{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:15:13Z","timestamp":1760238913791,"version":"build-2065373602"},"reference-count":43,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,8,12]],"date-time":"2022-08-12T00:00:00Z","timestamp":1660262400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Jazz Pharmaceuticals"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medical Sciences"],"abstract":"<jats:p>Adverse reactions during and shortly after infusing asparaginase for the treatment of acute lymphoblastic leukemia can increase in severity with later doses, limiting further use and increasing relapse risk. Although asparaginase is associated with hyperammonemia, the magnitude of the increase in serum ammonia immediately after the infusion and in response to multiple infusions has not been examined. The concurrence of hyperammonemia and infusion reactions was studied using weaned juvenile pigs that received 12 infusions of Erwinia asparaginase (Erwinase; 1250 U\/kg) over 28 days, with two 5-day recovery periods without asparaginase after the eighth and eleventh doses. Infusion reactions and prolonged hyperammonemia (&gt;50 \u00b5M ammonia 48 h after the infusion) began after the fourth dose and increased with later doses. Dense sampling for 60 min revealed an acute phase of hyperammonemia that peaked within 20 min after starting the first infusion (298 + 62 \u00b5M) and lasted less than 1 h, without apparent symptoms. A pronounced acute hyperammonemia after the final infusion (1260 + 250 \u00b5M) coincided with severe symptoms and one mortality during the infusion. The previously unrecognized acute phase of hyperammonemia associated with asparaginase infusion coincides with infusion reactions. The juvenile pig is a translational animal model for understanding the causes of acute and chronic hyperammonemia, differentiating from hypersensitivity reactions, and for improving infusion protocols to reduce acute hyperammonemia and to allow the continued use of asparaginase.<\/jats:p>","DOI":"10.3390\/medsci10030043","type":"journal-article","created":{"date-parts":[[2022,8,15]],"date-time":"2022-08-15T03:33:20Z","timestamp":1660534400000},"page":"43","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multiple Asparaginase Infusions Cause Increasingly Severe Acute Hyperammonemia"],"prefix":"10.3390","volume":"10","author":[{"given":"Randal K","family":"Buddington","sequence":"first","affiliation":[{"name":"Resonance, Arlington, TN 38002, USA"},{"name":"College of Health Studies, University of Memphis, Memphis, TN 38152, USA"},{"name":"Molecular and Cellular Physiology, LSU Health Sciences, Shreveport, LA 71104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karyl K","family":"Buddington","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Memphis, Memphis, TN 38152, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Scott C.","family":"Howard","sequence":"additional","affiliation":[{"name":"Resonance, Arlington, TN 38002, USA"},{"name":"College of Nursing, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1002\/jcph.1336","article-title":"Analyses of Adverse Drug Reactions-Nationwide Active Surveillance Network: Canadian Pharmacogenomics Network for Drug Safety Database","volume":"59","author":"Tanoshima","year":"2019","journal-title":"J. Clin. Pharmacol."},{"key":"ref_2","first-page":"103","article-title":"High incidence of symptomatic hyperammonemia in children with acute lymphoblastic leukemia receiving pegylated asparaginase","volume":"7","author":"Prinsen","year":"2013","journal-title":"JIMD Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1200\/JCO.19.03024","article-title":"Impact of Asparaginase Discontinuation on Outcome in Childhood Acute Lymphoblastic Leukemia: A Report From the Children\u2019s Oncology Group","volume":"38","author":"Gupta","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/j.anai.2020.01.010","article-title":"Evaluation of hypersensitivity reactions to cancer chemotherapeutic agents in pediatric patients","volume":"124","author":"Guzelkucuk","year":"2020","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1586\/17474086.2016.1142370","article-title":"Asparaginase Erwinia chrysanthemi as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia who have developed hypersensitivity to E. coli-derived asparaginase","volume":"9","author":"Figueiredo","year":"2016","journal-title":"Expert Rev. Hematol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1002\/cncr.25489","article-title":"L-asparaginase treatment in acute lymphoblastic leukemia: A focus on Erwinia asparaginase","volume":"117","author":"Pieters","year":"2011","journal-title":"Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1797","DOI":"10.1080\/10428194.2017.1386305","article-title":"Asparaginase activity levels and monitoring in patients with acute lymphoblastic leukemia","volume":"59","author":"Salzer","year":"2018","journal-title":"Leuk. Lymphoma"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4205","DOI":"10.1002\/cncr.29641","article-title":"Allergic reactions and antiasparaginase antibodies in children with high-risk acute lymphoblastic leukemia: A children\u2019s oncology group