Browsing by Author "Pharmacology and Toxicology, School of Medicine"
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Item 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation(Elsevier, 2024) Joglar, José A.; Chung, Mina K.; Armbruster, Anastasia L.; Benjamin, Emelia J.; Chyou, Janice Y.; Cronin, Edmond M.; Deswal, Anita; Eckhardt, Lee L.; Goldberger, Zachary D.; Gopinathannair, Rakesh; Gorenek, Bulent; Hess, Paul L.; Hlatky, Mark; Hogan, Gail; Ibeh, Chinwe; Indik, Julia H.; Kido, Kazuhiko; Kusumoto, Fred; Link, Mark S.; Linta, Kathleen T.; Marcus, Gregory M.; McCarthy, Patrick M.; Patel, Nimesh; Patton, Kristen K.; Perez, Marco V.; Piccini, Jonathan P.; Russo, Andrea M.; Sanders, Prashanthan; Streur, Megan M.; Thomas, Kevin L.; Times, Sabrina; Tisdale, James E.; Valente, Anne Marie; Van Wagoner, David R.; Pharmacology and Toxicology, School of MedicineAim: The "2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Patients With Atrial Fibrillation" provides recommendations to guide clinicians in the treatment of patients with atrial fibrillation. Methods: A comprehensive literature search was conducted from May 12, 2022, to November 3, 2022, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. Additional relevant studies, published through November 2022, during the guideline writing process, were also considered by the writing committee and added to the evidence tables, where appropriate. Structure: Atrial fibrillation is the most sustained common arrhythmia, and its incidence and prevalence are increasing in the United States and globally. Recommendations from the "2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation" and the "2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation" have been updated with new evidence to guide clinicians. In addition, new recommendations addressing atrial fibrillation and thromboembolic risk assessment, anticoagulation, left atrial appendage occlusion, atrial fibrillation catheter or surgical ablation, and risk factor modification and atrial fibrillation prevention have been developed.Item 318. Beta-lactam Therapeutic Drug Monitoring Improves Attainment of Target Drug Levels in Critically Ill Patients(Oxford University Press, 2023-11-27) Ausman, Sara; Braga, Shienna; Hagy, Natalie T.; Rivera, Christina G.; Moreland-Head, Lindsay; Wessel, Rebecca; Abu Saleh, Omar M.; Rule, Andrew D.; Gajic, Ognjen; Barreto, Erin F.; Pharmacology and Toxicology, School of MedicineBackground: Critically ill patients, particularly those treated with extracorporeal devices or at extremes of weight, experience pharmacokinetic variability which can compromise beta-lactam (BL) antibiotic target attainment and treatment response. Therapeutic drug monitoring (TDM) for BL antibiotics can improve precision pharmacotherapy but has had limited implementation. The objective of this study was to evaluate the frequency of BL target attainment among adult intensive care unit (ICU) patients who underwent TDM. Methods: This observational study evaluated adults treated with cefepime, piperacillin/tazobactam or meropenem in ICUs at the Mayo Clinic in Rochester, Minnesota who underwent TDM from June-September 2022. During the study timeframe, multidisciplinary teams were encouraged to perform BL TDM on patients requiring extracorporeal membrane oxygenation, continuous kidney replacement therapy, or at an extreme of body weight (weight < 40 kg or >120 kg or BMI < 18 kg/m2 or > 40 kg/m2). Percentage of patients with initial serum trough concentrations within the therapeutic range was calculated. Results: During the study timeframe, 59 trough concentrations were performed on critically ill patients, of which 5 were excluded due to uninterpretable results. Of the remaining 54 BL trough concentrations analyzed, 49 (91%) were initial troughs during the antibiotic course, and 5 (9%) were repeat troughs. Thirty-six (73%) of the initial trough concentrations were within the therapeutic range. Among the trough concentrations outside the therapeutic range, 10 (77%) were too high, and 3 (23%) were too low (Table 2). Dose adjustment occurred in 19 (39%) of initial trough evaluations, including 6 which were adjusted despite a level within the therapeutic range. All of the repeat trough concentrations drawn during the same antibiotic course were within the therapeutic range (n = 5/5; 100%). Conclusion: One-fourth of initial BL trough concentrations were