Comparative evaluation of fifteen anti-sickling agents

Blood ◽  
1983 ◽  
Vol 61 (4) ◽  
pp. 693-704 ◽  
Author(s):  
H Chang ◽  
SM Ewert ◽  
RM Bookchin ◽  
RL Nagel
Keyword(s):  
Nitrogen Mustard ◽  
Potent Inhibitor ◽  
Oxygen Affinity ◽  
Red Cell ◽  
Red Cell Indices ◽  
Oxygen Affinity Of Hemoglobin ◽  
High Concentrations ◽  
Further Development

Abstract Fifteen compounds reported to be inhibitors of gelation or sickling were studied by standard methods. These tests included (1) the determination of the solubility of deoxyhemoglobin S or Csat, (2) evaluation of sickling in whole SS blood at various pO2s, (3) measurement of the oxygen affinity of hemoglobin and blood, and (4) examination of red cell indices and morphology. Among the 4 noncovalent agents tested, butylurea was the most potent inhibitor of gelation and sickling in vitro; however, relatively high concentrations were required compared to the covalent agents. In the latter group, bis-(3,5 dibromosalicyl)-fumarate, nitrogen mustard, and dimethyladipimidate were especially effective inhibitors of gelation and/or sickling. All of these compounds require further development before they can be considered for clinical use.

scholarly journals Comparative evaluation of fifteen anti-sickling agents

Blood ◽  
1983 ◽  
Vol 61 (4) ◽  
pp. 693-704
Author(s):  
H Chang ◽  
SM Ewert ◽  
RM Bookchin ◽  
RL Nagel
Keyword(s):  
Nitrogen Mustard ◽  
Potent Inhibitor ◽  
Oxygen Affinity ◽  
Red Cell ◽  
Red Cell Indices ◽  
Oxygen Affinity Of Hemoglobin ◽  
High Concentrations ◽  
Further Development

Fifteen compounds reported to be inhibitors of gelation or sickling were studied by standard methods. These tests included (1) the determination of the solubility of deoxyhemoglobin S or Csat, (2) evaluation of sickling in whole SS blood at various pO2s, (3) measurement of the oxygen affinity of hemoglobin and blood, and (4) examination of red cell indices and morphology. Among the 4 noncovalent agents tested, butylurea was the most potent inhibitor of gelation and sickling in vitro; however, relatively high concentrations were required compared to the covalent agents. In the latter group, bis-(3,5 dibromosalicyl)-fumarate, nitrogen mustard, and dimethyladipimidate were especially effective inhibitors of gelation and/or sickling. All of these compounds require further development before they can be considered for clinical use.

scholarly journals Red cell 2,3-diphosphoglycerate and oxygen affinity of hemoglobin in patients with thyroid disorders

Blood ◽  
1978 ◽  
Vol 52 (1) ◽  
pp. 181-185
Author(s):  
CG Zaroulis ◽  
IA Kourides ◽  
CR Valeri
Keyword(s):  
Blood Cell ◽  
Oxygen Transport ◽  
Red Blood Cell ◽  
Clinical Status ◽  
Oxygen Affinity ◽  
Red Cell ◽  
Transport Function ◽  
Oxygen Affinity Of Hemoglobin ◽  
2,3 Dpg

We measured red blood cell 2,3-diphosphoglycerate (2,3-DPG), adenosine triphosphate (ATP), and the P50 value in vitro of the oxyhemoglobin dissociation curve, which is the oxygen tension at half saturation of hemoglobin, in order to quantitate red blood cell oxygen transport function in individuals who were diagnosed as hypothyroid, euthyroid, or hyperthyroid based on measurements of thyroxine (T4), triiodothyronine (T3), thyrotropin (TSH), and their clinical status. Hypothyroid (mean T4 2.8 microgram/dl, T3 49 ng/dl, TSH 37 microU/ml) and hyperthyroid (mean T4 14 microgram/dl, T3 271 ng/dl, TSH less than 0.7 microU/ml) patients had normal red cell 2,3-DPG and ATP levels and normal P50 values in vitro. The known changes in oxygen consumption produced by alterations in thyroid hormone levels in patients with hypothyroidism or hyperthyroidism did not affect red blood cell oxygen transport function.

scholarly journals Red cell 2,3-diphosphoglycerate and oxygen affinity of hemoglobin in patients with thyroid disorders

