaching ESL, and ESL student assessment. This is a required course for Elementary, Early Childhood, Secondary English, Foreign Language, and Special Education majors. The development of the survey instrument was a multi-step process that began with a compilation of actual statements made by preservice teachers. …
The liver is the predominant organ of metabolism for many endogenous and foreign chemicals. Cytosolic sulfotransferases (SULTs) catalyze the sulfonation of drugs and other xenobiotics, as well as hormones, neurotransmitters, and sterols, with consequences that include enhanced drug elimination, hormone inactivation, and procarcinogen bioactivation. SULTs are classified into six gene families, but only SULT1 and SULT2 enzymes are expressed in human liver. We characterized the developmental expression patterns of SULT1 and SULT2 mRNAs and proteins in human liver samples using reverse transcription quantitative polymerase chain reaction (RT-qPCR), RNA sequencing, and targeted quantitative proteomics. Using a set of prenatal, infant, and adult liver specimens, RT-qPCR analysis demonstrated that SULT1A1 (transcript variant 1) expression did not vary appreciably during development; SULT1C2, 1C4, and 1E1 mRNA levels were highest in prenatal and/or infant liver, and 1A2, 1B1, and 2A1 mRNA levels were highest in infant and/or adult. Hepatic SULT1A1 (transcript variant 5), 1C3, and 2B1 mRNA levels were low regardless of developmental stage. Results obtained with RNA sequencing of a different set of liver specimens (prenatal and pediatric) were generally comparable results to those of the RT-qPCR analysis, with the additional finding that SULT1A3 expression was highest during gestation. Analysis of SULT protein content in a library of human liver cytosols demonstrated that protein levels generally corresponded to the mRNAs, with the major exception that SULT1C4 protein levels were much lower than expected based on mRNA levels. These findings further support the concept that hepatic SULTs play important metabolic roles throughout the human life course, including early development.
Chiral inversion of R(−)‐ to S(+)‐ibuprofen in children with cystic fibrosis was investigated. Children with cystic fibrosis (n = 38, ages 2–13 years) were administered a single oral dose of racemic ibuprofen (20 mg/kg), and the pharmacokinetics of ibuprofen was found to be stereoselective. Mean C max , AUC, apparent CL/F, and V area /F of S‐ibuprofen were significantly different from those of R‐ibuprofen. The enantiomeric ratio of plasma AUC (S:R = 2.09:1) and of free and conjugated ibuprofen in urine (S:R = 13.9:1) of children with cystic fibrosis was not different from reported values for healthy children and adults. No significant gender difference was observed for any of the pharmacokinetic parameters determined. However, there was an inverse linear relationship between the CL/F of R‐ibuprofen and age in children with cystic fibrosis. Apparent CL/F was higher in children with cystic fibrosis than previously reported for healthy children; therefore, higher doses of ibuprofen would be necessary for children with cystic fibrosis.
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