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    Potential Application of FSNY-1 as Smoking Cessation Drug
    (2020) Forster, Michael; Hill, Rebecca; Shetty, Ritu; Bunce, Bailey
    Purpose: Varenicline, an FDA-approved drug, is effective in the treatment of nicotine addiction. However, varenicline has been shown to cause central nervous system effects in greater than 10% of users. The purpose of this study was to develop alternative treatments with potentially less side effects. Methods: A novel compound, FSNY-1 was tested for its ability to inhibit biphasic psychomotor stimulant and depressant effects of nicotine in mice. Different groups of young mice were pretreated with FSNY-1 (5, 10 mg/kg), or: varenicline (3 mg/kg), mecamylamine (2.5 mg/kg), or hexamethonium (3 mg/kg) prior to nicotine injection, and placed into chambers for recording locomotor activity for 120 minutes. Results: FSNY-1 and hexamethonium selectively blocked the stimulant phase of nicotine effects. Mecamylamine attenuated the stimulant and depressant phases of nicotine's action. Although varenicline blocked the stimulant effect of nicotine, it had a depressant effect when administered alone. FSNY-1 alone had neither a stimulant nor depressant effect. Conclusion: Based on these results, it can be predicted that FSNY-1 will be useful in the treatment of nicotine addiction without side effects associated with varenicline. It is significant that hexamethonium, which does not cross the blood-brain barrier, had a profile identical to FSNY-1. This supports the conclusion that ability to block autonomic outflow may be sufficient condition for clinical efficacy. Thus, inhibition of peripheral actions of nicotine may represent a significant target for new drug development. Additional studies will be needed to further test therapeutic potential of FSNY-1.
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    Role of AIBP in Chronic Pain
    (2020) Oh, Hyuckjin
    Chronic pain is defined as pain that lasts or recurs for more than 3 to 6 months. Activation of NMDA receptors (NMDAR) have been associated with chronic pain and hyperalgesia. The purpose of this study is to focus on the role of AIBP (Apolipoprotein A-I binding protein) on NMDAR, which will be evaluated by measuring the membrane potential via the port-a-patch. It was hypothesized that the simultaneous application of both the NMDA agonist and AIBP would lead to a significant inhibition of the NMDAR. The Patch-clamp electrophysiology technique was used to measure the membrane potential and thus the impact of AIBP on NMDAR. In this procedure, the cells/solutions were added onto the disposable recording chip, where a cell is automatically captured and sealed by suction using a computer-controlled pump. The membrane potentials for the NMDA agonist, independent application of AIBP, and the simultaneous application of NMDA agonist and AIBP were measured separately. The concurrent application of AIBP and NMDA agonist lead to consistent decline in amplitude and stabilization compared to control, supporting preexisting scientific literature. Based on these results, AIBP appears to effectively modulate the NMDA receptor leading to significant inhibition and stabilization of the NMDAR. The findings suggest that AIBP does play a role in modulating activation of the NMDAR. This study demonstrates preliminary evidence for the inhibitory role of AIBP on NMDAR. In future studies, we wish to evaluate the effect of AIBP on Tryp channels as well as in vivo studies.
