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- Scott, James S., et al.
(author)
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Circumventing seizure activity in a series of G protein coupled receptor 119 (GPR119) agonists
- 2014
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In: Journal of Medicinal Chemistry. - : American Chemical Society. - 0022-2623 .- 1520-4804. ; 57:21, s. 8984-8998
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Journal article (peer-reviewed)abstract
- Agonism of GPR119 is viewed as a potential therapeutic approach for the treatment of type II diabetes and other elements of metabolic syndrome. During progression of a previously disclosed candidate 1 through mice toxicity studies, we observed tonic-clonic convulsions in several mice at high doses. An in vitro hippocampal brain slice assay was used to assess the seizure liability of subsequent compounds, leading to the identification of an aryl sulfone as a replacement for the 3-cyano pyridyl group. Subsequent optimization to improve the overall profile, specifically with regard to hERG activity, led to alkyl sulfone 16. This compound did not cause tonic-clonic convulsions in mice, had a good pharmacokinetic profile, and displayed in vivo efficacy in murine models. Importantly, it was shown to be effective in wild-type (WT) but not GPR119 knockout (KO) animals, consistent with the pharmacology observed being due to agonism of GPR119.
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| 2. |
- Solmi, Francesca, et al.
(author)
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Prevalence of purging at age 16 and associations with negative outcomes among girls in three community-based cohorts.
- 2015
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In: Journal of Child Psychology and Psychiatry. - : Wiley. - 0021-9630 .- 1469-7610. ; 56:1, s. 87-96
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Journal article (peer-reviewed)abstract
- BACKGROUND: The comorbidity of purging behaviours, such as vomiting, inappropriate use of laxatives, diuretics or slimming medications, has been examined in literature. However, most studies do not include adolescents, individuals who purge in the absence of binge eating, or those purging at subclinical frequency. This study examines the prevalence of purging among 16-year-old girls across three countries and their association with substance use and psychological comorbidity.METHODS: Data were obtained by questionnaire in 3 population-based cohorts (Avon Longitudinal Study of Parents and Children (ALSPAC), United Kingdom, n = 1,608; Growing Up Today Study (GUTS), USA, n = 3,504; North Finland Birth Cohort (NFBC85/86), Finland, n = 2,306). Multivariate logistic regressions were employed to estimate associations between purging and outcomes. Four models were fit adjusting for binge eating and potential confounders of these associations.RESULTS: In ALSPAC, 9.7% of girls reported purging in the 12-months prior to assessment, 7.3% in GUTS, and 3.5% in NFBC. In all 3 cohorts, purging was associated with adverse outcomes such as binge drinking (ALSPAC: odds ratio (OR) = 2.0, 95% confidence interval (CI) = 1.4-2.9; GUTS: OR = 2.5, 95% CI = 1.5-4.0; NFBC: OR = 1.7, 95% CI = 1.0-2.8), drug use (ALSPAC: OR = 2.9, 95% CI = 1.8-4.7; GUTS: OR = 4.5, 95% CI = 2.8-7.3; NFBC: OR = 4.1, 95% CI = 2.6-6.6), depressive symptoms in ALSPAC (OR = 2.2, 95% CI = 1.5-3.1) and GUTS(OR = 3.7, 95% CI = 2.2-6.3), and several psychopathology measures including clinical anxiety/depression in NFBC (OR = 11.2, 95% CI = 3.9, 31.7).CONCLUSIONS: Results show a higher prevalence of purging behaviours among girls in the United Kingdom compared to those in the United States and Finland. Our findings support evidence highlighting that purging in adolescence is associated with negative outcomes, independent of its frequency and binge eating.
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