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1. The survival of B cells is compromised in kidney disease

Author

Peroumal, Doureradjou, Jawale, Chetan V., Choi, Wonseok, Rahimi, Hossein, Antos, Danielle, Li, De-dong, Wang, Shuxia, Manakkat Vijay, Godhev K., Mehta, Isha, West, Raymond, Thangaraju, Muthusamy, Nolin, Thomas D., Das, Jishnu, Alcorn, John F., and Biswas, Partha S.

Published
2024
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7. Indirect Measurement of Hepatic Drug Clearance by Fitting Dynamical Models

Author

Franchetti, Yoko, Nolin, Thomas D., and Franchetti, Franz

Subjects
Quantitative Biology - Quantitative Methods
Abstract

We present an indirect signal processing-based measurement method for biological quantities in humans that cannot be directly measured. We develop the method by focusing on estimating hepatic enzyme and drug transporter activity through breath-biopsy samples clinically obtained via the erythromycin breath test (EBT): a small dose of radio-labeled drug is injected and the subsequent content of radio-labeled CO$_2$ is measured repeatedly in exhaled breath; the resulting time series is analyzed. To model EBT we developed a 14-variable non-linear reduced order dynamical model that describes the behavior of the drug and its metabolites in the human body well enough to capture all biological phenomena of interest. Based on this system of coupled non-linear ordinary differential equations (ODEs) we treat the measurement problem as inverse problem: we estimate the ODE parameters of individual patients from the measured EBT time series. These estimates then provide a measurement of the liver activity of interest. The parameters are hard to estimate as the ODEs are stiff and the problem needs to be regularized to ensure stable convergence. We develop a formal operator framework to capture and treat the specific non-linearities present, and perform perturbation analysis to establish properties of the estimation procedure and its solution. Development of the method required 150,000 CPU hours at a supercomputing center, and a single production run takes CPU 24 hours. We introduce and analyze the method in the context of future precision dosing of drugs for vulnerable patients (e.g., oncology, nephrology, or pediatrics) to eventually ensure efficacy and avoid toxicity., Comment: This preprint is based on Chapter 2 of the PhD dissertation of Y Franchetti. The dissertation thesis is available at http://d-scholarship.pitt.edu/id/eprint/39885

Published
2020

15. Extracorporeal Treatment for Gabapentin and Pregabalin Poisoning: Systematic Review and Recommendations From the EXTRIP Workgroup

Author

Alhatali, Badria, Anseeuw, Kurt, Bird, Steven, Berling, Ingrid, Bunchman, Timothy E., Chin, Paul K., Doi, Kent, Galvao, Tais, Goldfarb, David S., Hassanian, Hossein, Hoegberg, Lotte C.G., Kallab, Siba, Kebede, Sofia, Kielstein, Jan T., Lewington, Andrew, Macedo, Etienne M., MacLaren, Rob, Megarbane, Bruno, Mowry, James B., Nolin, Thomas D., Roy, Jean-Philippe, Vijayan, Anitha, Walsh, Steven J., Wong, Anselm, Wood, David M., Bouchard, Josée, Yates, Christopher, Calello, Diane P., Gosselin, Sophie, Roberts, Darren M., Lavergne, Valéry, Hoffman, Robert S., Ostermann, Marlies, Peng, Ai, and Ghannoum, Marc

Published
2022
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20. Contributors