Blood ◽  
1978 ◽  
Vol 52 (1) ◽  
pp. 181-185 ◽  
Author(s):  
CG Zaroulis ◽  
IA Kourides ◽  
CR Valeri
Keyword(s):  
Blood Cell ◽  
Oxygen Transport ◽  
Red Blood Cell ◽  
Clinical Status ◽  
Oxygen Affinity ◽  
Red Cell ◽  
Transport Function ◽  
Oxygen Affinity Of Hemoglobin ◽  
2,3 Dpg

Abstract We measured red blood cell 2,3-diphosphoglycerate (2,3-DPG), adenosine triphosphate (ATP), and the P50 value in vitro of the oxyhemoglobin dissociation curve, which is the oxygen tension at half saturation of hemoglobin, in order to quantitate red blood cell oxygen transport function in individuals who were diagnosed as hypothyroid, euthyroid, or hyperthyroid based on measurements of thyroxine (T4), triiodothyronine (T3), thyrotropin (TSH), and their clinical status. Hypothyroid (mean T4 2.8 microgram/dl, T3 49 ng/dl, TSH 37 microU/ml) and hyperthyroid (mean T4 14 microgram/dl, T3 271 ng/dl, TSH less than 0.7 microU/ml) patients had normal red cell 2,3-DPG and ATP levels and normal P50 values in vitro. The known changes in oxygen consumption produced by alterations in thyroid hormone levels in patients with hypothyroidism or hyperthyroidism did not affect red blood cell oxygen transport function.

Determination of interdependent ligand effects on human red cell oxygen affinity

1982 ◽  
Vol 42 (4) ◽  
pp. 339-345
Author(s):  
W. G. Zijlstra ◽  
B. Oeseburg ◽  
G. Kwant ◽  
A. Zwart
Keyword(s):  
Oxygen Affinity ◽  
Red Cell ◽  
Ligand Effects

scholarly journals Effect of oxalate and malonate on red cell metabolism

Blood ◽  
1987 ◽  
Vol 70 (5) ◽  
pp. 1389-1393
Author(s):  
E Beutler ◽  
L Forman ◽  
C West
Keyword(s):  
Pyruvate Kinase ◽  
Cell Metabolism ◽  
Inhibitory Effect ◽  
Red Cells ◽  
Red Cell ◽  
Acid Analogue ◽  
2,3 Dpg

The addition of oxalate to blood stored in Citrate-phosphate-dextrose (CPD) produces a marked improvement in 2,3-diphosphoglycerate (2,3-DPG) preservation; an increase in 2,3-DPG levels can also be documented in short-term incubation studies. Oxalate is a potent in vitro inhibitor of red cell lactate dehydrogenase, monophosphoglycerate mutase, and pyruvate kinase (PK). In the presence of fructose 1,6-diphosphate the latter inhibitory effect is competitive with phospho(enol)pyruvate (PEP). Determination of the levels of intermediate compounds in red cells incubated with oxalate suggest the presence of inhibition at the PK step, indicating that this is the site of oxalate action. Apparent inhibition at the glyceraldehyde phosphate dehydrogenase step is apparently due to an increase in the NADH/NAD ratio. Oxalate had no effect on the in vivo viability of rabbit red cells stored in CPD preservatives for 21 days. Greater understanding of the toxicity of oxalate is required before it can be considered suitable as a component of preservative media, but appreciation of the mechanism by which it affects 2,3-DPG levels may be important in design of other blood additives. Malonate, the 3-carbon dicarboxylic acid analogue of oxalate late did not inhibit pyruvate kinase nor affect 2,3-DPG levels.

scholarly journals Mechanism of red cell 2,3-diphosphoglycerate increase in neonatal lambs

Blood ◽  
1983 ◽  
Vol 61 (5) ◽  
pp. 920-924 ◽  
Author(s):  
NA Noble ◽  
CA Jansen ◽  
PW Nathanielsz ◽  
KR Tanaka
Keyword(s):  
Oxygen Affinity ◽  
Glucose Consumption ◽  
Red Cell ◽  
Sequential Effects ◽  
Blood Ph ◽  
Tenfold Increase ◽  
Hemoglobin Oxygen Affinity ◽  
Ph Increase ◽  
Neonatal Lambs