outside of the therapeutic range. BL levels outside the therapeutic range prompted dose adjustment to improve the potential for effectiveness or limit the potential for toxicity. BL TDM appears to be a promising strategy to enhance precision pharmacotherapy in the critically ill.Item 8-aminoquinolines effective against Pneumocystis carinii in vitro and in vivo(American Society for Microbiology, 1999-10) Queener, Sherry F.; Bartlett, Marilyn S.; Nasr, Mohamed; Smith, James W.; Pharmacology and Toxicology, School of MedicineThe activities of 25 8-aminoquinolines were compared in tests assessing the ability of the compounds to inhibit the growth of Pneumocystis carinii in culture. Six compounds were effective at or below 0.03 microM: CDRI 80/53, NSC19894, NSC305805, NSC305812, WR182234, and primaquine. Four others were effective at between 0.2 and 0.03 microM: NSC305835, WR225448, WR238605, and WR242511. Fourteen drugs were also tested in a standard model of P. carinii pneumonia in rats at daily doses of 2 mg/kg of body weight in drinking water. CDRI 80/53, NSC305805, NSC305835, and WR225448 were extremely effective in the animal model. The effectiveness of WR238605, WR242511, and primaquine in the rat model has been reported elsewhere (M. S. Bartlett, S. F. Queener, R. R. Tidwell, W. K. Milhouse, J. D. Berman, W. Y. Ellis, and J. W. Smith, Antimicrob. Agents Chemother. 35:277-282, 1991). The length of the alkyl chain separating the nitrogens in the substituent at position 8 of the quinoline ring was a strong determinant of anti-P. carinii activity.Item A common language for Gulf War Illness (GWI) research studies: GWI common data elements(Elsevier, 2022) Cohen, Devra E.; Sullivan, Kimberly A.; McNeil, Rebecca B.; Gulf War Illness Common Data Elements Working Group; Symptoms Assessment Working Group; McNeil, Rebecca B.; Ashford, Wes; Bested, Alison; Bunker, James; Cheema, Amanpreet; Cohen, Devra E.; Cook, Dane; Cournoyer, Jeffrey; Craddock, Travis; Golier, Julia; Hardie, Anthony; Helmer, Drew; Lindheimer, Jacob B.; Janulewicz Lloyd, Patricia; Kerr, Kathleen; Krengel, Maxine; Nadkarni, Shree; Nugent, Shannon; Paris, Bonnie; Reinhard, Matthew; Rumm, Peter; Schneiderman, Aaron; Sims, Kellie J.; Steele, Lea; Turner, Marsha; Systems Assessment Working Group; Sullivan, Kimberly A.; Abdullah, Laila; Abreu, Maria; Abu-Donia, Mohamed; Aenlle, Kristina; Arocho, Jimmy; Balbin, Elizabeth; Baraniuk, James; Block, Karen; Block, Michelle; DeBeer, Bryann; Engdahl, Brian; Filipov, Nikolay; Fletcher, Mary Ann; Kalasinsky, Victor; Kokkotou, Efi; Lidie, Kristy; Little, Deborah; Loging, William; Morris, Marianna; Nathanson, Lubov; Nichols, Montra Denise; Pasinetti, Giulio; Shungu, Dikoma; Waziry, Paula; VanLeeuwen, Jon; Younger, Jarred; Pharmacology and Toxicology, School of MedicineAims: The Gulf War Illness programs (GWI) of the United States Department of Veteran Affairs and the Department of Defense Congressionally Directed Medical Research Program collaborated with experts to develop Common Data Elements (CDEs) to standardize and systematically collect, analyze, and share data across the (GWI) research community. Main methods: A collective working group of GWI advocates, Veterans, clinicians, and researchers convened to provide consensus on instruments, case report forms, and guidelines for GWI research. A similar initiative, supported by the National Institute of Neurologic Disorders and Stroke (NINDS) was completed for a comparative illness, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), and provided the foundation for this undertaking. The GWI working group divided into two sub-groups (symptoms and systems assessment). Both groups reviewed the applicability of instruments and forms recommended by the NINDS ME/CFS CDE to GWI research within specific domains and selected assessments of deployment exposures. The GWI CDE recommendations were finalized in March 2018 after soliciting public comments. Key findings: GWI CDE recommendations are organized in 12 domains that include instruments, case report forms, and guidelines. Recommendations were categorized as core (essential), supplemental-highly recommended (essential for specified conditions, study types, or designs), supplemental (commonly collected, but not required), and exploratory (reasonable to use, but require further validation). Recommendations will continually be updated as GWI research progresses. Significance: