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Mesangial cell hypercellularity and iron accumulation in the kidney associated with administration of a sickle hemoglobin modulator in CD-1 mice.
Vet Pathol
December 2024
Pfizer Inc., Cambridge, MA.
The kidney plays an important role in iron homeostasis and mesangial cells (MCs) are phagocytic cells important for glomerular homeostasis. Sickle hemoglobin (HbS) modulators are promising clinical candidates for treatment of sickle cell disease. Although they prevent disease pathophysiology of HbS polymerization and red blood cell (RBC) sickling by increasing hemoglobin oxygen affinity, higher oxygen affinity can also cause transient tissue hypoxia with compensatory increases in erythropoiesis and subsequent increases in RBC turnover.
View Article and Find Full Text PDFEffects of drugs on the oxygen dissociation curve-a scoping review.
Eur J Clin Pharmacol
February 2025
Department of Anaesthesiology and Intensive Care Medicine, Medical University of Innsbruck, Innsbruck, Austria.
Purpose: The shape and position of the hemoglobin-oxygen dissociation curve (ODC) is of critical importance in medicine, as it determines the uptake of O in the lungs and the delivery of O to the tissues. Numerous reports have identified affinity-modulating effects of drugs in humans. Such effects may be relevant to conditions such as pulmonary diffusion disorders, peripheral vascular disease, or coronary artery disease.
View Article and Find Full Text PDFFT-4202, a selective pyruvate kinase R activator for sickle cell disease.
Exp Hematol
January 2025
Forma Therapeutics, Inc., Watertown, MA.
Anemia in patients with sickle cell disease (SCD) increases 2,3-diphosphoglycerate (2,3-DPG), decreasing hemoglobin-oxygen (HbO) affinity to improve oxygen offloading and promote hemoglobin polymerization (sickling) of red blood cells (RBCs). We report the discovery of FT-4202, an investigational, selective pyruvate kinase type-R (PKR) activator with a multimodal mechanism of action and potential to increase ATP and decrease 2,3-DPG, resulting in increased HbO affinity, decreased Hb polymerization, and improved RBC health. FT-4202 was identified via structure-enabled lead optimization medicinal chemistry using X-ray crystallography, molecular modeling, and thermal shift assays.
View Article and Find Full Text PDFHemoglobin-oxygen affinity changes in neonatal blood transfusions: RBC selection insights.
Pediatr Res
October 2024
Section of Newborn Critical Care, Department of Pediatrics, University of Calgary, Calgary, AB, Canada.
Background: Despite preterm newborns often requiring blood transfusions, we have an incomplete understanding of the impact of adult packed red blood cell (pRBC) transfusions on fetal red blood cell (RBC) oxygen affinity. We investigated the influence of adult pRBC on oxygen binding in fetal RBCs obtained from the umbilical cord of preterm newborns. This included exploring the influence of the biological age of adult pRBCs on the oxygen affinity of fetal blood.
View Article and Find Full Text PDFFetal Hemoglobin Decrease During Voxelotor Treatment.
Eur J Haematol
February 2025
Sickle Cell Referral Center, Department of Internal Medicine, Henri-Mondor University Hospital- UPEC, Créteil, France.
Voxelotor modifies hemoglobin-oxygen affinity improving anemia and reducing hemolysis in sickle cell patients. However, the impact of Voxelotor on fetal hemoglobin (HbF) levels is unknown. We describe here variations of percentage of HbF measured by high performance liquid chromatography and mean corpuscular fetal Hb in a cohort of sickle cell patients treated with Voxelotor at Henri Mondor Sickle Cell Referral Center.
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