Author

Abernethy, Darrell R., primary, Agoram, Balaji, additional, Allen, John M., additional, Arnold, Mark E., additional, Atkinson, Arthur J., additional, Bateman, Thomas J., additional, Bergman, Kimberly, additional, Booth, Brian, additional, Boulton, David W., additional, Branch, Robert A., additional, Burckart, Gilbert J., additional, Buschmann, Mary, additional, Carmichael, Owen, additional, Chamberlain, Christine, additional, Chen, Ligong, additional, Daniels, Charles E., additional, Das, Promi, additional, Delfino, Jana G., additional, Van Den Anker, John N., additional, Dreisbach, Albert W., additional, Dyszel, Michael, additional, Earp, Justin C., additional, ElZarrad, M. Khair, additional, Enogieru, Osatohanmwen J., additional, Fletcher, Elimika Pfuma, additional, Foster, David M., additional, Frederiksen, Marilynn C., additional, Galetin, Aleksandra, additional, Garzone, Pamela D., additional, Giacomini, Kathleen M., additional, Gibbs, Megan A., additional, Gilbert, Jack A, additional, Gnjidic, Danijela, additional, Gombar, Charles T., additional, Grant, Denis M., additional, Grudzinskas, Charles, additional, Hamren, Bengt, additional, Holford, Nicholas H.G., additional, Huang, Shiew-Mei, additional, Iacona, Renee, additional, Isoherranen, Nina, additional, Jin, Denise, additional, Jones, Bridgette L., additional, Kearns, Gregory L., additional, Kortepeter, Cindy, additional, Kunkoski, Elizabeth, additional, Lau, S.W. Johnny, additional, Leptak, Christopher, additional, Lertora, Juan J.L., additional, Lesko, Lawrence J., additional, Liu, Jiang, additional, Liu, Qi, additional, Madabushi, Rajanikanth, additional, Miller, Raymond, additional, Mould, Diane R., additional, Muñoz, Monica, additional, Nolin, Thomas D., additional, Noveck, Robert Joseph, additional, Obach, R. Scott, additional, Pacanowski, Michael, additional, Paine, Mary F., additional, Peck, Carl C., additional, Ramamoorthy, Anuradha, additional, Rodrigues, A. David, additional, Rowland, Malcolm, additional, Sahajwalla, Chandrahas G., additional, Sahre, Martina Dagmar, additional, Schuck, Robert N., additional, Sharma, Khushboo, additional, Sissung, Tristan, additional, Stika, Catherine S., additional, Takimoto, Chris H., additional, Tomkinson, Helen, additional, Uetrecht, Jack, additional, Vicini, Paolo, additional, Vo, Karen D., additional, Wagner, John A., additional, Wang, Yaning, additional, Wang, Yow-Ming C., additional, Wells, Peter G., additional, Wick, Michael J., additional, Yee, Sook Wah, additional, Yin, Ophelia, additional, Zgheib, Nathalie K., additional, Zhang, Lei, additional, and Zhu, Hao, additional

Published
2022
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23. Population Pharmacokinetic Model of Vitamin D 3 and Metabolites in Chronic Kidney Disease Patients with Vitamin D Insufficiency and Deficiency.

Author

Tuey, Stacey M., Ghimire, Avisek, Guzy, Serge, Prebehalla, Linda, Roque, Amandla-Atilano, Roda, Gavriel, West 3rd, Raymond E., Chonchol, Michel B., Shah, Nirav, Nolin, Thomas D., and Joy, Melanie S.

Subjects
CHOLECALCIFEROL, VITAMIN D deficiency, CHRONIC kidney failure, CHRONICALLY ill, VITAMIN D
Abstract

Vitamin D insufficiency and deficiency are highly prevalent in patients with chronic kidney disease (CKD), and their pharmacokinetics are not well described. The primary study objective was to develop a population pharmacokinetic model of oral cholecalciferol (VitD3) and its three major metabolites, 25-hydroxyvitamin D3 (25D3), 1,25-dihydroxyvitamin D3 (1,25D3), and 24,25-dihydroxyvitamin D3 (24,25D3), in CKD patients with vitamin D insufficiency and deficiency. CKD subjects (n = 29) were administered one dose of oral VitD3 (5000 I.U.), and nonlinear mixed effects modeling was used to describe the pharmacokinetics of VitD3 and its metabolites. The simultaneous fit of a two-compartment model for VitD3 and a one-compartment model for each metabolite represented the observed data. A proportional error model explained the residual variability for each compound. No assessed covariate significantly affected the pharmacokinetics of VitD3 and metabolites. Visual predictive plots demonstrated the adequate fit of the pharmacokinetic data of VitD3 and metabolites. This is the first reported population pharmacokinetic modeling of VitD3 and metabolites and has the potential to inform targeted dose individualization strategies for therapy in the CKD population. Based on the simulation, doses of 600 International Unit (I.U.)/day to 1000 I.U./day for 6 months are recommended to obtain the target 25D3 concentration of between 30 and 60 ng/mL. These simulation findings could potentially contribute to the development of personalized dosage regimens for vitamin D treatment in patients with CKD. [ABSTRACT FROM AUTHOR]

Published
2024
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24. Alpha-2-adrenergic agonists reduce resting energy expenditure in humans during external cooling.

