scholarly journals Evaluation of extracorporeal alkylation of red cells as a potential treatment for sickle cell anemia

Blood ◽  
1976 ◽  
Vol 47 (3) ◽  
pp. 481-488 ◽  
Author(s):  
S Charache ◽  
R Dreyer ◽  
I Zimmerman ◽  
CK Hsu
Keyword(s):  
Cell Survival ◽  
Alkylating Agent ◽  
Nitrogen Mustard ◽  
Alkylating Agents ◽  
Red Cells ◽  
Red Cell ◽  
Cell Life ◽  
Red Cell Survival ◽  
Toxic Reactions ◽  
Unacceptable Toxicity

Abstract Nitrogen mustard and nor-nitrogen mustard inhibit sickling, but the concentrations required would be associated with unacceptable toxicity if these agents were administered to patients. Red cells could be treated extracorporeally and infused back into donors, if the alkylating agent could be removed or inactivated, if the treatment per se did not significantly shorten red cell survival, and if viable alkylated lymphocytes could be eliminated from the treated blood. To estimate whether these conditions could be met in a clinical trial, red cells from four dogs were alkylated at 6-wk intervals. No toxic reactions were observed, although not all nor-nitrogen mustard was removed by the washing procedure. Red cell survival was shortened to about half that of control cells, using concentrations of alkylating agent which reduce sickling by 50%. Lymphocytes from treated blood could still exclude trypan blue, but could not be shown to circulate after reinfusion into donor dogs. If alkylating agents are used to treat patients' cells, inhibition of sickling may outweigh the shortening of red cell life span induced by the treatment; blood should probably be irradiated before infusion to avoid administration of alkylated and potentially mutated, but viable, lymphocytes.

scholarly journals Evaluation of extracorporeal alkylation of red cells as a potential treatment for sickle cell anemia

Blood ◽  
1976 ◽  
Vol 47 (3) ◽  
pp. 481-488
Author(s):  
S Charache ◽  
R Dreyer ◽  
I Zimmerman ◽  
CK Hsu
Keyword(s):  
Cell Survival ◽  
Alkylating Agent ◽  
Nitrogen Mustard ◽  
Alkylating Agents ◽  
Red Cells ◽  
Red Cell ◽  
Cell Life ◽  
Red Cell Survival ◽  
Toxic Reactions ◽  
Unacceptable Toxicity

Nitrogen mustard and nor-nitrogen mustard inhibit sickling, but the concentrations required would be associated with unacceptable toxicity if these agents were administered to patients. Red cells could be treated extracorporeally and infused back into donors, if the alkylating agent could be removed or inactivated, if the treatment per se did not significantly shorten red cell survival, and if viable alkylated lymphocytes could be eliminated from the treated blood. To estimate whether these conditions could be met in a clinical trial, red cells from four dogs were alkylated at 6-wk intervals. No toxic reactions were observed, although not all nor-nitrogen mustard was removed by the washing procedure. Red cell survival was shortened to about half that of control cells, using concentrations of alkylating agent which reduce sickling by 50%. Lymphocytes from treated blood could still exclude trypan blue, but could not be shown to circulate after reinfusion into donor dogs. If alkylating agents are used to treat patients' cells, inhibition of sickling may outweigh the shortening of red cell life span induced by the treatment; blood should probably be irradiated before infusion to avoid administration of alkylated and potentially mutated, but viable, lymphocytes.

THE EFFECT OF SULPHAEMOGLOBIN ON RED CELL VIABILITY

1957 ◽  
Vol 35 (1) ◽  
pp. 1171-1181
Author(s):  
L. G. Israels ◽  
A. Chutorian ◽  
G. E. Delory ◽  
Esther Israels
Keyword(s):  
Cell Viability ◽  
Life Span ◽  
Cell Survival ◽  
Red Cells ◽  
Red Cell ◽  
Disappearance Rate ◽  
Cell Life ◽  
Red Cell Survival ◽  
Calcium Sulphide ◽  
True Measure

Sulphaemoglobinaemia was produced in rabbits by the injection of para-aminopropriophenone and calcium sulphide. The disappearance of this pigment from the blood was used as an index of red cell survival. Sulphaemoglobin disappeared in an exponential fashion, indicating a mean red cell life span of 36 days. The red cells were also tagged with Cr51, and this method of measuring erythrocyte life span yielded values strongly suggesting that sulphaemoglobin in the red cell impairs its viability and leads to random cell destruction. Under these conditions it would seem that the disappearance rate of sulphaemoglobin is not a true measure of red cell survival.

