L-Asparaginase Loaded Red Blood Cells: From Prescription to Injection

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4252-4252 ◽  
Author(s):  
Jerome Bailly ◽  
Veronique Sezanne ◽  
Yann Godfrin
Keyword(s):  
Side Effects ◽  
Red Blood Cells ◽  
Medicinal Product ◽  
Safety Profile ◽  
Blood Cells ◽  
Blood Bank ◽  
Blood Type ◽  
Rbc Membrane ◽  
Preservative Solution ◽  
Qualified Person

Abstract Abstract 4252 L-asparaginase has been a mainstay of acute lymphoblastic leukemia (ALL) treatment since decades and its efficacy has been demonstrated in a broad range of patient's profiles. However its use is hampered by frequent and/or significant toxicities. L-asparaginase loaded in homologous red blood cells (GRASPA®) is a new pharmaceutical formulation of the enzyme. This cell-based medicinal product allows a better safety profile and an improvement of the pharmacokinetics and pharmacodynamics of the enzyme. As demonstrated by several teams performing different technologies of entrapment (Alpar-HO, 1985; Updike-SJ, 1985; Naqi-A 1988; Kravtzoff-R, 1996; Kwon-YM, 2010; Domenech-C, 2010), L-asparaginase remains active entrapped inside the red blood cell (RBC), while asparagine is constently and actively “pumped” through the membrane of the red cells thanks to N+ channel system. Thus, L-asparaginase loaded RBCs act as “cellular bioreactors”. Indeed, plasmatic asparagine diffuses through the RBC membrane to the intra cellular compartment where it is cleaved by the entrapped L-asparaginase. Thanks to the RBC membrane, the enzyme is protected from body reaction thus reducing the side effects. L-asparaginase loaded red blood cells is a cell-based medicinal product for personalized medicine. The physician prescribes the drug, then the hospital orders the product to the company. The patient weight, the ABO blood type and a valid irregular antibody screening (IAS) have to be joined with this order. The qualified person on the manufacturing site, orders immediately to a blood bank a leukocytes reduced packed RBC unit compatible with the patient. The product is manufactured under cGMP using a 3-hours automated process: (1) a washing step removes the preservative solution from the packed RBC, (2) L-asparaginase is mixed to the RBC washed suspension, (3) the mixture is dialyzed against a hypotonic solution and resealed, (4) a final washing step allows to purify the product, finally (5) the preservative solution is added. According to the prescribed dosage (IU/Kg), the volume of GRASPA® is adjusted in the final product PVC bag. Indeed, the product release specifications are constant and reproducible from batch to batch such as the corpuscular concentration of L-asparaginase (117±19, IU/ml), extracellular hemoglobin (0.11±0.03 g/dL), osmotic fragility (<3.5 g/L of NaCl), extracellular L-asparaginase (0.4±0.2 IU/ml ie <1% of the total activity). Based on these specifications, the qualified person releases the product and ships it (kept at 2–8°C) to the prescriber, meaning the delay between order and delivery is less than 2 days. Currently a 72h shelf-life for the final product is considered. The traceability system assures the linkage between the blood bank and patient's hospital. The manufacturing Key Peformance Indicators:GMP batches manufactured since 01/04/09:148Delivery Rate (since Apr. 2009)Clinical Batches delivered on time100 %Conformance rateGMP batches released (since Apr. 2009)94 %Conformance rate6 last months (since feb. 2011)100 % To date, 135 batches of GRAPSA® were administered to 71 patients enrolled in 3 clinical trials. In ALL patients, hypersensitive reaction, coagulation disorders, hepatic disorders are significantly reduced. The dose of 150IU/kg is currently used in a phase II/III pivotal trial in children and adults with ALL relapse. The dose of 100 IU/kg is optimal (efficacy/tolerance) in newly diagnosed patients over 55yo. Indeed this frail subpopulation of patients can difficultly receive current forms of L-asparaginase due to the known side effects. A phase I clinical trial in pancreatic carcinoma confirmed the good safety profile (also at 150IU/kg) of this form of L-asparaginase even in solid tumors, offering new perspectives in patients where asparagine synthetase in tumor cells is down. Disclosures: Bailly: ERYTECH Pharma: Employment. Sezanne:ERYTECH Pharma: Employment. Godfrin:ERYTECH Pharma: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Incidencia de la Flebotomía Terapéutica en Pacientes con Policitemia “Vera” diagnosticados por Hematocrito y Hemoglobina en el Banco de Sangre. “Riobamba” / Therapeutic Phlebotomy Incidence in Patients with Polycythemia "Vera" Diagnosed by Hematocrit and Hemoglobin in the Blood Bank. "Riobamba"

