Prolyl hydroxylase inhibitor desidustat improves anemia in erythropoietin hyporesponsive state
Many anemic chronic kidney disease (CKD) patients are refractory to erythropoietin (EPO) effects due to inflammation, deranged iron utilization, and generation of EPO antibodies. This work assessed the effect of desidustat, an inhibitor of hypoxia inducible factor (HIF) prolyl hydroxylase (PHD), on...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-01-01
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| Series: | Current Research in Pharmacology and Drug Discovery |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2590257122000220 |
| _version_ | 1828269799746043904 |
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| author | Amit A. Joharapurkar Vishal J. Patel Samadhan G. Kshirsagar Maulik S. Patel Hardikkumar H. Savsani Chetan Kajavadara Darshan Valani Mukul R. Jain |
| author_facet | Amit A. Joharapurkar Vishal J. Patel Samadhan G. Kshirsagar Maulik S. Patel Hardikkumar H. Savsani Chetan Kajavadara Darshan Valani Mukul R. Jain |
| author_sort | Amit A. Joharapurkar |
| collection | DOAJ |
| description | Many anemic chronic kidney disease (CKD) patients are refractory to erythropoietin (EPO) effects due to inflammation, deranged iron utilization, and generation of EPO antibodies. This work assessed the effect of desidustat, an inhibitor of hypoxia inducible factor (HIF) prolyl hydroxylase (PHD), on EPO-refractory renal anemia. Sprague Dawley rats were made anemic by cisplatin (5 mg/kg, IP, single dose) and turpentine oil (5 mL/kg, SC, once a week). These rats were given recombinant human EPO (rhEPO, 1 μg/kg) and desidustat (15 or 30 mg/kg) for eight weeks. Separately, rhEPO (1–5 μg/kg) was given to anemic rats to sustain the normal hemoglobin levels and desidustat (15 mg/kg) for eight weeks. In another experiment, the anemic rats were treated rhEPO (5 μg/kg) for two weeks and then desidustat (15 mg/kg) for the next two weeks. Dosing of rhEPO was thrice a week, and for desidustat, it was on alternate days. Desidustat inhibited EPO-resistance caused by rhEPO treatment, decreased hepcidin, IL-6, IL-1β, and increased iron and liver ferroportin. Desidustat reduced EPO requirement and anti-EPO antibodies. Desidustat also maintained normal hemoglobin levels after cessation of rhEPO treatment. Thus, novel prolyl hydroxylase inhibitor desidustat can treat EPO resistance via improved iron utilization and decreased inflammation. |
| first_indexed | 2024-04-13T05:33:53Z |
| format | Article |
| id | doaj.art-5bcbcc2bbe114ad1b82577f127c341d0 |
| institution | Directory Open Access Journal |
| issn | 2590-2571 |
| language | English |
| last_indexed | 2024-04-13T05:33:53Z |
| publishDate | 2022-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Current Research in Pharmacology and Drug Discovery |
| spelling | doaj.art-5bcbcc2bbe114ad1b82577f127c341d02022-12-22T03:00:20ZengElsevierCurrent Research in Pharmacology and Drug Discovery2590-25712022-01-013100102Prolyl hydroxylase inhibitor desidustat improves anemia in erythropoietin hyporesponsive stateAmit A. Joharapurkar0Vishal J. Patel1Samadhan G. Kshirsagar2Maulik S. Patel3Hardikkumar H. Savsani4Chetan Kajavadara5Darshan Valani6Mukul R. Jain7Corresponding author. Department of Pharmacology and Toxicology, Zydus Research Centre, Cadila Healthcare Limited, Sarkhej Bavla NH 8A, Moraiya, Ahmedabad, 382210, India.; Department of Pharmacology and Toxicology, Zydus Research Centre, Cadila Healthcare Limited, Sarkhej Bavla NH 8A, Moraiya, Ahmedabad, Gujarat, IndiaDepartment of Pharmacology and Toxicology, Zydus Research Centre, Cadila