The GWI CDEs reflect the consensus recommendations of GWI research community stakeholders and will allow studies to standardize data collection, enhance data quality, and facilitate data sharing.Item A complex signature network that controls the upregulation of PRMT5 in colorectal cancer(Elsevier, 2022-03) Wei, Han; Hartley, Antja-Voy; Motolani, Aishat; Jiang, Guanglong; Safa, Ahmad; Prabhu, Lakshmi; Liu, Yunlong; Lu, Tao; Pharmacology and Toxicology, School of MedicineItem A decade of epigenetic research in Toxoplasma gondii(Elsevier, 2010) Dixon, Stacy E.; Stilger, Krista L.; Elias, Eliana V.; Naguleswaran, Arunasalam; Sullivan, William J., Jr.; Pharmacology and Toxicology, School of MedicineIn the past 10 years, the field of parasitology has witnessed an explosion of studies investigating gene regulation. In this review, we will describe recent advances largely stemming from the study of Toxoplasma gondii, a significant opportunistic pathogen and useful model for other apicomplexan protozoa. Surprising findings have emerged, including the discovery of a wealth of epigenetic machinery in these primitive eukaryotes, unusual histone variants, and a battery of plant-like transcription factors. We will elaborate on how these unusual features impact parasite physiology and potential therapeutics as we summarize some of the key discoveries from the last decade. We will close by proposing a few questions to address in the next 10 years.Item A GCN2-Like Eukaryotic Initiation Factor 2 Kinase Increases the Viability of Extracellular Toxoplasma gondii Parasites(American Society for Microbiology, 2011) Konrad, Christian; Wek, Ronald C.; Sullivan, William J., Jr.; Pharmacology and Toxicology, School of MedicineToxoplasmosis is a significant opportunistic infection caused by the protozoan parasite Toxoplasma gondii, an obligate intracellular pathogen that relies on host cell nutrients for parasite proliferation. Toxoplasma parasites divide until they rupture the host cell, at which point the extracellular parasites must survive until they find a new host cell. Recent studies have indicated that phosphorylation of Toxoplasma eukaryotic translation initiation factor 2-alpha (TgIF2α) plays a key role in promoting parasite viability during times of extracellular stress. Here we report the cloning and characterization of a TgIF2α kinase designated TgIF2K-D that is related to GCN2, a eukaryotic initiation factor 2α (eIF2α) kinase known to respond to nutrient starvation in other organisms. TgIF2K-D is present in the cytosol of both intra- and extracellular Toxoplasma parasites and facilitates translational control through TgIF2α phosphorylation in extracellular parasites. We generated a TgIF2K-D knockout parasite and demonstrated that loss of this eIF2α kinase leads to a significant fitness defect that stems from an inability of the parasite to adequately adapt to the environment outside host cells. This phenotype is consistent with that reported for our nonphosphorylatable TgIF2α mutant (S71A substitution), establishing that TgIF2K-D is the primary eIF2α kinase responsible for promoting extracellular viability of Toxoplasma. These studies suggest that eIF2α phosphorylation and translational control are an important mechanism by which vulnerable extracellular parasites protect themselves while searching for a new host cell. Additionally, TgIF2α is phosphorylated when intracellular parasites are deprived of nutrients, but this can occur independently of TgIF2K-D, indicating that this activity can be mediated by a different TgIF2K.Item A novel micellular fluorogenic substrate for quantitating the activity of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma (PLCγ) enzymes(Public Library of Science, 2024-03-29) Visvanathan, Ramya; Utsuki, Tadanobu; Beck, Daniel E.; Clayton, W. Brent; Lendy, Emma; Sun, Kuai-lin; Liu, Yinghui; Hering, Kirk W.; Mesecar, Andrew; Zhang, Zhong-Yin; Putt, Karson S.; Pharmacology and Toxicology, School of MedicineThe activities of the phospholipase C gamma (PLCγ) 1 and 2 enzymes are essential for numerous cellular processes. Unsurprisingly, dysregulation of PLCγ1 or PLCγ2 activity is associated with multiple maladies including immune disorders, cancers, and neurodegenerative diseases. Therefore, the modulation of either of these two enzymes has been suggested as a therapeutic strategy to combat these diseases. To aid in the discovery of