Dual 5-HT2A and 5-HT2C Receptor Inverse Agonist That Affords In Vivo Antipsychotic Efficacy with Minimal hERG Inhibition for the Treatment of Dementia-Related Psychosis.

Psychosis is a distressing symptom commonly occurring in people with dementia. To treat Parkinson's disease psychosis, pimavanserin (1), a 5-HT2A receptor inverse agonist having minimal 5-HT2C receptor affinity and no dopamine D2 receptor affinity, was approved in the United States, but not for dementia-related psychosis due to limited efficacy issues. Herein, we report on the identification of a potent and dual 5-HT2A and 5-HT2C receptor inverse agonist 8 having minimal hERG inhibition, after having demonstrated the involvement of both 5-HT2A and 5-HT2C receptors to deliver antipsychotic efficacy in an MK-801-induced locomotor model and having conducted 5-HT2A and 5-HT2C occupancy studies including a surrogate method. The introduction of a spirocyclopropyl group boosting 5-HT2C affinity in 1 followed by further optimization to control lipophilicity resulted in balanced dual potency and metabolic stability, and mitigating hERG inhibition led to 8 that showed significant antipsychotic efficacy due to the involvement of both receptors.

Induction of necrosis symptoms by potato virus X in AGO2-silenced tomato plants associates with reduced transcript accumulation of copper chaperon for superoxide dismutase gene.

RNA silencing is a prominent antiviral defense mechanism in plants. When infected with a virus, RNA silencing-deficient plants tend to show exacerbated symptoms along with increased virus accumulation. However, how symptoms are exacerbated is little understood. Here, we investigated the role of the copper chaperon for superoxide dismutase (CCS) 1, in systemic necrosis observed in Argonaute (AGO)2-silenced tomato plants infected with potato virus X (PVX). While infection with the UK3 strain of PVX induced mosaic symptoms in tomato plants, systemic necrosis occurred when AGO2 was silenced. The CCS1 mRNA level was reduced and micro RNA398 (miR398), which potentially target CCS1, was increased in AGO2-knockdown tomato plants infected with PVX-UK3. Ectopic expression of CCS1 using recombinant PVX attenuated necrosis, suggesting that CCS1 alleviates systemic necrosis by activating superoxide dismutases to scavenge reactive oxygen species. Previous reports have indicated a decrease in the levels of CCS1 and superoxide dismutases along with an increased level of miR398 in plants infected with other viruses and viroids, and thus might represent shared regulatory mechanisms that exacerbate symptoms in these plants.

Prevalência de hiperglicemia de estresse em uma unidade de terapia intensiva / Prevalence of stress hyperglycemia in an intensive care unit

Objetivo: Avaliar a prevalência e o manejo da hiperglicemia de estresse em pacientes internados em uma unidade de terapia intensiva. Métodos: Estudo retrospectivo, realizado de janeiro a junho de 2018. Os dados foram obtidos a partir de 582 prontuá- rios eletrônicos, considerando os valores glicêmicos durante a hospitalização, história prévia ou não de diabetes mellitus, causas do internamento, tempo de permanência na unidade de terapia intensiva, presença de complicações durante o internamento e conduta utilizada em caso de hiperglicemia de estresse. Resulta- dos: Dos 582 pacientes internados na unidade de terapia intensi- va, 579 tiveram sua glicemia indicada nos prontuários analisados; 341 (58,9%) apresentaram hiperglicemia em algum momento da internação, sendo a hiperglicemia de estresse caracterizada em 200 pacientes (35%). A duração média de internamento desses pacientes foi de 8,39±10,9 dias, e a causa mais frequente de inter- namento foi devido a pós-operatório por diversas causas, somando 148 indivíduos (74%). Dentro os pacientes, 72 (36%) apresenta- ram alguma complicação. Além disso, 13 casos (6,5%) evoluíram para óbito. Conclusão: Estudos disponíveis sobre alvos de gli- cose em pacientes críticos das unidades de terapia intensiva apresentam difícil interpretação devido às diferenças subs- tanciais no grupo de populações e aos protocolos de gestão de pacientes utilizados em vários centros. Todavia, a prevalência da hiperglicemia de estresse encontrada nesta amostra é se- melhante à de outras casuísticas estudadas. O índice eleva- do de complicações enfatiza a necessidade de padronização nos critérios para diagnóstico e tratamento da hiperglicemia de estresse objetivando melhor prognóstico desses pacientes independentemente da causa do internamento.

Objective: To evaluate the prevalence and management of stress hyperglycemia in patients hospitalized in anintensive care unit. Methods: Retrospective study, carried out from January to June 2018. Data were obtained from 582 electronic medical records, considering glycemic values during hospitalization, existence of previous history of Diabetes Mellitus, causes of hospitalization, length of stay in the intensive care unit, presence of complications during hospitalization, and behavior used in case of stress hyper- glycemia. Results: Of the 582 patients admitted in the ICU, 579 had their glycemia indicated in the charts analyzed: 341 (58,9%) had hyperglycemia in a certain moment of hospitalization, with stress hyperglycemia being present in 200 patients (35%). The average duration of hospitalization of these patients was 8,39 ± 10,9 days, and the most frequent cause of hospitalization was postoperative for various causes, totaling 148 individuals (74%). Of the patients, 72 (36%) presented some type of complication and 13 patients (6,5%) died. Conclusion: Available studies on glucose targets in critical intensive care unit patients are difficult to be interpre- ted because of substantial differences in the study populations and of patient management protocols used at various centers. However, the prevalence of stress hyperglycemia found in this sample is similar to that of other study groups. The high com- plication rate emphasizes the need for standardization of the criteria for diagnosis and treatment of stress hyperglycemia aiming at a better prognosis of these patients regardless of the cause of hospitalization.