Healthcare Limited, Sarkhej Bavla NH 8A, Moraiya, Ahmedabad, Gujarat, IndiaDepartment of Pharmacology and Toxicology, Zydus Research Centre, Cadila Healthcare Limited, Sarkhej Bavla NH 8A, Moraiya, Ahmedabad, Gujarat, IndiaDepartment of Pharmacology and Toxicology, Zydus Research Centre, Cadila Healthcare Limited, Sarkhej Bavla NH 8A, Moraiya, Ahmedabad, Gujarat, IndiaDepartment of Pharmacology and Toxicology, Zydus Research Centre, Cadila Healthcare Limited, Sarkhej Bavla NH 8A, Moraiya, Ahmedabad, Gujarat, IndiaDepartment of Pharmacology and Toxicology, Zydus Research Centre, Cadila Healthcare Limited, Sarkhej Bavla NH 8A, Moraiya, Ahmedabad, Gujarat, IndiaDepartment of Pharmacology and Toxicology, Zydus Research Centre, Cadila Healthcare Limited, Sarkhej Bavla NH 8A, Moraiya, Ahmedabad, Gujarat, IndiaDepartment of Pharmacology and Toxicology, Zydus Research Centre, Cadila Healthcare Limited, Sarkhej Bavla NH 8A, Moraiya, Ahmedabad, Gujarat, IndiaMany anemic chronic kidney disease (CKD) patients are refractory to erythropoietin (EPO) effects due to inflammation, deranged iron utilization, and generation of EPO antibodies. This work assessed the effect of desidustat, an inhibitor of hypoxia inducible factor (HIF) prolyl hydroxylase (PHD), on EPO-refractory renal anemia. Sprague Dawley rats were made anemic by cisplatin (5 mg/kg, IP, single dose) and turpentine oil (5 mL/kg, SC, once a week). These rats were given recombinant human EPO (rhEPO, 1 μg/kg) and desidustat (15 or 30 mg/kg) for eight weeks. Separately, rhEPO (1–5 μg/kg) was given to anemic rats to sustain the normal hemoglobin levels and desidustat (15 mg/kg) for eight weeks. In another experiment, the anemic rats were treated rhEPO (5 μg/kg) for two weeks and then desidustat (15 mg/kg) for the next two weeks. Dosing of rhEPO was thrice a week, and for desidustat, it was on alternate days. Desidustat inhibited EPO-resistance caused by rhEPO treatment, decreased hepcidin, IL-6, IL-1β, and increased iron and liver ferroportin. Desidustat reduced EPO requirement and anti-EPO antibodies. Desidustat also maintained normal hemoglobin levels after cessation of rhEPO treatment. Thus, novel prolyl hydroxylase inhibitor desidustat can treat EPO resistance via improved iron utilization and decreased inflammation.http://www.sciencedirect.com/science/article/pii/S2590257122000220EPO resistanceDesidustatInflammationAntibody |
| spellingShingle | Amit A. Joharapurkar Vishal J. Patel Samadhan G. Kshirsagar Maulik S. Patel Hardikkumar H. Savsani Chetan Kajavadara Darshan Valani Mukul R. Jain Prolyl hydroxylase inhibitor desidustat improves anemia in erythropoietin hyporesponsive state Current Research in Pharmacology and Drug Discovery EPO resistance Desidustat Inflammation Antibody |
| title | Prolyl hydroxylase inhibitor desidustat improves anemia in erythropoietin hyporesponsive state |
| title_full | Prolyl hydroxylase inhibitor desidustat improves anemia in erythropoietin hyporesponsive state |
| title_fullStr | Prolyl hydroxylase inhibitor desidustat improves anemia in erythropoietin hyporesponsive state |
| title_full_unstemmed | Prolyl hydroxylase inhibitor desidustat improves anemia in erythropoietin hyporesponsive state |
| title_short | Prolyl hydroxylase inhibitor desidustat improves anemia in erythropoietin hyporesponsive state |
| title_sort | prolyl hydroxylase inhibitor desidustat improves anemia in erythropoietin hyporesponsive state |
| topic | EPO resistance Desidustat Inflammation Antibody |
| url | http://www.sciencedirect.com/science/article/pii/S2590257122000220 |
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