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    Significant Elevation in Triglycerides Following Introduction of Atypical Antipsychotics
    (2020) Neelakantan, Suguna; Kunkel, Claire
    Background: Atypical antipsychotics are drugs that block D2 and 5HT2 receptors and are used for conditions including Schizophrenia and Bipolar disorder. They have a lower risk of extrapyramidal side effects than first-generation antipsychotics, but they do carry their own risks, including weight gain, diabetes, and hyperlipidemia. Triglycerides over 1,000 mg/dL have been shown to be a risk factor for pancreatitis, heart attack, and stroke. Case Description: 54-year-old white female with history of Bipolar Depression presented for maintenance lab work. Though she did not report any new medications to the primary care physician (PCP), she had been started on Lurasidone by her Psychiatrist. Her bloodwork showed very high triglycerides of 1,724 mg/dL (normal: < 149 mg/dL) compared to her previous triglycerides of 226 mg/dL. At this time, the Psychiatrist switched the patient to Olanzapine due to insurance coverage, but this medication was also not reported to the PCP. The labs were redrawn two months later, and the triglycerides were still very high at 1,489 mg/dL. A provider attributed the triglyceride level to diet and started the patient on cholesterol medications. A thorough medication reconciliation revealed Olanzapine, and we suspected this atypical antipsychotic to be the cause of the patient's sudden elevation in triglycerides and changed the medication to Lamotrigine. Five weeks after discontinuing Olanzapine, the patient's triglycerides returned to to 157 mg/dL. Discussion: This case illustrates the importance of performing thorough medication reconciliations for all patients in the primary care setting, especially after a hospitalization or specialist consult.
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    High disease and medication exposure burden associated with patients on chronic dialysis
    (2020) Rasu, Rafia; Bhachawat, Neal
    IRBexempt#2018-197.Background:Patients with end stage renal disease(ESRD), in addition to chronic dialysis, also receive multiple drug therapies for co-morbidities;Patients manage on average, 10-12 daily medications in regimens, increasing the risk of drug-related adverse effects and medication nonadherence. We want to determine the most common P2Y12-I taken by patients and other medications frequently used by this group. Methods:A retrospective cohort of ESRD patients started on a P2Y12-I between July 20,2011 and December 31,2014 was identified through United States Renal Data System(USRDS) registry data. Within USRDS, we used Medicare Part A, Part B, and mostly Part D pharmacy claims to accurately capture entire prescription filling number to this patient population. Results:The study cohort was restricted to ESRD patients with a known first service date for dialysis prior to study end date, December 31, 2014. 36,590 patients were followed on average 367days(IQR:147, 1627). Median age for patients receiving P2Y12-I was 64(IQR: 55, 73), 54%male, 41%Caucasians. Patients were on dialysis for 3.8years, taking 7 medications(median:7, IQR:5,10) and had 7 different co-morbidities. Top10 medications routinely used (% of patients): Clopidogrel(95%), Sevelamer(39%), Amlodipine(32%), Carvedilol(30%), Calcium Acetate(28%), Metoprolol(27%), Lisinopril(26%), Atorvastatin(26%) and Cinacalcet HCL(26%). Majority medications were antihypertensive drugs and ion-removing agents. Conclusion:Due to the complex medication regimen and high rate of comorbidities in this population, de-prescribing methods may be the next step moving forwards. The goal of this method is to reduce medication burdens and drug adverse events while improving quality of life through targeted deprescribing methods.
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    Pain Treatment in Elderly Population with Cancer Diagnosis
    (2020) Rasu, Rafia; Bhachawat, Neal
    IRBexempt#2020-013.Purpose:Cancer incidence increases with age. One prevalent symptom of cancer is chronic pain,which is frequently treated with opioids and other pain medications. As patients age, physiologic changes occur which alter drug pharmacokinetics, making elderly patients susceptible to drug adverse effects. Falls are a leading cause of death in the elderly and seniors taking opioids are 5-times more likely to suffer one. Our goal is to identify pain treatment in elderly cancer patients, note patient-specific factors and any adverse events.Methods:A cross-sectional study analyzing pain prescriptions to manage acute or chronic pain associated with cancer in patients, age 65+. The population data will be compiled from the National Ambulatory Medical Care Survey (NAMCS)database provided by CDC. Diagnosis was based on ICD-9/10codes and medication codes identified by NAMCS for patient visits.Results:Reported in the NAMCSdatabase between2006and2017 was 276,166,738(weighted frequencies) cancer patient visits with pain medication treatment. Data consisted of 71%white, 53%female. There was almost a 2-fold increase in patient visits from the 2006-2008data period(18%), to the 2009-2011data period(31%). Peak trend was in 2009-2011(p value < 0.001). Cancer diagnoses varied but included:6%prostate,2%colon,5%breast, 4%lung cancers. Out of the 276,166,738 visits,3%were taking opioids,8%mixed opioids,2%nsaids,3%apap and 84%other pain medications. Population regionally:37%South,23%Midwest,22%West,18%Northeast(p value< 0.05). Interestingly, 83% experienced a fall as an adverse event. Conclusion:A notable amount of fall events recorded in this population, greater than the CDC estimated national average;we recommend further assessing this risk. Identifed regional variation: South having majority of pain prescriptions and Northeast havingthe fewest.
