Carboxylesterases belong to Phase I group of drug metabolizing enzymes. They hydrolyze a variety of drug esters, amides, carbamates and similar structures. There are five 'carboxylesterase' genes listed in the Human Genome Organization database. In this review, we will focus on the CES1, CES2 and CES3 genes and their protein products that have been partially characterized. Several variants of these three CESs result from alternate splicing, single nucleotide polymorphisms and multiple copy variants. The three CESs, are largely localized to tissues that are major sites of drug metabolism like the mucosa of the gastrointestinal tract, lungs and liver but, they differ in tissue-specific expression. The amino acid alignment of the three CESs reveals important conserved catalytic and structural residues. There are interesting insertions and deletions that may affect enzymatic function as determined by homology modeling of CES3 using the CES1 three-dimensional structure. A comparison of the substrate specificity of CES1 versus CES2 reveals broad but distinct substrate preferences. There is little information on the substrate specificity of CES3 but it seems to have a lower catalytic efficiency than the other two CESs for selected substrates.

Objective Finding medication to support treatment of anorexia nervosa has been difficult. Neuroscience based approaches may help in this effort. Recent brain imaging studies in adults and adolescents with anorexia nervosa suggest that dopamine related reward circuits are hypersensitive and could provide a treatment target. Method Here we present a retrospective chart review of 106 adolescents with anorexia nervosa some of whom were treated with the dopamine D2 receptor partial agonist aripiprazole during treatment in a specialized eating disorder program. Results The results show that aripiprazole treatment was associated with greater increase in body mass index (BMI) during treatment. Discussion The use of dopamine receptor agonists may support treatment success in anorexia nervosa and should be further investigated.

Objective: A consortium of 8 academic child and adolescent psychiatry programs in the United States and Canada examined their pivot from inperson, clinic-based services to home-based telehealth during the COVID-19 pandemic. The aims were to document the transition across diverse sites and to present recommendations for future telehealth service planning. Method: Consortium sites completed a Qualtrics survey assessing site characteristics, telehealth practices, service use, and barriers to and facilitators of telehealth service delivery prior to (pre) and during the early stages of (post) the COVID-19 pandemic. The design is descriptive. Results: All sites pivoted from in-person services to home-based telehealth within 2 weeks. Some sites experienced delays in conducting new intakes, and most experienced delays establishing teleÀgroup therapy. No-show rates and use of telephony versus videoconferencing varied by site. Changes in telehealth practices (eg, documentation requirements, safety protocols) and perceived barriers to telehealth service delivery (eg, regulatory limitations, inability to bill) occurred preÀ/postÀCOVID-19. Conclusion: A rapid pivot from in-person services to home-based telehealth occurred at 8 diverse academic programs in the context of a global health crisis. To promote ongoing use of home-based telehealth during future crises and usual care, academic programs should continue documenting the successes and barriers to telehealth practice to promote equitable and sustainable telehealth service delivery in the future.

This neoadjuvant regimen was safe and demonstrated significant antitumor activity. High TP tumor gene expression was associated with obtaining pCR.

(1-piperidino)-1-piperidino] carbonyloxycamptothecin or Irinotecan] is a carbamate prodrug that is activated in vivo by carboxylesterase (CES)-2 to SN-38 (7-ethyl-10-hydroxycamptothecin), a potent topoisomerase I inhibitor. There is high interindividual variation when CPT-11 is used in the treatment of colorectal cancer. Several splice variants of CES2 are reported in the expressed sequence tag database. Real-time polymerase chain reaction was used to determine the abundance of the CES2 and splice variant of human carboxylesterase 2 (CES2⌬ 458 -473 ) transcripts in 10 paired samples of human tumor and normal colon tissue. The results showed that the CES2⌬ 458 -473 transcript accounts for an average of 6% of total CES2 transcripts in colon tissue, and there is large interindividual variation in CES2 expression in both tumor and normal colon samples. The carboxylesterase activity of the colon samples was determined by 4-methylumbelliferyl acetate hydrolysis assays and nondenaturing polyacrylamide gel electrophoresis followed by activity staining. Significant, positive correlations were found between CES2 expression levels and both measures of carboxylesterase activity. We cloned and expressed the CES2⌬ 458 -473 protein in Sf9 insect cells. The purification profiles and preliminary characterization of the CES2⌬ 458 -473 protein indicated that the expressed protein is folded and glycosylated like CES2. However, in vitro assays show that the CES2⌬ 458 -473 protein lacks 4-methylumbelliferyl acetate and irinotecan hydrolase activities. In conclusion, we found that the CES2⌬ 458 -473 protein is an inactive splice variant of CES2 and that its transcript is spliced at a relatively constant rate in tumor and normal colon tissue.CPT-11 is a semisynthetic camptothecin derivative that is approved for the treatment of metastatic colorectal cancer. Currently, several studies are evaluating the efficacy of CPT-11 in the treatment of solid tumors (Conroy et al., 2005;Delord et al., 2005;Reardon et al., 2005;Stathopoulos et al., 2005). Metabolism of CPT-11 is complex with the involvement of several enzymatic reactions (Rivory, 2000;Slatter et al., 2000). CYP3A4-dependent oxidation of CPT-11 results in the formation of APC and NPC (Haaz et al., 1998;Sai et al., 2001); carboxylesterase-dependent hydrolysis of CPT-11 and NPC results in the formation of the active metabolite SN-38 (Humerickhouse et al., 2000;Khanna et al., 2000;Sanghani et al., 2004) and UGT1A1 glucuronidates SN-38 to form the inactive SN-38-glucuronide (Hanioka et al., 2001). The key step in the metabolism of CPT-11 is its activation by carboxylesterases. There are three known human carboxylesterases, CES1, CES2, and CES3. CES2 has 100-and 2000-fold greater catalytic efficiency for irinotecan hydrolysis than CES1 and CES3, respectively . Therefore, CES2, which is predominantly expressed in the liver, small intestines, and colon (Satoh et al., 2002), is the most important carboxylesterase for the activation of CPT-11. Clinical data, reported by Xu et al....