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    Computational Pharmacology for Identifying and Refining Novel Inhibitors of the Regulator of G protein Signaling type-12 (RGS12) Protein Target
    (2023) Agogo-Mawuli, Percy; Siderovski, David
    Purpose: Substance use disorders arise from persistent changes in CNS synaptic transmission, as caused by initial exposure to illicit substances that heighten dopamine levels in the brain’s reward circuitry (a key event in establishing long-term drug-seeking behavior) [1,2]. The Siderovski lab recently discovered that mice lacking Regulator of G protein Signaling-12 (RGS12) are attenuated in their normal hyperlocomotion elicited by acute cocaine, amphetamine, or methamphetamine [3,4]. RGS12-deficient mice have increased dopamine transporter (DAT) expression and increased dopamine uptake within the ventral striatum [3]. The target for RGS12’s action as a Galpha-directed GTPase-accelerating protein (GAP) is the presynaptic kappa opioid receptor (KOR) [4], as KOR activation is known to attenuate striatal dopaminergic tone [5]. Our hypothesis is that RGS12 directly modulates the output of dynorphin / KOR signaling to dopamine reuptake. Developing RGS12 inhibitors would provide complementary pharmacological means to test this hypothesis pre-clinically, including in rodent models. However, to date, there are no small-molecule inhibitors of the G-alpha: RGS domain protein-protein interaction that are not thiol-reactive covalent modifiers of the RGS protein (a highly undesirable chemical property anathematic to further drug development) [6]. Methods: Using the AtomNet® model, a deep convolutional neural network for structure-based drug discovery, we screened millions of compounds against the NMR structure of the RGS12 RGS domain (Protein Data Bank id 2EBZ; state 2) to identify 96 candidate compounds, followed by experimental testing of these candidate compounds using the Transcreener® GDP RGScreen™ developed in partnership with BellBrook Labs [7,8]. Follow-up computational chemistry is being performed with Schrödinger's suite of molecular dynamics software. Results: Two hits out of the 96 candidate compounds were discovered to exhibit reproducible, double-digit micromolar IC50 values in the Transcreener® GDP RGScreen™ assay. We then tested 192 analogs of the two original hits and discovered 33 analogs with measurable IC50 values. Of the 33 congeneric compounds, all but one of the active congeners were structurally related to one of the original two hits, with a wide spread of IC50 values and many with improved potencies (IC50RGS12 = 0.84 – 153.2 microM). These hits do not inhibit the intrinsic GTPase activity of G-alpha. Conclusions: To increase diversity of the chemical scaffolds capable of inhibiting RGS12 function in vitro, we are now performing computational modeling of this initial set of 33 congeneric compounds, including CPU-based molecular docking and GPU-based shape screening of new chemical libraries (including those sourced from MilliporeSigma, MolPort, and Enamine) using Schrödinger algorithms on a local HPC cluster. In vitro binding and structural studies, cell-based studies, and pre-clinical animal studies are also being planned to further characterize these congeneric compounds and future divergent chemotypes. References: [1] [2] [3] [4] [5] [6] [7] [8]
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    Post-operative acute dyskinetic reaction with possible association to Ondansetron administration
    (2023) Broadbent, Dallen; Capps, Zachary; Mickelson, Cody
    Background: Acute dyskinetic reactions after the administration of general anesthesia are uncommon, with the differential diagnosis including adverse drug reaction, local anesthetic reaction, in addition to a possible underlying psychiatric illness. Prior cases studies have been published demonstrating cross-reactivity and extrapyramidal symptom-onset with the temporal association of Ondansetron administration. Case Description: 38-year-old female, with PMHx of T1DM, depression, anxiety, OSA, GERD, and chronic generalized muscle weakness, was scheduled to undergo an elective Laproscopic Cholecystectomy. Home medications reviewed prior to the procedure included Cymbalta, Wellbutrin, Protonix, PO Zofran, and Insulin. Anesthesia given for induction was Versed (2 mg), Fentanyl (100 mcg), IV Lidocaine (70 mg), Propofol (200 mg), defasciculating dose of Rocuronium (5 mg), Succinylcholine (120 mg) prior to intubation. Additional Rocuronium (35 mg) was later administered. Intra-operatively, IV Decadron (10 mg), IV Zofran (4 mg), Toradol (30 mg), Ephedrine (10 mg), Dilaudid (1 mg), Labetalol (10 mg), and Sugammadex (200mg) were provided for proper maintenance of vital signs, pain control, and paralytic reversal. Glucose level was monitored and maintained throughout the case with patient’s continuous glucose monitor. Procedure lasted approximately 40 minutes, with no associated complications. Patient displayed spontaneously breathing prior to extubation