Quantitative measurement of erythropoiesis in the dog

1960 ◽  
Vol 198 (1) ◽  
pp. 183-186 ◽  
Author(s):  
S. M. Weissman ◽  
T. A. Waldmann ◽  
N. I. Berlin
Keyword(s):  
Life Span ◽  
Cell Survival ◽  
Cell Volume ◽  
Quantitative Measurement ◽  
Red Cells ◽  
Red Cell ◽  
Red Cell Volume ◽  
Cell Life ◽  
Red Cell Survival

The quantitative measurement of erythropoiesis requires the simultaneous determination of total red cell volume, rate of production of red cells and the red cell life span. The total red cell volume was measured with autologous Cr51-labeled red cells, the rate of production of red cells from the rate of disappearance of radioiron from the plasma and uptake by red cells, the red cell life span with C14-labeled glycine and the apparent red cell survival T1/2 with Cr51. The average total red cell volume of the dogs studied was 38.6 cc/kg; the plasma radioiron T1/2 was 66 minutes; the red cell radio-iron uptake was 80%; the serum iron was 102 µg/100 cc, and the plasma volume calculated from the peripheral hematocrit and total red cell volume was 46 cc/kg, and from the extrapolation to t0 of the radioiron disappearance was 48 cc/kg. From these figures the plasma iron turnover was calculated to be 0.63 mg/kg/day and the red cell iron renewal rate 1.26%/day. The average red cell life span was 108 days; the average apparent T1/2 of Cr51 red cell survival was 24.3 days; the average elution rate of Cr51 was 1.77%/day.

scholarly journals Metabolic effects of antisickling amounts of nitrogen and nor-nitrogen mustard on rabbit and human erythrocytes

Blood ◽  
1975 ◽  
Vol 45 (6) ◽  
pp. 779-788 ◽  
Author(s):  
EF Jr Roth ◽  
RL Nagel ◽  
G Neuman ◽  
G Vanderhoff ◽  
BH Kaplan ◽  
...  
Keyword(s):  
Cell Survival ◽  
Glutathione Reductase ◽  
Nitrogen Mustard ◽  
Sulfhydryl Group ◽  
Red Cells ◽  
Metabolic Effects ◽  
Red Cell ◽  
Metabolic Studies ◽  
Heinz Body ◽  
Red Cell Survival

Abstract Nitrogen mustard (NH2) and Nor-nitrogen mustard (Nor-HN2) both inhibit the polymerization of deoxyhemoglobin S in solution and in intact erythrocytes. Metabolic studies were undertaken to determine the feasability of an extracorporeal treatment with these or related agents. Glucose utilization, hexose monophosphate shunt activity, methemoglobin reduction, and incubation with acetylphenylhydrazine for Heinz body formation were performed, as well as specific assays for hexokinase, pyruvate kinase, glucose-6-phosphate dehydrogenase, glutathione reductase, ATP, reduced glutathione (GSH), and survival of autologous mustard-treated cells in rabbits. HN2 was found to enter red cells rapidly and bind to intracellular contents. Metabolic studies revealed no significant inhibition or alteration of function by Nor-HN2 at 10 mg/ml of whole blood. Rabbit red cell survival was also normal. HN2, however, inhibited glutathione reductase and blocked the free sulfhydryl group of GSH by forming serveral addition products of alkylated GSH. Heinz body test with acetylphenylhydrazine became positive in HN2-treated cells, and rabbit red cell survival was shortened considerably in the concentration range used to inhibit sickling. Ascorbic acid stimulation of the hexose shunt pathway was inhibited by HN2, but methylene blue stimulation remained unaffected. 14-C-HN2 remains bound to red cells in vivo, and the disappearance of radioactivity is similar to that found with 14-C-DFP (disopropylfluorophosphate). Oxygen affinity of both HN2 and Nor-HN2 treated human red cells remains virtually the same as that found in control samples. It is concluded that Nor-HN2 may be a suitable agent for an extracorporeal therapy, and that each mustard needs to be evaluated individually for its antisickling effects and its suitability for extracorporeal use.

scholarly journals Red cell life span in sickle cell-hemoglobin C disease with a note about sickle cell-hemoglobin O ARAB

Blood ◽  
1975 ◽  
Vol 45 (2) ◽  
pp. 273-279 ◽  
Author(s):  
PR McCurdy ◽  
L Mahmood ◽  
AS Sherman
Keyword(s):  
Cell Survival ◽  
Sickle Cell ◽  
Red Cells ◽  
Red Cell ◽  
Relative Ease ◽  
Hemoglobin C ◽  
Cell Life ◽  
Red Cell Survival ◽  
Beta 2 ◽  
The One