PLCγ family enzyme modulators that could be developed into therapeutic agents, we have synthesized a high-throughput screening-amenable micellular fluorogenic substrate called C16CF3-coumarin. Herein, the ability of PLCγ1 and PLCγ2 to enzymatically process C16CF3-coumarin was confirmed, the micellular assay conditions were optimized, and the kinetics of the reaction were determined. A proof-of-principle pilot screen of the Library of Pharmacologically Active Compounds 1280 (LOPAC1280) was performed. This new substrate allows for an additional screening methodology to identify modulators of the PLCγ family of enzymes.Item A novel survivin dimerization inhibitor without a labile hydrazone linker induces spontaneous apoptosis and synergizes with docetaxel in prostate cancer cells(Elsevier, 2022) Peery, Robert; Cui, Qingbin; Kyei-Baffour, Kwaku; Josephraj, Sophia; Huang, Caoqinglong; Dong, Zizheng; Dai, Mingji; Zhang, Jian-Ting; Liu, Jing-Yuan; Pharmacology and Toxicology, School of MedicineSurvivin, a member of the inhibitor of apoptosis protein family, exists as a homodimer and is aberrantly upregulated in a wide spectrum of cancers. It was thought to be an ideal target due to its lack of expression in most adult normal tissues and importance in cancer cell survival. However, it has been challenging to target survivin due to its "undruggable" nature. We previously attempted to target its dimerization domain with a hypothesis that inhibiting survivin dimerization would promote its degradation in proteasome, which led to identification of a lead small-molecule inhibitor, LQZ-7F. LQZ-7F consists of a flat tetracyclic aromatic core with labile hydrazone linking a 1,2,5-oxadiazole moiety. In this study, we tested the hypothesis that LQZ-7F could be developed as a prodrug because the labile hydrazone linker could be hydrolyzed, releasing the tetracyclic aromatic core. To this end, we synthesized the tetracyclic aromatic core (LQZ-7F1) using reported procedure and tested LQZ-7F1 for its biological activities. Here we show that LQZ-7F1 has a significantly improved potency with submicromolar IC50's and induces spontaneous apoptosis in prostate cancer cells. It also more effectively inhibits survivin dimerization and induces survivin degradation in a proteasome-dependent manner than LQZ-7F. We also show that the combination of LQZ-7F1 and docetaxel have strong synergism in inhibiting prostate cancer cell survival. Together, we conclude that the hydrazone linker with the oxadiazole tail is dispensable for survivin inhibition and the survivin dimerization inhibitor, LQZ-7F, may be developed as a prodrug for prostate cancer treatment and to overcome docetaxel resistance.Item A transcriptional network required for bradyzoite development in Toxoplasma gondii is dispensable for recrudescent disease(Springer Nature, 2023-09-28) Sokol-Borrelli, Sarah L.; Reilly, Sarah M.; Holmes, Michael J.; Orchanian, Stephanie B.; Massmann, Mackenzie D.; Sharp, Katherine G.; Cabo, Leah F.; Alrubaye, Hisham S.; Martorelli Di Genova, Bruno; Lodoen, Melissa B.; Sullivan, William J., Jr.; Boyle, Jon P.; Pharmacology and Toxicology, School of MedicineIdentification of regulators of Toxoplasma gondii bradyzoite development and cyst formation is the most direct way to address the importance of parasite development in long-term persistence and reactivation of this parasite. Here we show that a T. gondii gene (named Regulator of Cystogenesis 1; ROCY1) is sufficient for T. gondii bradyzoite formation in vitro and in vivo. ROCY1 encodes an RNA binding protein that has a preference for 3' regulatory regions of hundreds of T. gondii transcripts, and its RNA-binding domains are required to mediate bradyzoite development. Female mice infected with ΔROCY1 parasites have reduced (>90%) cyst burden. While viable parasites can be cultivated from brain tissue for up to 6 months post-infection, chronic brain-resident ΔROCY1 parasites have reduced oral infectivity compared to wild type. Despite clear defects in bradyzoite formation and oral infectivity, ΔROCY1 parasites were able to reactivate with similar timing and magnitude as wild type parasites for up to 5 months post-infection. Therefore while ROCY1 is a critical regulator of the bradyzoite developmental pathway, it is not required for parasite reactivation, raising new questions about the persisting life stage responsible for causing recrudescent disease.