and was transferred to the Post-Anesthesia Care Unit (PACU). While in the PACU, vitals were stable with patient speaking and asking questions to nurse within 15 minutes. Patient was transferred back to Same-Day Surgery (SDS), where she requested additional nausea medication ad was given IV Zofran (4 mg). Minutes later, the patient began showing signs of acute dyskinesia of the head, neck, and upper extremities, in addition to acute dystonia of the eyes, consistent with extrapyramidal symptoms. Within 5 minutes of symptom onset, Diphenhydramine (50 mg) and Versed (3 mg), were given to alleviate the extrapyramidal side-effects. Limited symptom improvement was noted, and patient was subsequently given Ativan (2 mg). Patient showed improvement after the administration of Ativan and was transferred to the ICU for close observation. Treatment, with IV Benadryl and Ativan, was continued for the proceeding 48 hours in the ICU. Patient’s condition continually improved, with occasional relapse of mild symptoms. Although definitive etiology of patient’s symptoms is unknown, Neurology was consulted and agreed that symptoms could have been caused by a medication reaction to Ondansetron, in addition to possible exacerbation of an underlying psychiatric illness. It was confirmed that proper treatment was provided with complete resolution of symptoms expected, with no long-term sequelae. Conclusion: This case illustrates and provides additional insight on the proper treatment regimen for the rare occurrence of acute dyskinetic reaction post-anesthesia, associated with administration of Ondansetron.
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    Impact of Chronic Obstructive Pulmonary Disease Home and Discharge Inhaler Regimens on Exacerbation Severity and Hospital Readmission
    (2023) Spivey, Faith; Howard, Meredith; Nguyen, Quang; Obioma, Jessica; Torres, Brittany; Schillig, Jessica
    Purpose: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines are the standard for diagnosing and treating chronic obstructive pulmonary disease (COPD). According to GOLD, long-acting muscarinic antagonists (LAMA) should be the backbone of COPD management. Studies have shown patients with COPD who are treated with a LAMA experience a reduction in COPD exacerbations. The purpose of this study is to identify the impact of home inhalers for COPD on inpatient (non-critically ill) exacerbation severity and to analyze changes in COPD regimens following an exacerbation and the subsequent impact on hospital readmission. Methods: This study was a retrospective, observational, cohort study conducted at a community teaching hospital. Adult patients were included if they were admitted for a COPD exacerbation from 2018 to 2021. Patients were excluded if they had other respiratory disorders, infiltrates on chest X-ray, were on vasopressors, mechanical ventilation, or pregnant. Patients’ home, inpatient, and discharge medications for COPD (i.e. inhalers), readmission rates, and time to hospital readmission were extracted from the electronic medical record along with other baseline characteristics and laboratory values. Each patient was evaluated on their at-home medication regimen and placed into an inhaler treatment category (e.g. LAMA only, LAMA + LABA, etc.). The primary outcome of the study was to determine the rate of severe COPD exacerbations as stratified by at-home COPD inhaler regimen. Secondary outcomes include the readmission rate, time to readmission, and the percentage of patients with guideline directed LAMA added to therapy. The chi-square test was used to measure outcomes of categorical data, including association of medication regimen and COPD severity. An unpaired t-test was used to compare the impact of discharge inhaler regimens on time to hospital readmission. A two-way loglinear analysis was completed to analyze the association of home inhalers on severity of COPD exacerbation as well as the association of discharge inhaler on hospital readmission. Results: A total of 288 patients were included in the study. No association was found between home inhaler regimen and patients admitted with severe versus non-severe COPD exacerbation. There was also no association identified between discharge medications and hospital readmission rates, with the exception of the LAMA only group, which did show there was a significant decrease in readmission rate compared to other groups (18.2% vs. 81.8%) (p=0.05). Finally, there was no association between the categories of home inhalers on severity of COPD exacerbation or time to readmission. A total 21 patients were previously not on a LAMA and had a LAMA added to their therapy at discharge (9.9%). Conclusion: No association was found between the majority of home or discharge inhaler regiments and defined outcomes, with the exception of patients discharging on a LAMA only had a lower readmission rate. There was also an increase in patients with a LAMA containing regimen at discharge, which is consistent with the GOLD guideline recommendations.