{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T14:30:41Z","timestamp":1790865041579,"version":"4.1.0"},"reference-count":32,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2009,1,6]],"date-time":"2009-01-06T00:00:00Z","timestamp":1231200000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["European J of Haematology"],"published-print":{"date-parts":[[2009,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    <jats:bold>Objectives:\u2002<\/jats:bold>\n                    Fetal hemoglobin (HbF) induction involves NO\u2010cGMP signaling pathways.\n                    <jats:sc>l<\/jats:sc>\n                    \u2010arginine, an NO precursor, and the phosphodiesterase (PDE) 5 inhibitor sildenafil, which potentiates cGMP, were studied in adults with sickle cell disease (SCD) who were stably on HU.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Methods:\u2002<\/jats:bold>\n                    Twenty four courses of\n                    <jats:sc>l<\/jats:sc>\n                    \u2010arginine (0.1\u20130.2\u2003g\/kg divided TID) or sildenafil (25\u2013100\u2003mg TID), assigned based on gender due to concerns about sildenafil\u2010related priapism, were successfully completed. Biochemical assays, pulmonary pressures, and cardiopulmonary exercise capacity are reported from patients in whom serial values are available. Hematologic responses are reported in 14 subjects with HbSS who had stable baseline HbF levels.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Results:\u2002<\/jats:bold>\n                    <jats:sc>l<\/jats:sc>\n                    \u2010arginine increased plasma arginine and ornithine, but not citrulline, suggesting diversion by plasma arginase from NO, and citrulline, generation. Glutathione increased only in patients on\n                    <jats:sc>l<\/jats:sc>\n                    \u2010arginine. Sildenafil increased plasma cGMP and citrulline, but not other amino acids. Pulmonary pressures and 6\u2010min walk distances improved only in patients on sildenafil. In subjects with stable baseline HbF levels, HbF levels changed little from a normalized baseline on\n                    <jats:sc>l<\/jats:sc>\n                    \u2010arginine, decreasing by 2.9\u2003\u00b1\u200316.1%,\n                    <jats:italic>n<\/jats:italic>\n                    \u2003=\u20036;\n                    <jats:italic>P<\/jats:italic>\n                    \u2003=\u2003n.s., but increased on sildenafil, by 7.5\u2003\u00b1\u200311.7%,\n                    <jats:italic>n<\/jats:italic>\n                    \u2003=\u20038,\n                    <jats:italic>P<\/jats:italic>\n                    \u2003&lt;\u20030.05. Absolute reticulocyte counts initially decreased in patients on sildenafil.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Conclusions:\u2002<\/jats:bold>\n                    <jats:sc>l<\/jats:sc>\n                    \u2010arginine, at doses that increase plasma arginine levels, altered redox potential in red cells. The lack of clinically detectable efficacy of\n                    <jats:sc>l<\/jats:sc>\n                    \u2010arginine may be due to increased arginine metabolism in SCD patients.\n                    <jats:italic>In vivo<\/jats:italic>\n                    augmentation of the cyclic nucleotide pathway by PDE inhibition may induce HbF slightly, but strikingly improves hemodynamic and functional status in SCD.\n                  <\/jats:p>","DOI":"10.1111\/j.1600-0609.2009.01210.x","type":"journal-article","created":{"date-parts":[[2009,1,6]],"date-time":"2009-01-06T12:42:18Z","timestamp":1231245738000},"page":"315-321","source":"Crossref","is-referenced-by-count":52,"title":["Hematologic, biochemical, and cardiopulmonary effects of\n                    <scp>l<\/scp>\n                    \u2010arginine supplementation or phosphodiesterase 5 inhibition in patients with sickle cell disease who are on hydroxyurea therapy"],"prefix":"10.1111","volume":"82","author":[{"given":"Jane A.","family":"Little","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristine Partovi","family":"Hauser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina E.","family":"Martyr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Harris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Maric","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia R.","family":"Morris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jung H.","family":"Suh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oswaldo","family":"Castro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Machado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory","family":"Kato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark T.","family":"Gladwin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2009,2,19]]},"reference":[{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199505183322001"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.289.13.1645"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.2174\/1568026054679362"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200316672"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.exphem.2006.03.018"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.98.4.1847"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.exphem.2003.12.006"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.20129"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1097\/00043426-200011000-00009"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00277-004-0856-9"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.294.1.81"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200208-967OC"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V99.4.1103"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2006.08.025"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9343(02)01165-8"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1743-6109.2006.00333.x"},{"issue":"5","key":"e_1_2_6_18_2","first-page":"E740","article-title":"Differential regulation of arginases and inducible nitric oxide synthase in murine macrophage cells","volume":"275","author":"Morris SM","year":"1998","journal-title":"Am J Physiol"},{"key":"e_1_2_6_19_2","first-page":"1076","article-title":"Combination erythropoietin\u2010hydroxyurea therapy in sickle cell disease: experience from the National Institutes of Health and a literature review","volume":"91","author":"Little JA","year":"2006","journal-title":"Haematologica"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-04-081703"},{"key":"e_1_2_6_21_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200610-1498OC"},{"key":"e_1_2_6_22_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V80.3.816.816"},{"key":"e_1_2_6_23_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V91.12.4472"},{"key":"e_1_2_6_24_2","first-page":"23","article-title":"Polymorphisms near a chromosome 6q QTL area are associated with modulation of fetal hemoglobin levels in sickle cell anemia","volume":"50","author":"Wyszynski DF","year":"2004","journal-title":"Cell Mol Biol (Noisy-le-grand)"},{"key":"e_1_2_6_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.tpj.6500433"},{"key":"e_1_2_6_26_2","doi-asserted-by":"publisher","DOI":"10.1124\/pr.58.3.5"},{"key":"e_1_2_6_27_2","first-page":"1138","article-title":"Comparison of arginase activity in red blood cells of lower mammals, primates, and man: evolution to high activity in primates","volume":"37","author":"Spector EB","year":"1985","journal-title":"Am J Hum Genet"},{"key":"e_1_2_6_28_2","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1345.058"},{"key":"e_1_2_6_29_2","doi-asserted-by":"publisher","DOI":"10.1097\/00043426-200308000-00008"},{"key":"e_1_2_6_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0891-5849(99)00176-8"},{"key":"e_1_2_6_31_2","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/128.8.1249"},{"key":"e_1_2_6_32_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2005.05625.x"},{"key":"e_1_2_6_33_2","doi-asserted-by":"crossref","DOI":"10.1182\/blood.V110.11.2252.2252","article-title":"Arginine therapy does not benefit children with sickle cell anemia \u2013 Results of the CSCC Clinical Trial Consortium Multi\u2010institutional Study","author":"Styles L","year":"2007","journal-title":"Blood"}],"container-title":["European Journal of Haematology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fj.1600-0609.2009.01210.x","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/j.1600-0609.2009.01210.x","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,28]],"date-time":"2023-09-28T17:05:15Z","timestamp":1695920715000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/j.1600-0609.2009.01210.x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,2,19]]},"references-count":32,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2009,4]]}},"alternative-id":["10.1111\/j.1600-0609.2009.01210.x"],"URL":"https:\/\/doi.org\/10.1111\/j.1600-0609.2009.01210.x","archive":["Portico"],"relation":{},"ISSN":["0902-4441","1600-0609"],"issn-type":[{"value":"0902-4441","type":"print"},{"value":"1600-0609","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,2,19]]}}}