Red cell survival was measured in ten subjects with S-C disease and one with S-O Arab (alpha 2 beta 2–121 glu yields lys) disease using both DF32p and 51Cr as tags. Red cell volume was slightly reduced in most patients (87% plus or minus 20% of predicted normal). In nine SC patients, mean red cell life (DF32p) was 28.9 plus or minus 4.0 days. For one SC subject it was significantly longer (47.9 days), as it was for the one with S-O Arab. The S-O Arab subject had irreversibly sickled cells in the peripheral blood, shereas those with SC had few (less than 1/1000 red cells) or none. The S-O Arab hemolysate gelled at a hemmoglobin concentration (16.2 g/100ml) near that for sickle cell anemia hemolysates (15.9 plus or minus 1.0 g/100 ml; n equals 8) but significantly lower than that for SC hemolysates (21.6 plus or minus 1.9 g/100 ml; n equals 5). It seems likely that properties of S-C red cells other than their relative ease of sickling contribute significantly to their rate of hemolysis.

Effect of temperature on erythropoiesis and red cell survival in the frog

1962 ◽  
Vol 203 (3) ◽  
pp. 401-403 ◽  
Author(s):  
M. J. Cline ◽  
T. A. Waldmann
Keyword(s):  
Life Span ◽  
Cell Survival ◽  
Cell Volume ◽  
Environmental Temperature ◽  
Red Cells ◽  
Effect Of Temperature ◽  
Red Cell ◽  
Cell Life ◽  
Red Cell Survival ◽  
Environmental Temperatures

The effect of environmental temperature on erythropoiesis and erythrocyte life span was studied in frogs maintained at 4 C or 24–26 C. The red cell incorporation of radioiron was used as an index of the rate of erythropoiesis and diisopropylfluorophosphate-P32 was used to measure red cell survival. The red cell life span in frogs kept at 24–26 C was approximately 200 days. The incorporation of Fe59 into circulating red cells during the first 10 days after isotope administration was significantly greater in frogs at 24–26 C than in frogs at 4 C. The peripheral hematocrit decreased in groups of frogs kept at 4 C during the period of observation. The inconstancy of the hematocrit and presumably of the total red cell volume did not permit any definite conclusions regarding the apparently longer erythrocyte life span at low environmental temperatures.

scholarly journals Metabolic effects of antisickling amounts of nitrogen and nor-nitrogen mustard on rabbit and human erythrocytes

Blood ◽  
1975 ◽  
Vol 45 (6) ◽  
pp. 779-788
Author(s):  
EF Jr Roth ◽  
RL Nagel ◽  
G Neuman ◽  
G Vanderhoff ◽  
BH Kaplan ◽  
...  
Keyword(s):  
Cell Survival ◽  
Glutathione Reductase ◽  
Nitrogen Mustard ◽  
Sulfhydryl Group ◽  
Red Cells ◽  
Metabolic Effects ◽  
Red Cell ◽  
Metabolic Studies ◽  
Heinz Body ◽  
Red Cell Survival

Nitrogen mustard (NH2) and Nor-nitrogen mustard (Nor-HN2) both inhibit the polymerization of deoxyhemoglobin S in solution and in intact erythrocytes. Metabolic studies were undertaken to determine the feasability of an extracorporeal treatment with these or related agents. Glucose utilization, hexose monophosphate shunt activity, methemoglobin reduction, and incubation with acetylphenylhydrazine for Heinz body formation were performed, as well as specific assays for hexokinase, pyruvate kinase, glucose-6-phosphate dehydrogenase, glutathione reductase, ATP, reduced glutathione (GSH), and survival of autologous mustard-treated cells in rabbits. HN2 was found to enter red cells rapidly and bind to intracellular contents. Metabolic studies revealed no significant inhibition or alteration of function by Nor-HN2 at 10 mg/ml of whole blood. Rabbit red cell survival was also normal. HN2, however, inhibited glutathione reductase and blocked the free sulfhydryl group of GSH by forming serveral addition products of alkylated GSH. Heinz body test with acetylphenylhydrazine became positive in HN2-treated cells, and rabbit red cell survival was shortened considerably in the concentration range used to inhibit sickling. Ascorbic acid stimulation of the hexose shunt pathway was inhibited by HN2, but methylene blue stimulation remained unaffected. 14-C-HN2 remains bound to red cells in vivo, and the disappearance of radioactivity is similar to that found with 14-C-DFP (disopropylfluorophosphate). Oxygen affinity of both HN2 and Nor-HN2 treated human red cells remains virtually the same as that found in control samples. It is concluded that Nor-HN2 may be a suitable agent for an extracorporeal therapy, and that each mustard needs to be evaluated individually for its antisickling effects and its suitability for extracorporeal use.