2016 ◽  
Vol 5 (2) ◽  
pp. 65-70
Author(s):  
Byron Geovanny Hidalgo Cajo ◽  
Libia Cristina Tinajero Novillo ◽  
Angel Gualberto Mayacela ◽  
Edwin Gilberto Choca Alcoser ◽  
Ivan Mesias Hidalgo Cajo ◽  
...  
Keyword(s):  
Side Effects ◽  
Red Blood Cells ◽  
Polycythemia Vera ◽  
Blood Viscosity ◽  
Blood Cells ◽  
Myeloproliferative Neoplasm ◽  
Blood Bank ◽  
High Morbidity ◽  
Remarkable Improvement ◽  
Timely Treatment

ABSTRACTPolycythemia is an increase in the total volume of red blood cells in blood, in effect hematocrit levels above 52% (men) or 48% (women) concentration greater than 18.5 g / dl (men) and 16.5 g / dl (women) demonstrate the presence of this myeloproliferative neoplasm which has high morbidity. The research was conducted with 172 patients, 141 men and 31 women. Phlebotomy is a method used to reduce high blood viscosity, and through which is drawn weekly 1 unit (500 cc) of blood until the hematocrit is 45%. To 62% of patients with phlebotomy compensation saline was performed, a remarkable improvement with therapeutic phlebotomy treatment is noticed; and, it was noted that no complications or side effects from successive bleeds, is a timely treatment, and effective.RESUMENLa policitemia es un aumento del volumen total de hematíes en sangre, en efecto cifras de hematocrito superiores al 52% (hombres) o 48% (mujeres), concentración de hemoglobina superior a 18,5 g/dl (hombres) y a 16,5 g/dl  (mujeres), demuestran la presencia de esta neoplasia mieloproliferativa que tiene alta tasa de morbilidad.   La investigación se realizó con 172 pacientes, 141  hombres y 31 mujeres. La flebotomía es un método utilizado para reducir la alta viscosidad sanguínea, y por medio de la cual se extrae semanalmente 1 unidad (500 cm³) de sangre hasta que el hematocrito sea de 45%.  Al 62% de los pacientes junto con la flebotomía se  realizó compensaciones con solución salina, se notó una mejoría notable con el tratamiento de las flebotomías terapéuticas; y, se observó que no existe ninguna complicación o efecto secundario por las sucesivas extracciones de sangre, es un tratamiento oportuno, y eficaz.

scholarly journals Hemoglobin Oxidation in Stored Blood Accelerates Hemolysis and Oxidative Injury to Red Blood Cells

2020 ◽  
Vol 12 (04) ◽  
pp. 244-249
Author(s):  
Ibrahim Mustafa ◽  
Tameem Ali Qaid Hadwan
Keyword(s):  
Red Blood Cells ◽  
Blood Cells ◽  
Morphological Changes ◽  
Hemoglobin Concentration ◽  
Red Cell Membrane ◽  
Rbc Membrane ◽  
Hemoglobin Oxidation ◽  
Rbc Indices ◽  
Methemoglobin Formation ◽  
Stored Blood

Abstract Introduction Maintaining blood supply is a challenge in blood banks. Red blood cells (RBCs) stored at 4°C experience issues of biochemical changes due to metabolism of cells, leading to changes collectively referred to as “storage lesions.” Oxidation of the red cell membrane, leading to lysis, contributes to these storage lesions. Methods Blood bags with CPD-SAGM stored at 4°C for 28 days were withdrawn aseptically on days 1, 14, and 28. Hematology analyzer was used to investigate RBC indices. Hemoglobin oxidation was studied through spectrophotometric scan of spectral change. RBC lysis was studied with the help of Drabkin's assay, and morphological changes were observed by light and scan electron microscopy. Results RBCs show progressive changes in morphology echinocytes and spherocytes on day 28. There was 0.85% RBC lysis, an approximately 20% decrease in percentage oxyhemoglobin, and a 14% increase in methemoglobin formation, which shows hemoglobin oxidation on day 28. Conclusions Oxidative damage to RBC, with an increase in storage time was observed in the present study. The observed morphological changes to RBC during the course of increased time shows that there is progressive damage to RBC membrane and a decrease in hemoglobin concentration; percentage RBC lysis is probably due to free hemoglobin and iron.