Author

Callaway, Clifton W., Flickinger, Katharyn L., Weissman, Alexandra, Guyette, Francis X., DeMaio, Ryann, Jonsson, Andrea, Wu, Victor, Monteleone, Jenna L., Prescott, Peter, Birabaharan, Jonathan, Buysse, Daniel J., Empey, Philip E., Nolin, Thomas D., and West III, Raymond E.

Subjects
MUSCLE relaxants, TEMPERATURE control, ORAL medication, DEXMEDETOMIDINE, BLOOD pressure
Abstract

Intravenous alpha-2-adrenergic receptor agonists reduce energy expenditure and lower the temperature when shivering begins in humans, allowing a decrease in core body temperature. Because there are few data about similar effects from oral drugs, we tested whether single oral doses of the sedative dexmedetomidine (1 µg/kg sublingual or 4 µg/kg swallowed) or the muscle relaxant tizanidine (8 mg or 16 mg), combined with surface cooling, reduce energy expenditure and core body temperature in humans. A total of 26 healthy participants completed 41 one-day laboratory studies measuring core body temperature using an ingested telemetry capsule and measuring energy expenditure using indirect calorimetry for up to 6 hours after drug ingestion. Dexmedetomidine induced a median 13% – 19% peak reduction and tizanidine induced a median 15% – 22% peak reduction in energy expenditure relative to baseline. Core body temperature decreased a median of 0.5°C – 0.6°C and 0.5°C – 0.7°C respectively. Decreases in temperature occurred after peak reductions in energy expenditure. Energy expenditure increased with a decrease in core temperature in control participants but did not occur after 4 µg/kg dexmedetomidine or 16 mg tizanidine. Plasma levels of dexmedetomidine but not tizanidine were related to mean temperature change. Decreases in heart rate, blood pressure, respiratory rate, cardiac stroke volume index, and cardiac index were associated with the change in metabolic rate after higher drug doses. We conclude that both oral dexmedetomidine and oral tizanidine reduce energy expenditure and allow decrease in core temperature in humans. [ABSTRACT FROM AUTHOR]

Published
2024
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26. In Situ Formation of Fibronectin‐Enriched Protein Corona on Epigenetic Nanocarrier for Enhanced Synthetic Lethal Therapy

Author

Luo, Zhangyi, primary, Wan, Zhuoya, additional, Ren, Pengfei, additional, Zhang, Bei, additional, Huang, Yixian, additional, West, Raymond E., additional, Huang, Haozhe, additional, Chen, Yuang, additional, Nolin, Thomas D., additional, Xie, Wen, additional, Wang, Junmei, additional, Li, Song, additional, and Sun, Jingjing, additional

Published
2024
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27. Clinical Use of the Urine Biomarker [TIMP-2] × [IGFBP7] for Acute Kidney Injury Risk Assessment

Author

Vijayan, Anitha, Faubel, Sarah, Askenazi, David J, Cerda, Jorge, Fissell, William H, Heung, Michael, Humphreys, Benjamin D, Koyner, Jay L, Liu, Kathleen D, Mour, Girish, Nolin, Thomas D, Bihorac, Azra, Group, American Society of Nephrology Acute Kidney Injury Advisory, Basu, Rajit K, Bhatt, Udayan Y, Connor, Michael J, Davidson, Alan J, de Caestecker, Mark P, Doi, Kent, Golestaneh, Ladan, Mour, Girish K, Singh, Prabhleen, and Thakar, Charuhas V