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    Synthesis and Bioactivity of Nitric Oxide Donor and Antioxidant Drug Hybrid
    (2020) Nguyen, Ngoc; Weston, Courtney; Acharya, Suchismita; Khowaja, Sanober
    Purpose: In ischemic stroke or peripheral artery disease, there is a blockage of the arteries that results in increased free radicals and cell death. Our goal was to synthesize a hybrid compound SA-9-01 and assess the NO releasing and reactive oxygen species (ROS) scavenging ability using chemical assays. We hypothesize that the hybrid compound will prevent cell death by improving blood circulation and neutralizing ROS. Methods: SA-9-01 was synthesized using a synthetic procedure similar to a previously designed analog SA-2 and structure was verified by 1HNMR. The NO releasing activity was determined using the Griess assay by measuring the total nitrite formation. The xanthine oxidase assay was used to measure the ROS scavenging activity. Results: Compound SA-9 (25 mM) released NO at concentrations between 1.35-1.40 µM at t=90 mins sufficient to provide therapeutic activity, while a known NO donor SIN-1 released between 2-15 µM at same concentration and time point. From the xanthine oxidase assay, the scavenging ratio for SA-9-01 (250 µM) was about 20-25% at t=100 mins and comparable to previously described compound SA-2 and Baicalein (the positive control). Conclusion: Compound SA-9-01 was synthesized successfully with the correct chemical structure and was found to be a tautomer of the first batch SA-9. The Griess assay demonstrated that SA-9 releases physiological level of NO. SA-9-01 also demonstrated ROS scavenging activity. The testing of SA-9-01 in cells is under progress.
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    Synthesis and Bioactivity Study of Novel Hybrid Antioxidant
    (2020) Weston, Courtney; Khowaja, Sanober; Acharya, Suchismita; Nguyen, Ngoc
    Purpose: Antioxidant enzymes are the first line defense for preventing oxidative stress (OS) by scavenging free radicals, and different enzymes scavenge different reactive oxygen species (ROS). We focused on two major antioxidants: superoxide dismutase (SOD), which removes superoxide; and glutathione peroxidase (GPx), which removes hydrogen peroxide radicals. The purpose was to synthesize a hybrid compound with multiple antioxidant activities and to test the total ROS scavenging ability using a chemical assay. The goal is to use this class of compound as a method of preventing and treating ophthalmologic diseases related to oxidative damage. Methods: Synthesis of a hybrid antioxidant MN-1-26 was carried out using an amide coupling reaction between 4-amino Tempol (a SOD mimetic) and NHBoc methionine followed by purification using liquid chromatography. Structure confirmation was done using proton NMR. The ROS scavenging chemical assay was conducted following a literature protocol where pyrogallol was used as the ROS generator. Changes in UV absorbance were measured at different time points to compare MN-1-26 (250µm) with SA-2 (a known SOD mimetic) and Baicalein (a polyphenolic antioxidant) as positive controls. Result: Compound MN-1-26 has the correct chemical structure, determined by proton NMR, with the highest superoxide scavenging ratio (28%) at 90 minutes compared to SOD mimetic SA-2 (22%), and Baicalein (24%). Conclusion: The hybrid antioxidant demonstrated superior ROS scavenging activity over individual antioxidants. Further cellular studies of MN-1-26 are under progress, with the goal of reducing OS and cell death in vitro.