THE EFFECT OF SULPHAEMOGLOBIN ON RED CELL VIABILITY

1957 ◽  
Vol 35 (12) ◽  
pp. 1171-1181 ◽  
Author(s):  
L. G. Israels ◽  
A. Chutorian ◽  
G. E. Delory ◽  
Esther Israels
Keyword(s):  
Cell Viability ◽  
Life Span ◽  
Cell Survival ◽  
Red Cells ◽  
Red Cell ◽  
Disappearance Rate ◽  
Cell Life ◽  
Red Cell Survival ◽  
Calcium Sulphide ◽  
True Measure

Sulphaemoglobinaemia was produced in rabbits by the injection of para-aminopropriophenone and calcium sulphide. The disappearance of this pigment from the blood was used as an index of red cell survival. Sulphaemoglobin disappeared in an exponential fashion, indicating a mean red cell life span of 36 days. The red cells were also tagged with Cr51, and this method of measuring erythrocyte life span yielded values strongly suggesting that sulphaemoglobin in the red cell impairs its viability and leads to random cell destruction. Under these conditions it would seem that the disappearance rate of sulphaemoglobin is not a true measure of red cell survival.

scholarly journals Red cell life span in sickle cell-hemoglobin C disease with a note about sickle cell-hemoglobin O ARAB

Blood ◽  
1975 ◽  
Vol 45 (2) ◽  
pp. 273-279 ◽  
Author(s):  
PR McCurdy ◽  
L Mahmood ◽  
AS Sherman
Keyword(s):  
Cell Survival ◽  
Sickle Cell ◽  
Red Cells ◽  
Red Cell ◽  
Relative Ease ◽  
Hemoglobin C ◽  
Cell Life ◽  
Red Cell Survival ◽  
Beta 2 ◽  
The One

Abstract Red cell survival was measured in ten subjects with S-C disease and one with S-O Arab (alpha 2 beta 2–121 glu yields lys) disease using both DF32p and 51Cr as tags. Red cell volume was slightly reduced in most patients (87% plus or minus 20% of predicted normal). In nine SC patients, mean red cell life (DF32p) was 28.9 plus or minus 4.0 days. For one SC subject it was significantly longer (47.9 days), as it was for the one with S-O Arab. The S-O Arab subject had irreversibly sickled cells in the peripheral blood, shereas those with SC had few (less than 1/1000 red cells) or none. The S-O Arab hemolysate gelled at a hemmoglobin concentration (16.2 g/100ml) near that for sickle cell anemia hemolysates (15.9 plus or minus 1.0 g/100 ml; n equals 8) but significantly lower than that for SC hemolysates (21.6 plus or minus 1.9 g/100 ml; n equals 5). It seems likely that properties of S-C red cells other than their relative ease of sickling contribute significantly to their rate of hemolysis.

scholarly journals Excess Hemolysis in Subjects with Severe Iron Deficiency Anemia Associated and Nonassociated with Hookworm Infection

Blood ◽  
1965 ◽  
Vol 25 (1) ◽  
pp. 73-91 ◽  
Author(s):  
MIGUEL LAYRISSE ◽  
JESÚS LINARES ◽  
MARCEL ROCHE ◽  
Adelina Ojeda ◽  
Alvaro Carstens ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Cell Survival ◽  
Iron Deficiency Anemia ◽  
Red Cells ◽  
Deficiency Anemia ◽  
Intrinsic Defect ◽  
Red Cell ◽  
Hookworm Infection ◽  
Iron Treatment ◽  
Red Cell Survival

Abstract An excess hemolysis was found in subjects with iron deficiency anemia associated with hookworm infection. Red cell survival, measured with Cr51 and DFP32 in the subjects before deworming, showed a marked disproportion between the decrease of the survival and the amount of daily intestinal blood loss in most cases. Excess of hemolysis was still present after more than 90 per cent of the parasites were removed. Red cell survival became normal after correction of anemia through iron treatment. Excess of hemolysis was also present in noninfected subjects with iron deficiency anemia due to other causes. The reduction in the survival of the erythrocytes from infected subjects transfused into normal recipients shows that the hemolytic process is due to an intrinsic defect of the red cells. The low values of hemoglobinemia and the presence of haptoglobins in the plasma indicate that hemoglobin has not been liberated in excess intravascularly. Finally, the fact that the red cells from an infected patient taken after deworming survived normally in splenectomized recipients indicates that the spleen is probably the principal site of the red cell destruction. The clinical and autopsy findings suggest that splenic function is not pathologically increased, but rather that this organ is acting physiologically at a more rapid rate, "culling" the abnormal circulating red cells and thus leading to a decrease in red cell survival. The studies presented here also indicate that the hookworm infection per se does not induce hemolysis.

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