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Research, Prevention, Kidney Disease, 4.2 Evaluation of markers and technologies, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, Renal and urogenital, Acute Kidney Injury, Biomarkers, Clinical Trials as Topic, Decision Trees, Early Diagnosis, Humans, Insulin-Like Growth Factor Binding Proteins, Risk Assessment, Tissue Inhibitor of Metalloproteinase-2, Acute kidney injury, biomarker, [TIMP-2] x [IGFBP7], diagnosis, critically ill, tissue inhibitor of metalloproteinase 2, insulin-like growth factor binding protein 7, NephroCheck, early detection, risk assessment, renal dysfunction, decreased kidney function, American Society of Nephrology Acute Kidney Injury Advisory Group, [TIMP-2] × [IGFBP7], Public Health and Health Services, Urology & Nephrology, Clinical sciences
Abstract

Acute kidney injury (AKI) is a serious complication, commonly occurring in the critically ill population, with devastating short- and long-term consequences. Despite standardization of the definition and staging of AKI, early recognition remains challenging given that serum creatinine level is a marker, albeit imperfect, of kidney function and not kidney injury. Furthermore, the delay in increase in serum creatinine level after loss of glomerular filtration also prevents timely detection of decreased kidney function in patients with AKI. During the past decade, numerous clinical investigations have evaluated the utility of several biomarkers in the early diagnosis and risk stratification of AKI. In 2014, the US Food and Drug Administration approved the marketing of a test based on the combination of urine concentrations of tissue inhibitor of metalloproteinase 2 and insulin-like growth factor binding protein 7 ([TIMP-2] × [IGFBP7]) to determine whether certain critically ill patients are at risk for developing moderate to severe AKI. The optimal role of this biomarker in the diagnosis, management, and prognosis of AKI in different clinical settings requires further clarification. In this perspective, we summarize the biological actions of these 2 cell-cycle arrest biomarkers and present important considerations regarding the clinical application, interpretation, and limitations of this novel test for the early detection of AKI.

Published
2016

31. Extracorporeal Treatment for Tricyclic Antidepressant Poisoning: Recommendations from the EXTRIP Workgroup

Author

Yates, Christopher, Galvao, Tais, Sowinski, Kevin M, Mardini, Karine, Botnaru, Tudor, Gosselin, Sophie, Hoffman, Robert S, Nolin, Thomas D, Lavergne, Valéry, Ghannoum, Marc, and workgroup, the EXTRIP

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Neurosciences, Antidepressive Agents, Tricyclic, Evidence-Based Medicine, Humans, Practice Guidelines as Topic, Renal Dialysis, EXTRIP workgroup, Urology & Nephrology, Clinical sciences
Abstract

The Extracorporeal Treatments In Poisoning (EXTRIP) workgroup was formed to provide recommendations on the use of extracorporeal treatments (ECTR) in poisoning. Here, the workgroup presents its results for tricyclic antidepressants (TCAs). After an extensive literature search, using a predefined methodology, the subgroup responsible for this poison reviewed the articles, extracted the data, summarized findings, and proposed structured voting statements following a predetermined format. A two-round modified Delphi method was chosen to reach a consensus on voting statements and RAND/UCLA Appropriateness Method to quantify disagreement. Blinded votes were compiled, returned, and discussed in person at a meeting. A second vote determined the final recommendations. Seventy-seven articles met inclusion criteria. Only case reports, case series, and one poor-quality observational study were identified yielding a very low quality of evidence for all recommendations. Data on 108 patients, including 12 fatalities, were abstracted. The workgroup concluded that TCAs are not dialyzable and made the following recommendation: ECTR is not recommended in severe TCA poisoning (1D). The workgroup considers that poisoned patients with TCAs are not likely to have a clinical benefit from extracorporeal removal and recommends it NOT to be used in TCA poisoning.

