RESUMO
Valproic acid (VPA) is a common anti-epileptic drug and known neurodevelopmental toxicant. Although the exact mechanism of VPA toxicity remains unknown, recent findings show that VPA disrupts redox signaling in undifferentiated cells but has little effect on fully differentiated neurons. Redox imbalances often alter oxidative post-translational protein modifications and could affect embryogenesis if developmentally critical proteins are targeted. We hypothesize that VPA causes redox-sensitive post-translational protein modifications that are dependent upon cellular differentiation states. Undifferentiated P19 cells and P19-derived neurons were treated with VPA alone or pretreated with D3T, an inducer of the nuclear factor erythroid 2-related factor 2 (NRF2) antioxidant pathway, prior to VPA exposure. Undifferentiated cells treated with VPA alone exhibited an oxidized glutathione redox couple and increased overall protein oxidation, whereas differentiated neurons were protected from protein oxidation via increased S-glutathionylation. Pretreatment with D3T prevented the effects of VPA exposure in undifferentiated cells. Taken together, our findings support redox-sensitive post-translational protein alterations in undifferentiated cells as a mechanism of VPA-induced developmental toxicity and propose NRF2 activation as a means to preserve proper neurogenesis.
RESUMO
OBJECTIVES: The primary objective was to evaluate chronic obstructive pulmonary disease (COPD) interventions in a pharmacist-led telemedicine clinic. Secondary objectives were to quantify emergency department (ED) visits and hospitalizations for COPD exacerbations. SETTING: A single-center, outpatient telemedicine clinic within the Veterans Affairs (VA) Tennessee Valley Healthcare System from January 2021 to June 2021. PRACTICE DESCRIPTION: Patients with an active COPD diagnosis and assigned to a primary care team within the local VA were reviewed for enrollment. Visits were conducted through VA video connect or telephone. During these appointments, pertinent information was collected and pharmacotherapy and nonpharmacotherapy interventions were implemented to optimize COPD management. PRACTICE INNOVATION: Visits were conducted by a postgraduate year 2 ambulatory care pharmacy resident under supervision of a clinical pharmacy specialist with a scope of practice. Appointments were virtual to reduce coronavirus disease 2019 exposure and increase access to care. Patients were identified through a COPD patient report and provider referral to target high-risk patients. EVALUATION: Interventions made were documented at each visit. Chart review and patient interview were used to quantify ED visits or hospitalizations for COPD exacerbations occurring the year before or during clinic enrollment. RESULTS: Of 82 charts reviewed, 18 patients were eligible for enrollment. Eleven were followed as 7 patients did not show for initial visits. A total of 31 COPD interventions occurred including 13 nonpharmacotherapy (i.e., inhaler education, smoking cessation) and 18 pharmacotherapy (i.e., optimization of COPD regimens). An average of 3 COPD interventions were completed per patient followed. No ED visits and 2 hospitalizations for a COPD exacerbation occurred during the study period. This cohort had 1 ED visit and 10 hospitalizations the year before enrollment. CONCLUSION: This telemedicine clinic experience, albeit a small study population, suggests an opportunity for pharmacists to provide pharmacotherapy and nonpharmacotherapy interventions, which may improve COPD-related outcomes and access to care.