scholarly journals Black and white teas as potential agents to combine with amphotericin B and protect red blood cells from amphotericin B-mediated toxicity

2018 ◽  
Vol 78 (4) ◽  
pp. 673-678 ◽  
Author(s):  
V. M. Oliveira ◽  
N. M. Khalil ◽  
E. Carraro
Keyword(s):  
Side Effects ◽  
Red Blood Cells ◽  
Amphotericin B ◽  
Blood Cells ◽  
Fungal Infections ◽  
Black Tea ◽  
Additive Effects ◽  
Antifungal Effect ◽  
Black And White ◽  
Fungicidal Substance

Abstract Amphotericin B is a fungicidal substance that is treatment of choice for most systemic fungal infections affecting immunocompromised patients. However, severe side effects have limited the utility of this drug. The aim of this study was to evaluate the antifungal effect of the combination of amphotericin B with black tea or white tea and protective of citotoxic effect. The present study shows that white and black teas have additive effects with amphotericin B against some species Candida. In addition, the combination of white and black tea with amphotericin B may reduce the toxicity of amphotericin B to red blood cells. Our results suggest that white and black tea is a potential agent to combine with amphotericin for antifungal efficacy and to reduce the amphotericin dose to lessen side effects.

Bleeding after salvarsan

1927 ◽  
Vol 23 (11) ◽  
pp. 1183-1183
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Side Effects ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Adverse Side Effects ◽  
The Central Nervous System ◽  
Capillary Walls

The adverse side effects of salvarsan injections include bleeding from the nose, gums, kidney, lung, etc. The reason for this is the permeability of the capillary walls to red blood cells due to irritation of the central nervous system in persons who are too sensitive to salvarsan. They are caused by the permeability of the capillary walls to red blood cells, caused by irritation of the central nervous system in persons over-sensitive to salvarsan.

scholarly journals Sensing of red blood cells with decreased membrane deformability by the human spleen

2018 ◽  
Vol 2 (20) ◽  
pp. 2581-2587 ◽  
Author(s):  
Innocent Safeukui ◽  
Pierre A. Buffet ◽  
Guillaume Deplaine ◽  
Sylvie Perrot ◽  
Valentine Brousse ◽  
...  
Keyword(s):  
Red Blood Cells ◽  
Blood Cells ◽  
Ex Vivo ◽  
Volume Ratio ◽  
Red Cells ◽  
Human Spleen ◽  
Rbc Membrane ◽  
Membrane Rigidity ◽  
Cellular Deformability ◽  
Distinct Features

Abstract The current paradigm in the pathogenesis of several hemolytic red blood cell disorders is that reduced cellular deformability is a key determinant of splenic sequestration of affected red cells. Three distinct features regulate cellular deformability: membrane deformability, surface area-to-volume ratio (cell sphericity), and cytoplasmic viscosity. By perfusing normal human spleens ex vivo, we had previously showed that red cells with increased sphericity are rapidly sequestered by the spleen. Here, we assessed the retention kinetics of red cells with decreased membrane deformability but without marked shape changes. A controlled decrease in membrane deformability (increased membrane rigidity) was induced by treating normal red cells with increasing concentrations of diamide. Following perfusion, diamide-treated red blood cells (RBCs) were rapidly retained in the spleen with a mean clearance half-time of 5.9 minutes (range, 4.0-13.0). Splenic clearance correlated positively with increased membrane rigidity (r = 0.93; P &lt; .0001). To determine to what extent this increased retention was related to mechanical blockade in the spleen, diamide-treated red cells were filtered through microsphere layers that mimic the mechanical sensing of red cells by the spleen. Diamide-treated red cells were retained in the microsphilters (median, 7.5%; range, 0%-38.6%), although to a lesser extent compared with the spleen (median, 44.1%; range, 7.3%-64.0%; P &lt; .0001). Taken together, these results have implications for understanding the sensitivity of the human spleen to sequester red cells with altered cellular deformability due to various cellular alterations and for explaining clinical heterogeneity of RBC membrane disorders.