Published
2014

43. List of Contributors

Author

Abramovitz, Blaise, primary, Adu, Dwomoa, additional, Afshinnia, Farsad, additional, Agarwal, Anupam, additional, Andrews, Sarah C., additional, Appel, Gerald, additional, Bailey, James L., additional, Bakris, George L., additional, Bauer, Carolyn A., additional, Baxi, Pravir V., additional, Berns, Jeffrey S., additional, Birks, Peter, additional, Bomback, Andrew, additional, Bose, Anirban, additional, Brosius, Frank C., additional, Brown, Lee K., additional, Bushinsky, David A., additional, Busse, Laurence W., additional, Campbell, Ruth C., additional, Canney, Mark, additional, Cathro, Helen, additional, Chávez-Iñiguez, Jonathan, additional, Chawla, Lakhmir S., additional, Chen, Sheldon, additional, Chertow, Glenn M., additional, Chew, Emily Y., additional, Chonchol, Michel, additional, Clegg, Deborah J., additional, Clive, David M., additional, Clive, Pia H., additional, Cohen, Scott D., additional, Collins, Ashte' K., additional, Cooper, James E., additional, Correa-Rotter, Ricardo, additional, Cukor, Daniel, additional, Dalal, Monica, additional, Davenport, Andrew, additional, Davis, Scott, additional, Davison, Sara N., additional, Delanaye, Pierre, additional, de Zeeuw, Dick, additional, Dobre, Mirela A., additional, Drawz, Paul, additional, Ebert, Natalie, additional, Eggers, Paul, additional, Ferrè, Silvia, additional, Freedman, Barry I., additional, Furth, Susan L., additional, Gao, Bixia, additional, García-García, Guillermo, additional, Gashti, Casey N., additional, Germino, Gregory G., additional, Goldsmith, David, additional, Golestaneh, Ladan, additional, Goligorsky, Michael S., additional, Greenberg, Arthur, additional, Gregg, L. Parker, additional, Guay-Woodford, Lisa M., additional, Hamm, Lee, additional, Hart, Allyson, additional, Haselby, Danielle, additional, Hedayati, S. Susan, additional, Heerspink, Hiddo J.L., additional, Herzog, Charles A., additional, Hostetter, Thomas H., additional, House, Andrew A., additional, Hruska, Keith A., additional, Ishani, Areef, additional, Isom, Robert T., additional, James, Matthew T., additional, Jhaveri, Kenar D., additional, Johansen, Kirsten, additional, Johnson, Richard J., additional, Kang, Duk-Hee, additional, Kanno, Hiroko, additional, Kanno, Yoshihiko, additional, Karambelkar, Amrita D., additional, Karet Frankl, Fiona E., additional, Khoury, Charbel C., additional, Kimmel, Paul L., additional, Kopp, Jeffrey B., additional, Korbet, Stephen M., additional, Kruzel-Davila, Etty, additional, Kummer, Andrew, additional, LaFave, Laura, additional, Lakkis, Jay I., additional, Lerman, Lilach O., additional, Levin, Adeera, additional, Lew, Susie Q., additional, Luyckx, Valerie A., additional, Mattoo, Tej K., additional, Maynard, Sharon E., additional, McCullough, Peter A., additional, Mehrotra, Rajnish, additional, Meyer, Timothy W., additional, Mitch, William E., additional, Moe, Orson W., additional, Mohandes, Samer, additional, Moss, Alvin H., additional, Moxey-Mims, Marva, additional, Murugapandian, Sangeetha, additional, Nath, Karl A., additional, Neugarten, Joel, additional, Neyra, Javier A., additional, Nissenson, Allen R., additional, Nobakht, Ehsan, additional, Nolin, Thomas D., additional, Norris, Keith C., additional, Norton, Jenna M., additional, Nowak, Kristen L., additional, Ojo, Akinlolu O., additional, Pahl, Madeleine V., additional, Paller, Mark S., additional, Palmer, Biff F., additional, Palmer, Nicholette D., additional, Patel, Samir S., additional, Pecoits-Filho, Roberto, additional, Peitzman, Steven J., additional, Peixoto, Aldo J., additional, Pham, Phuong-Thu T., additional, Pham, Phuong-Chi T., additional, Piraino, Beth, additional, Pisoni, Roberto, additional, Rabelink, Ton, additional, Radhakrishnan, Jai, additional, Rahman, Mahboob, additional, Raj, Dominic S., additional, Ramírez-Sandoval, Juan C., additional, Rangaswami, Janani, additional, Reckelhoff, Jane F., additional, Regunathan-Shenk, Renu, additional, Reule, Scott, additional, Ronco, Claudio, additional, Rosenberg, Mark E., additional, Rosner, Mitchell H., additional, Rovin, Brad, additional, Roy-Chaudhury, Prabir, additional, Ruebner, Rebecca, additional, Rule, Andrew D., additional, Sands, Jeff M., additional, Schlanger, Lynn E., additional, Schrauben, Sarah J., additional, Seliger, Stephen, additional, Shah, Maulin, additional, Sterns, Richard H., additional, Stites, Erik, additional, Sugatani, Toshifumi, additional, Textor, Stephen C., additional, Thadhani, Ravi, additional, Thajudeen, Bijin, additional, Thakar, Surabhi, additional, Thomas, George, additional, Townsend, Raymond R., additional, Turner, Jeffrey, additional, Unruh, Mark L., additional, Urquhart, Bradley L., additional, Vassalotti, Joseph A., additional, Vaziri, Nosratola D., additional, Velasquez, Manuel T., additional, Ver Halen, Nisha, additional, Waddy, Salina P., additional, Wang, Jinwei, additional, Weber, Marc, additional, Weir, Matthew R., additional, White, Christine A., additional, Whittier, William L., additional, Williams, Matthew J., additional, Wiseman, Alexander C., additional, Wymer, David C., additional, Wymer, David T.G., additional, Yee, Jerry, additional, Zhang, Luxia, additional, Zhuang, Shougang, additional, and Ziyadeh, Fuad N., additional

