{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T23:38:38Z","timestamp":1787787518543,"version":"build-2784847793"},"reference-count":23,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2024,7,8]],"date-time":"2024-07-08T00:00:00Z","timestamp":1720396800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Br J Haematol"],"published-print":{"date-parts":[[2024,9]]},"abstract":"<jats:title>Summary<\/jats:title>\n                  <jats:p>\n                    The mechanisms of action of\n                    <jats:sc>l<\/jats:sc>\n                    \u2010glutamine for the treatment of sickle cell disease (SCD) are not well understood and there are no validated clinical biomarkers to assess response. We conducted a three\u2010week, dose\u2010ascending trial of glutamine and measured the pharmacokinetic (PK) exposure parameters, peak concentration (\n                    <jats:italic>C<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    ) and area under the curve (AUC). We used a panel of biomarkers to investigate the pharmacodynamics (PD) of glutamine and studied PK\u2013PD relationships. There was no plasma accumulation of glutamine, glutamate, arginine or other amino acids over time, but modestly improved arginine bioavailability was observed. In standard analysis by dose levels over time, there were no measurable effects on blood counts, viscosity, ektacytometry or reactive oxygen species (ROS). In PK\u2013PD analysis, however, higher glutamine exposure (\n                    <jats:italic>C<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    or AUC) was associated with increased whole blood viscosity and cellular dehydration, yet also with higher haemoglobin concentration, increased haematocrit\u2010to\u2010viscosity ratio, decreased reticulocyte ROS, improved RBC deformability and decreased point of sickling. This novel PK\u2013PD analysis identified biomarkers reflecting the positive and negative effects of glutamine, helping to elucidate its mechanisms of action in SCD. PK\u2010optimized dosing to achieve glutamine exposure (AUC or\n                    <jats:italic>C<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    ) that is associated with salutary biological effects should be studied to support its therapeutic use.\n                  <\/jats:p>","DOI":"10.1111\/bjh.19632","type":"journal-article","created":{"date-parts":[[2024,7,8]],"date-time":"2024-07-08T19:44:55Z","timestamp":1720467895000},"page":"1147-1158","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["A pharmacokinetic\u2013pharmacodynamic analysis of\n                    <scp>l<\/scp>\n                    \u2010glutamine for the treatment of sickle cell disease: Implications for understanding the mechanism of action and evaluating response to therapy"],"prefix":"10.1111","volume":"205","author":[{"given":"Alina","family":"Sadaf","sequence":"first","affiliation":[{"name":"Division of Hematology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Dong","sequence":"additional","affiliation":[{"name":"Division of Translational and Clinical Pharmacology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"},{"name":"Department of Pediatrics University of Cincinnati College of Medicine  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Pfeiffer","sequence":"additional","affiliation":[{"name":"Division of Hematology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Korpik","sequence":"additional","affiliation":[{"name":"Erythrocyte Diagnostic Laboratory Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theodosia A.","family":"Kalfa","sequence":"additional","affiliation":[{"name":"Division of Hematology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"},{"name":"Department of Pediatrics University of Cincinnati College of Medicine  Cincinnati Ohio USA"},{"name":"Erythrocyte Diagnostic Laboratory Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Latham","sequence":"additional","affiliation":[{"name":"Division of Hematology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander A.","family":"Vinks","sequence":"additional","affiliation":[{"name":"Division of Translational and Clinical Pharmacology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"},{"name":"Department of Pediatrics University of Cincinnati College of Medicine  Cincinnati Ohio 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