scholarly journals Mechanics for the Adhesion and Aggregation of Red Blood Cells on Chitosan

2018 ◽  
Vol 34 (5) ◽  
pp. 725-732 ◽  
Author(s):  
K. Y. Chen ◽  
T. H. Lin ◽  
C. Y. Yang ◽  
Y. W. Kuo ◽  
U. Lei
Keyword(s):  
Red Blood Cells ◽  
Blood Cells ◽  
Biomedical Applications ◽  
Adhesion Force ◽  
Layer Structure ◽  
Optical Tweezer ◽  
Wound Dressings ◽  
Zeta Potentials ◽  
Rbc Membrane ◽  
Layer Structures

AbstractHemostasis, a process which causes bleeding to stop, can be enhanced using chitosan; but the detailed mechanism is unclear. Red blood cells (RBCs) adhere to chitosan because of their opposite charges, but the adhesion force is small, 3.83 pN as measured here using an optical tweezer, such that the direct adhesion cannot be the sole cause for hemostasis. However, it was observed in this study that layer structures of aggregated RBCs were formed next to chitosan objects in both static and flowing environments, but not formed next to cotton and rayon yarns. The layer structure is the clue for the initiation of hemostatsis. Through the supporting measurements of zeta potentials of RBCs and pH's using blood-chitosan mixtures, it is proposed here that the formation of the RBC layer structure next to chitosan objects is due to the reduction of repulsive electric double layer force between RBCs, because of the association of H+ deprotonated from chitosan with COO− on RBC membrane, under the DLVO (Derjaguin-Landau-Verwey-Overbeek) theory. The results are beneficial for designing effective chitosan-based wound dressings, and also for general biomedical applications.

scholarly journals Quantitative analysis of three-dimensional morphology and membrane dynamics of red blood cells during temperature elevation

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Keyvan Jaferzadeh ◽  
MinWoo Sim ◽  
NamGon Kim ◽  
InKyu Moon
Keyword(s):  
Red Blood Cells ◽  
Blood Cells ◽  
Three Dimensional ◽  
Membrane Dynamics ◽  
Mean Corpuscular Hemoglobin ◽  
Rbc Membrane ◽  
Membrane Fluctuations ◽  
Highly Correlated ◽  
3D Profile ◽  
Shape Changes

Abstract The optimal functionality of red blood cells is closely associated with the surrounding environment. This study was undertaken to analyze the changes in membrane profile, mean corpuscular hemoglobin (MCH), and cell membrane fluctuations (CMF) of healthy red blood cells (RBC) at varying temperatures. The temperature was elevated from 17 °C to 41 °C within a duration of less than one hour, and the holograms were recorded by an off-axis configuration. After hologram reconstruction, we extracted single RBCs and evaluated their morphologically related features (projected surface area and sphericity coefficient), MCH, and CMF. We observed that elevating the temperature results in changes in the three-dimensional (3D) profile. Since CMF amplitude is highly correlated to the bending curvature of RBC membrane, temperature-induced shape changes can alter CMF’s map and amplitude; mainly larger fluctuations appear on dimple area at a higher temperature. Regardless of the shape changes, no alterations in MCH were seen with temperature variation.

Outdated Red Blood Cells from the Blood Bank, for Determination of Antistreptolysin O Titers

1961 ◽  
Vol 35 (3_ts) ◽  
pp. 279-283
Author(s):  
Y. E. Crawford ◽  
R.P. Skinner ◽  
W.J. Lind ◽  
A. E. Heimann ◽  
D.E. Hutchings ◽  
...  
Keyword(s):  
Red Blood Cells ◽  
Blood Cells ◽  
Blood Bank

scholarly journals Monitoring the side effects with DSC caused by cyclophosphamide treatment

2019 ◽  
Vol 142 (2) ◽  
pp. 765-770
Author(s):  
Péter Farkas ◽  
Franciska Könczöl ◽  
Dénes Lőrinczy
Keyword(s):  
Side Effects ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Peripheral Nerves ◽  
Chemotherapeutic Agents ◽  
Cyclophosphamide Treatment ◽  
Micro Dsc ◽  
Induced Changes ◽  
First Time ◽  
Dose Dependent