Published
2020
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44. Clinical Use of the Urine Biomarker [TIMP-2] × [IGFBP7] for Acute Kidney Injury Risk Assessment

Author

Faubel, Sarah, Askenazi, David J., Basu, Rajit K., Bhatt, Udayan Y., Bihorac, Azra, Cerda, Jorge, Connor, Michael J., Jr., Davidson, Alan J., de Caestecker, Mark P., Doi, Kent, Fissell, William H., Golestaneh, Ladan, Heung, Michael, Humphreys, Benjamin D., Koyner, Jay L., Liu, Kathleen D., Mour, Girish K., Singh, Prabhleen, Thakar, Charuhas V., Vijayan, Anitha, Mour, Girish, and Nolin, Thomas D.

Published
2016
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47. Transdermal Detection of MB-102 and Correlation to Meropenem Pharmacokinetics During Continuous Renal Replacement Therapy: In Vivo Results

Author

Dorshow, Richard B., primary, Johnson, James R., additional, Shieh, Jeng-Jong, additional, Riley, I. Rochelle, additional, Rogers, Thomas E., additional, Pino, Christopher J., additional, Johnston, Kimberly A., additional, Tang, Peter, additional, Nolin, Thomas D., additional, Humes, H. David, additional, and Goldstein, Stuart L., additional

Published
2023
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49. Extracorporeal Treatment for Salicylate Poisoning: Systematic Review and Recommendations From the EXTRIP Workgroup

Author

Anseeuw, Kurt, Bhalla, Ashish, Burdmann, Emmanuel A., Calello, Diane P., Dargan, Paul I., Decker, Brian S., Goldfarb, David S., Galvo, Tais, Hoegberg, Lotte C., Laliberté, Martin, Li, Yi, Liu, Kathleen D., MacLaren, Robert, Mactier, Robert, Mégarbane, Bruno, Mowry, James B., Phan, Véronique, Roberts, Darren M., Wiegand, Timothy J., Winchester, James F., Yates, Christopher, Juurlink, David N., Gosselin, Sophie, Kielstein, Jan T., Ghannoum, Marc, Lavergne, Valéry, Nolin, Thomas D., and Hoffman, Robert S.

Published
2015
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