Análise das intervenções farmacêuticas clínicas em Unidade de Terapia Intensiva de um hospital de urgência e trauma / Analysis of clinical pharmaceutical interventions in the Intensive Care Unit of an emergency and trauma hospital

Analisar o perfil das intervenções farmacêuticas providas pelos farmacêuticos clínicos por meio da análise de prescrições médicas em uma Unidade de Terapia Intensiva (UTI) adulto generalista. Metodologia: Trata-se de um estudo transversal, prospectivo e observacional, com abordagem quantitativa, realizado na UTI de um hospital público referência em urgência e trauma do estado de Goiás. Os dados foram coletados no período de junho a agosto do ano de 2022, por meio da análise diária das prescrições. Resultados: A população estudada compreendeu 74 pacientes, em sua maioria do sexo masculino (68,92%), hipertensos (27,03%), e diabéticos (14,86%). Foram analisadas 568 prescrições, e identificados 489 problemas relacionados a medicamentos, sendo os mais prevalentes: medicamento inapropriado/desnecessário ou contraindicado (30,67%) e necessidade de medicamento adicional (24,34%). As classes de medicamentos mais envolvidas nos problemas foram: anti-infecciosos gerais para uso sistêmico (23,72%), e agentes do sistema nervoso (23,11%). Das intervenções farmacêuticas promovidas, 84,25% foram aceitas, com maior frequência: suspender medicamento (30,67%) e iniciar terapia medicamentosa (23,72%). Conclusão: Diante dos resultados apresentados, nota-se a boa taxa de aceitabilidade das intervenções, destacando a importância da atuação do farmacêutico clínico dentro da UTI na prevenção de problemas relacionados à farmacoterapia, bem como na melhoria dos desfechos terapêuticos

To analyze the profile of pharmaceutical interventions provided by clinical pharmacists through the analysis of medical prescriptions in a generalist adult Intensive Care Unit (ICU). Methodology: This is a cross-sectional, prospective and observational study, with a quantitative approach, conducted in the ICU of a public hospital that is a reference in emergency and trauma in the state of Goiás. Data were collected from June to August of 2022, through the daily analysis of prescriptions. Results: The population being studied comprised 74 patients, mostly male (68.92%), hypertensive (27.03%), and diabetic (14.86%). 568 prescriptions were analyzed, and 489 problems related to medication were identified, the most prevalent being: inappropriate/unnecessary or contraindicated medication (30.67%) and need for additional medication (24.34%). The drug classes most involved in the problems were: general anti-infectives for systemic use (23.72%) and nervous system agents (23.11%). Of the promoted pharmaceutical interventions, 84.25% were accepted, most frequently: discontinuing medication (30.67%) and starting medication therapy (23.72%). Conclusion: In view of the results presented, there is a good rate of acceptability of the interventions, highlighting the importance of the role of the clinical pharmacist within the ICU in preventing problems related to pharmacotherapy, as well as in improving therapeutic outcomes

Patient-derived three-dimensional cortical neurospheres to model Parkinson's disease.

There are currently no preventive or disease-modifying therapies for Parkinson's Disease (PD). Failures in clinical trials necessitate a re-evaluation of existing pre-clinical models in order to adopt systems that better recapitulate underlying disease mechanisms and better predict clinical outcomes. In recent years, models utilizing patient-derived induced pluripotent stem cells (iPSC) have emerged as attractive models to recapitulate disease-relevant neuropathology in vitro without exogenous overexpression of disease-related pathologic proteins. Here, we utilized iPSC derived from patients with early-onset PD and dementia phenotypes that harbored either a point mutation (A53T) or multiplication at the α-synuclein/SNCA gene locus. We generated a three-dimensional (3D) cortical neurosphere culture model to better mimic the tissue microenvironment of the brain. We extensively characterized the differentiation process using quantitative PCR, Western immunoblotting and immunofluorescence staining. Differentiated and aged neurospheres revealed alterations in fatty acid profiles and elevated total and pathogenic phospho-α-synuclein levels in both A53T and the triplication lines compared to their isogenic control lines. Furthermore, treatment of the neurospheres with a small molecule inhibitor of stearoyl CoA desaturase (SCD) attenuated the protein accumulation and aberrant fatty acid profile phenotypes. Our findings suggest that the 3D cortical neurosphere model is a useful tool to interrogate targets for PD and amenable to test small molecule therapeutics.

A Brain-Penetrant Stearoyl-CoA Desaturase Inhibitor Reverses α-Synuclein Toxicity.

Increasing evidence has shown that Parkinson's disease (PD) impairs midbrain dopaminergic, cortical and other neuronal subtypes in large part due to the build-up of lipid- and vesicle-rich α-synuclein (αSyn) cytotoxic inclusions. We previously identified stearoyl-CoA desaturase (SCD) as a potential therapeutic target for synucleinopathies. A brain-penetrant SCD inhibitor, YTX-7739, was developed and has entered Phase 1 clinical trials. Here, we report the efficacy of YTX-7739 in reversing pathological αSyn phenotypes in various in vitro and in vivo PD models. In cell-based assays, YTX-7739 decreased αSyn-mediated neuronal death, reversed the abnormal membrane interaction of amplified E46K ("3K") αSyn, and prevented pathological phenotypes in A53T and αSyn triplication patient-derived neurospheres, including dysregulated fatty acid profiles and pS129 αSyn accumulation. In 3K PD-like mice, YTX-7739 crossed the blood-brain barrier, decreased unsaturated fatty acids, and prevented progressive motor deficits. Both YTX-7739 treatment and decreasing SCD activity through deletion of one copy of the SCD1 gene (SKO) restored the physiological αSyn tetramer-to-monomer ratio, dopaminergic integrity, and neuronal survival in 3K αSyn mice. YTX-7739 efficiently reduced pS129 + and PK-resistant αSyn in both human wild-type αSyn and 3K mutant mice similar to the level of 3K-SKO. Together, these data provide further validation of SCD as a PD therapeutic target and YTX-7739 as a clinical candidate for treating human α-synucleinopathies.