AbstractPolyneuropathy is defined as a simultaneous malfunction of several peripheral nerves, which could be a side effect of a cancer therapy (using cyclophosphamide) as well. In the daily use, it is very important to know the kinetics and metabolism of anticancer drugs because this way we can estimate their undesirable consequences to avoid the unwanted complications. Nowadays, the application of DSC in diagnosis of different diseases using blood compounds is increasing; therefore, the purpose of recent study was to introduce at the first time the DSC in the detection of cyclophosphamide-induced changes in plasma and red blood cells in case of an experimental animal model. Guinea pigs (Cavia porcellus, n = 60, in 12 different groups) underwent to cyclophosphamide treatment administrated intraperitoneally with the dose comparable to the human dosage. At the end of treatments, the animals were euthanized, and the experimental samples (plasma end red blood cells) were analyzed by a SETARAM Micro DSC-II calorimeter. The denaturation temperatures and the calorimetric enthalpies were calculated from the heat flow curves. Our results exhibited a dose-dependent difference between thermal parameters of untreated and treated samples, demonstrating that DSC is applicable in this field too. After deconvolution of DSC scans, the changes could be assigned to the attacked compounds. Recently published papers call the attention for this technique more frequently in the medical diagnosis because this way from small amount of sample very quickly and economically possible to detect and predict the expected and unwanted side effects of chemotherapeutic agents.

Hypoxic Vasodilation by Red Blood Cells and Impairment in Vascular Disorders.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1585-1585
Author(s):  
John R. Pawloski ◽  
Timothy J. McMahon ◽  
Greg Ahearne ◽  
Claude A. Piantadosi ◽  
David J. Singel ◽  
...  
Keyword(s):  
Blood Flow ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Vascular Dysfunction ◽  
Aortic Ring ◽  
Efficient Production ◽  
Anion Exchanger 1 ◽  
Rbc Membrane ◽  
Tissue Po2 ◽  
Hypoxic Vasodilation

Abstract Physiological O2 gradients are principal regulators of blood flow in the microcirculation: position-to-position changes in hemoglobin (Hb) O2 saturation are coupled to regulated vasodilation (“hypoxic vasodilation”). The mechanism by which graded changes in O2 content of blood evoke this response has been a great challenge to understand. A new role for red blood cells (RBCs) in hypoxic dilation of blood vessels and inhibition of platelet activation involving release of nitric oxide (NO) bioactivity is described. We show that NO groups can be transferred within hemoglobin (Hb) from hemes to highly-conserved cysteine thiols (β-Cys93) to form bioactive S-nitrosohemoglobin (SNO-Hb), and that efficient production of SNO-Hb requires selective processing of NO within the β-subunits. Bioactive SNO-Hb is localized primarily to the RBC membrane through interaction with Band 3, the transmembrane anion-exchanger 1 protein (AE1). Upon deoxygenation, transfer of the NO group from β-Cys93 of Hb to a cysteine thiol within AE1 serves the RBC vasodilator activity. In this way, O2 binding in Hb modulates the release of NO bioactivity. We further show that RBC NO bioactivity is inversely proportional to pO2 and impaired in disease. In an aortic ring bioassay sparged with variable concentrations of O2, addition of normal human RBCs elicited graded responses from relaxation at tissue pO2 (~3–7 mm Hg, hypoxic vasodilation), to loss of relaxation and progressively greater contractions at pO2’s of 10–63 mm Hg (hyperoxic vasoconstriction). Notably, RBC SNO-Hb levels and hypoxic vasodilation are impaired in several diseases characterized by vascular dysfunction. For example, in RBCs from patients with pulmonary arterial hypertension (PAH), we found decreased (13% of control) SNO-Hb content (assessed by photolysis-chemiluminescence) and impaired O2-dependent vasodilation (bioassay). RBCs from patients with other ischemic disorders have also been examined: RBCs demonstrate a pathogenesis-based impairment in their ability to mediate hypoxic vasodilation by NO. These results confirm the (patho)physiologic importance of RBC NO, and suggest that RBC dysfunction may contribute to impaired blood flow in diseases of the heart, lung and blood.

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