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A pilot clinical phase II trial MemSID: Acute and durable changes of red blood cells of sickle cell disease patients on memantine treatment


Mahkro, Asya; Hegemann, Inga; Seiler, Elena; Simionato, Greta; Claveria, Viviana; Bogdanov, Nikolay; Sasselli, Clelia; Torgeson, Paul; Kaestner, Lars; Manz, Markus G; Goede, Jeroen S; Gassmann, Max; Bogdanova, Anna (2020). A pilot clinical phase II trial MemSID: Acute and durable changes of red blood cells of sickle cell disease patients on memantine treatment. eJHaem, 1(1):23-34.

Abstract

An increase in abundance and activity of N-methyl D-aspartate receptors (NMDAR) was previously reported for red blood cells (RBCs) of sickle cell disease (SCD) patients. Increased Ca2+uptake through the receptor supported dehydration and RBC damage. In a pilot phase IIa-b clinical trial MemSID, memantine, a blocker of NMDAR, was used for treatment of four patients for 12 months. Two more patients that have enrolled into the study did not finish it. One of them had psychotic event following the invol-untary overdose of the drug, whereas the other had vertigo and could not comply to the trial visits schedule. Acute and durable responses of RBCs of SCD patients to daily oral administration of memantine were monitored. Markers of RBC turnover, changes in cell density, and alterations in ion handling and RBC morphology were assessed. Acute transient shifts in intracellular Ca2+, volume and density, and reduction in plasma lactate dehydrogenate activity were observed already within the first month of treatment. Durable effects of memantine included (a) decrease in reticulocyte counts, (b) reduction in reticulocyte hemoglobinization, (c) advanced membrane maturation and its stabilization as follows from reduction in the number of NMDAR per cell and reduction in hemolysis, and (iv) rehydration and decrease in K+leakage from patients’ RBC. Memantine therapy resulted in reduction in number of cells with sickle morphology that was sustained at least over 2 months after therapy was stopped indicating an improvementin RBC longevity.

Abstract

An increase in abundance and activity of N-methyl D-aspartate receptors (NMDAR) was previously reported for red blood cells (RBCs) of sickle cell disease (SCD) patients. Increased Ca2+uptake through the receptor supported dehydration and RBC damage. In a pilot phase IIa-b clinical trial MemSID, memantine, a blocker of NMDAR, was used for treatment of four patients for 12 months. Two more patients that have enrolled into the study did not finish it. One of them had psychotic event following the invol-untary overdose of the drug, whereas the other had vertigo and could not comply to the trial visits schedule. Acute and durable responses of RBCs of SCD patients to daily oral administration of memantine were monitored. Markers of RBC turnover, changes in cell density, and alterations in ion handling and RBC morphology were assessed. Acute transient shifts in intracellular Ca2+, volume and density, and reduction in plasma lactate dehydrogenate activity were observed already within the first month of treatment. Durable effects of memantine included (a) decrease in reticulocyte counts, (b) reduction in reticulocyte hemoglobinization, (c) advanced membrane maturation and its stabilization as follows from reduction in the number of NMDAR per cell and reduction in hemolysis, and (iv) rehydration and decrease in K+leakage from patients’ RBC. Memantine therapy resulted in reduction in number of cells with sickle morphology that was sustained at least over 2 months after therapy was stopped indicating an improvementin RBC longevity.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Oncology and Hematology
04 Faculty of Medicine > Center for Integrative Human Physiology
05 Vetsuisse Faculty > Institute of Veterinary Physiology
05 Vetsuisse Faculty > Chair in Veterinary Epidemiology
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:1 July 2020
Deposited On:16 Jul 2020 06:38
Last Modified:29 Aug 2020 01:06
Publisher:Wiley Open Access
ISSN:2688-6146
OA Status:Hybrid
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1002/jha2.11
Project Information:
  • : FunderFP7
  • : Grant ID602121
  • : Project TitleCOMMITMENT - Combined Molecular Microscopy for Therapy and Personalized Medication in Rare Anaemias Treatments

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