report","volume":"121","author":"Ko","year":"2015","journal-title":"Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1928","DOI":"10.1002\/pbc.26123","article-title":"Allergic-like reactions to asparaginase: Atypical allergies without asparaginase inactivation","volume":"63","author":"Kloos","year":"2016","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_10","first-page":"107","article-title":"Changes of amino acid serum levels in pediatric patients with higher-risk acute lymphoblastic leukemia (CCG-1961)","volume":"18","author":"Grigoryan","year":"2004","journal-title":"In Vivo"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.2217\/fon-2016-0005","article-title":"Immunology of infusion reactions in the treatment of patients with acute lymphoblastic leukemia","volume":"12","author":"Asselin","year":"2016","journal-title":"Future Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1097\/MPH.0000000000001062","article-title":"Symptomatic Hyperammonemia With Erwinia chrysanthemi-derived Asparaginase in Pediatric Leukemia Patients","volume":"40","author":"Gossai","year":"2018","journal-title":"J. Pediatr. Hematol. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1080\/10428194.2017.1352090","article-title":"Acute central nervous system complications and ammonium levels in adult patients with acute lymphoblastic leukemia receiving l-asparaginase","volume":"59","author":"Strickler","year":"2018","journal-title":"Leuk. Lymphoma"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1177\/1078155221998738","article-title":"Ammonia level as a proxy of asparaginase inactivation in children: A strategy for classification of infusion reactions","volume":"28","author":"Santos","year":"2022","journal-title":"J. Oncol. Pharm. Pract."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1055\/s-2007-1025359","article-title":"Clinical experiences with adrenaline as therapy and prevention of E. coli-L-asparaginase-induced anaphylaxis","volume":"204","author":"Schwinger","year":"1992","journal-title":"Klin. Padiatr."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1177\/1043454217713455","article-title":"From the Children\u2019s Oncology Group: Evidence-Based Recommendations for PEG-Asparaginase Nurse Monitoring, Hypersensitivity Reaction Management, and Patient\/Family Education","volume":"34","author":"Woods","year":"2017","journal-title":"J. Pediatr. Oncol. Nurs."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1716","DOI":"10.3324\/haematol.2014.109413","article-title":"The toxicity of very prolonged courses of PEGasparaginase or Erwinia asparaginase in relation to asparaginase activity, with a special focus on dyslipidemia","volume":"99","author":"Tong","year":"2014","journal-title":"Haematologica"},{"key":"ref_18","first-page":"7","article-title":"Hypersensitivity rates in pediatric patients receiving intravenous or intramuscular asparaginase agents","volume":"10","author":"Halford","year":"2020","journal-title":"J. Hematol. Oncol. Pharm."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.bjhh.2017.08.002","article-title":"Reactions related to asparaginase infusion in a 10-year retrospective cohort","volume":"39","author":"Santos","year":"2017","journal-title":"Rev. Bras. Hematol. Hemoter."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1111\/vec.12695","article-title":"Plasma ammonia concentration after L-asparaginase therapy in 27 dogs with high-grade lymphoma or leukemia","volume":"28","author":"Speas","year":"2018","journal-title":"J. Vet. Emerg. Crit. Care"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1002\/pbc.21022","article-title":"Distinct fluctuations of ammonia levels during asparaginase therapy for childhood acute leukemia","volume":"49","author":"Steiner","year":"2007","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3","DOI":"10.3109\/08880018.2010.484852","article-title":"Transient hyperammonemia due to L-asparaginase therapy in children with acute lymphoblastic leukemia or non-Hodgkin lymphoma","volume":"28","author":"Kiess","year":"2011","journal-title":"Pediatr. Hematol. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1053\/j.gastro.2010.03.040","article-title":"Hyperammonemia induces neuroinflammation that contributes to cognitive impairment in rats with hepatic encephalopathy","volume":"139","author":"Rodrigo","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2237","DOI":"10.3109\/10428194.2011.596963","article-title":"Prevention and management of asparaginase\/pegasparaginase-associated toxicities in adults and older adolescents: Recommendations of an expert panel","volume":"52","author":"Stock","year":"2011","journal-title":"Leuk. Lymphoma"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"111870","DOI":"10.1016\/j.ecoenv.2020.111870","article-title":"Ammonia exposure causes the disruption of the solute carrier family gene network in pigs","volume":"210","author":"Xia","year":"2021","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"17664","DOI":"10.1074\/jbc.M116.728485","article-title":"Design and Characterization of Erwinia Chrysanthemi l-Asparaginase Variants with Diminished l-Glutaminase Activity","volume":"291","author":"Nguyen","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2369","DOI":"10.2527\/2000.7892369x","article-title":"Postnatal changes of plasma amino acids in suckling pigs","volume":"78","author":"Flynn","year":"2000","journal-title":"J. Anim. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1038\/ejcn.2015.144","article-title":"Plasma concentrations and intakes of amino acids in male meat-eaters, fish-eaters, vegetarians and vegans: A cross-sectional analysis in the EPIC-Oxford cohort","volume":"70","author":"Schmidt","year":"2016","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e28244","DOI":"10.1002\/pbc.28244","article-title":"Higher plasma asparaginase activity after intramuscular than intravenous Erwinia asparaginase","volume":"67","author":"Panetta","year":"2020","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"552","DOI":"10.3324\/haematol.2016.149195","article-title":"Population pharmacokinetics of intravenous Erwinia asparaginase in pediatric acute lymphoblastic leukemia patients","volume":"102","author":"Sassen","year":"2017","journal-title":"Haematologica"},{"key":"ref_31","first-page":"945860","article-title":"Clinical utility of ammonia concentration as a diagnostic test in monitoring of the treatment with L-asparaginase in children with acute lymphoblastic leukemia","volume":"2014","author":"Balwierz","year":"2014","journal-title":"Biomed. Res. Int."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1007\/s00280-003-0734-5","article-title":"L-Asparagine depletion levels and L-asparaginase activity in plasma of children with acute lymphoblastic leukemia under asparaginase treatment","volume":"53","author":"Tsurusawa","year":"2004","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.htct.2019.10.007","article-title":"Allergic reactions to asparaginase: Retrospective cohort study in pediatric patients with acute lymphoid leukemia","volume":"43","author":"Battistel","year":"2021","journal-title":"Hematol. Transfus. Cell Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.htct.2019.07.010","article-title":"Asparaginase: An old drug with new questions","volume":"42","author":"Cecconello","year":"2020","journal-title":"Hematol. Transfus. Cell Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1038\/leu.2008.165","article-title":"Pharmacokinetic, pharmacodynamic and intracellular effects of PEG-asparaginase in newly diagnosed childhood acute lymphoblastic leukemia: Results from a single agent window study","volume":"22","author":"Appel","year":"2008","journal-title":"Leukemia"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Horvath, T.D., Chan, W.K., Pontikos, M.A., Martin, L.A., Du, D., Tan, L., Konopleva, M., Weinstein, J.N., and Lorenzi, P.L. (2019). Assessment of l-Asparaginase Pharmacodynamics in Mouse Models of Cancer. Metabolites, 9.","DOI":"10.3390\/metabo9010010"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1038\/217758a0","article-title":"L-Asparaginase activity in human and animal sera","volume":"217","author":"Lee","year":"1968","journal-title":"Nature"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1007\/s12185-009-0419-x","article-title":"The ex vivo production of ammonia predicts L-asparaginase biological activity in children with acute lymphoblastic leukemia","volume":"90","author":"Watanabe","year":"2009","journal-title":"Int. J. Hematol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/2052-0492-2-22","article-title":"Hyperammonemia due to urea cycle disorders: A potentially fatal condition in the intensive care setting","volume":"2","author":"Machado","year":"2014","journal-title":"J. Intensive Care"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e27239","DOI":"10.1002\/pbc.27239","article-title":"Pegylated asparaginase as cause of fatal hyperammonemia in patients with latent urea cycle disorder","volume":"65","author":"Peters","year":"2018","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1007\/s12072-019-09971-2","article-title":"Asparaginase-induced hepatotoxicity: Rapid development of cholestasis and hepatic steatosis","volume":"13","author":"Kamal","year":"2019","journal-title":"Hepatol. Int."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1080\/10428194.2016.1213826","article-title":"Differentiating hypersensitivity versus infusion-related reactions in pediatric patients receiving intravenous asparaginase therapy for acute lymphoblastic leukemia","volume":"58","author":"Burke","year":"2017","journal-title":"Leuk. Lymphoma"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1007\/s00280-002-0466-y","article-title":"Anti-Erwinia asparaginase antibodies during treatment of childhood acute lymphoblastic leukemia and their relationship to outcome: A case-control study","volume":"50","author":"Schmiegelow","year":"2002","journal-title":"Cancer Chemother. Pharmacol."}],"container-title":["Medical Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3271\/10\/3\/43\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:08:01Z","timestamp":1760141281000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3271\/10\/3\/43"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,12]]},"references-count":43,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["medsci10030043"],"URL":"https:\/\/doi.org\/10.3390\/medsci10030043","relation":{},"ISSN":["2076-3271"],"issn-type":[{"type":"electronic","value":"2076-3271"}],"subject":[],"published":{"date-parts":[[2022,8,12]]}}}