HIF-PHD inhibitor desidustat ameliorates iron deficiency anemia.

Autor: Patel VJ; Department of Pharmacology and Toxicology, Zydus Research Centre, Zydus Lifesciences Limited, Sarkhej Bavla NH 8A, Moraiya, Ahmedabad 382210, India., Joharapurkar A; Department of Pharmacology and Toxicology, Zydus Research Centre, Zydus Lifesciences Limited, Sarkhej Bavla NH 8A, Moraiya, Ahmedabad 382210, India. Electronic address: amitjoharapurkar@zyduslife.com., Kshirsagar SG; Department of Pharmacology and Toxicology, Zydus Research Centre, Zydus Lifesciences Limited, Sarkhej Bavla NH 8A, Moraiya, Ahmedabad 382210, India., Patel MS; Department of Pharmacology and Toxicology, Zydus Research Centre, Zydus Lifesciences Limited, Sarkhej Bavla NH 8A, Moraiya, Ahmedabad 382210, India., Savsani HH; Department of Pharmacology and Toxicology, Zydus Research Centre, Zydus Lifesciences Limited, Sarkhej Bavla NH 8A, Moraiya, Ahmedabad 382210, India., Dodiya HS; Department of Pharmacology and Toxicology, Zydus Research Centre, Zydus Lifesciences Limited, Sarkhej Bavla NH 8A, Moraiya, Ahmedabad 382210, India., Rakhasiya MH; Department of Pharmacology and Toxicology, Zydus Research Centre, Zydus Lifesciences Limited, Sarkhej Bavla NH 8A, Moraiya, Ahmedabad 382210, India., Kajavadara C; Department of Pharmacology and Toxicology, Zydus Research Centre, Zydus Lifesciences Limited, Sarkhej Bavla NH 8A, Moraiya, Ahmedabad 382210, India., Valani D; Department of Pharmacology and Toxicology, Zydus Research Centre, Zydus Lifesciences Limited, Sarkhej Bavla NH 8A, Moraiya, Ahmedabad 382210, India., Jain MR; Department of Pharmacology and Toxicology, Zydus Research Centre, Zydus Lifesciences Limited, Sarkhej Bavla NH 8A, Moraiya, Ahmedabad 382210, India.
Jazyk: angličtina
Zdroj: Toxicology and applied pharmacology [Toxicol Appl Pharmacol] 2024 Feb; Vol. 483, pp. 116832. Date of Electronic Publication: 2024 Jan 22.
DOI: 10.1016/j.taap.2024.116832
Abstrakt: Iron deficiency anemia is caused by many pathological conditions like chronic kidney disease (CKD), inflammation, malnutrition and gastrointestinal abnormality. Current treatments that are erythropoiesis stimulating agents (ESAs) and iron supplementation are inadequate and often lead to tolerance and/or toxicity. Desidustat, a prolyl hydroxylase (PHD) inhibitor, is clinically used for the treatment of anemia with CKD. In this study, we investigated the effect of desidustat on iron deficiency anemia (IDA). IDA was induced in C57BL6/J mice by iron deficient diet feeding. These mice were then treated with desidustat (15 mg/kg, PO) and FeSO 4 (20 mg/kg) for five weeks and effect of the treatment on hematology, iron homeostasis, and bone marrow histology was observed. Effect of desidustat on iron metabolism in inflammation (LPS)-induced iron deficiency was also assessed. Both, Desidustat and FeSO 4 , increased MCV (mean corpuscular volume), MCH (mean corpuscular hemoglobin), hemoglobin, and HCT (hematocrit) in blood and increased iron in serum, liver, and spleen. Desidustat increased MCHC (mean corpuscular hemoglobin concentration) while FeSO 4 treatment did not alter it. FeSO 4 treatment significantly increased iron deposition in liver, and spleen, while desidustat increased iron in circulation and demonstrated efficient iron utilization. Desidustat increased iron absorption, serum iron and decreased hepcidin without altering tissue iron, while FeSO 4 increased serum and tissue iron by increasing hepcidin in LPS-induced iron deficiency. Desidustat increased erythroid population, especially iron-dependent polychromatic normoblasts and orthochromatic normoblasts, while FeSO 4 did not improve cell architecture. PHD inhibition by desidustat improved iron utilization in iron deficiency anemia, by efficient erythropoiesis.
Competing Interests: Declaration of competing interest All the authors are employees of Zydus Research Centre, Zydus Lifesciences LTD. No author of this manuscript has any potential competing interest.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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