Abstract The tenfold increase in red cell 2,3-diphosphoglycerate (DPG) concentration that occurs during the first 5 days of life in lambs is an important adaptation to extrauterine life. In lambs, DPG reduces hemoglobin oxygen affinity by the Bohr effect. Our data on 10 neonatal lambs suggest that the biochemical mechanism underlying this DPG increase involves the following: (1) a rise in plasma glucose from 40 to 100 mg/dl in the first 48 hr of life, which allows for increased glucose consumption in the highly glucose-permeable neonatal RBC; (2) a transitory rise in blood pH begins at birth, peaks at about 20 hr, and falls slightly; (3) the pH increase coincides with a threefold increase in RBC fructose-1,6-diphosphate (FDP) concentration due, we believe, to pH activation of phosphofructokinase; (4) glycolytic intermediates after the glyceraldehyde-3-phosphate dehydrogenase (GAPD) step do not rise in the first 24 hr of life, possibly due to insufficient inorganic phosphate (Pi), a substrate of GAPD; (5) plasma Pi increases from about 7 mg/dl at birth to 11 mg/dl at 72 hr, activates the GAPD, and FDP levels decline; and (6) the in vitro activity of the DPG synthetic enzyme, DPG mutase, is increased 12-fold in neonatal compared to adult RBC. We conclude that the postnatal rise in DPG is explained at least in part by the sequential effects of these metabolic changes.

In vitro determination of red cell alloantibody significance using an assay of monocyte-macrophage interaction with sensitized erythrocytes

1984 ◽  
Vol 56 (1) ◽  
pp. 19-29 ◽  
Author(s):  
Donald R. Branch ◽  
Michael T. Gallagher ◽  
Angeles P. Mison ◽  
Anita L. Sy Siok Hian ◽  
Lawrence D. Petz
Keyword(s):  
Red Cell

scholarly journals Effect of oxalate and malonate on red cell metabolism

Blood ◽  
1987 ◽  
Vol 70 (5) ◽  
pp. 1389-1393 ◽  
Author(s):  
E Beutler ◽  
L Forman ◽  
C West
Keyword(s):  
Pyruvate Kinase ◽  
Cell Metabolism ◽  
Inhibitory Effect ◽  
Red Cells ◽  
Red Cell ◽  
Acid Analogue ◽  
2,3 Dpg

Abstract The addition of oxalate to blood stored in Citrate-phosphate-dextrose (CPD) produces a marked improvement in 2,3-diphosphoglycerate (2,3-DPG) preservation; an increase in 2,3-DPG levels can also be documented in short-term incubation studies. Oxalate is a potent in vitro inhibitor of red cell lactate dehydrogenase, monophosphoglycerate mutase, and pyruvate kinase (PK). In the presence of fructose 1,6-diphosphate the latter inhibitory effect is competitive with phospho(enol)pyruvate (PEP). Determination of the levels of intermediate compounds in red cells incubated with oxalate suggest the presence of inhibition at the PK step, indicating that this is the site of oxalate action. Apparent inhibition at the glyceraldehyde phosphate dehydrogenase step is apparently due to an increase in the NADH/NAD ratio. Oxalate had no effect on the in vivo viability of rabbit red cells stored in CPD preservatives for 21 days. Greater understanding of the toxicity of oxalate is required before it can be considered suitable as a component of preservative media, but appreciation of the mechanism by which it affects 2,3-DPG levels may be important in design of other blood additives. Malonate, the 3-carbon dicarboxylic acid analogue of oxalate late did not inhibit pyruvate kinase nor affect 2,3-DPG levels.

scholarly journals Mechanism of red cell 2,3-diphosphoglycerate increase in neonatal lambs

Blood ◽  
1983 ◽  
Vol 61 (5) ◽  
pp. 920-924 ◽  
Author(s):  
NA Noble ◽  
CA Jansen ◽  
PW Nathanielsz ◽  
KR Tanaka
Keyword(s):  
Oxygen Affinity ◽  
Glucose Consumption ◽  
Red Cell ◽  
Sequential Effects ◽  
Blood Ph ◽  
Tenfold Increase ◽  
Hemoglobin Oxygen Affinity ◽  
Ph Increase ◽  
Neonatal Lambs

The tenfold increase in red cell 2,3-diphosphoglycerate (DPG) concentration that occurs during the first 5 days of life in lambs is an important adaptation to extrauterine life. In lambs, DPG reduces hemoglobin oxygen affinity by the Bohr effect. Our data on 10 neonatal lambs suggest that the biochemical mechanism underlying this DPG increase involves the following: (1) a rise in plasma glucose from 40 to 100 mg/dl in the first 48 hr of life, which allows for increased glucose consumption in the highly glucose-permeable neonatal RBC; (2) a transitory rise in blood pH begins at birth, peaks at about 20 hr, and falls slightly; (3) the pH increase coincides with a threefold increase in RBC fructose-1,6-diphosphate (FDP) concentration due, we believe, to pH activation of phosphofructokinase; (4) glycolytic intermediates after the glyceraldehyde-3-phosphate dehydrogenase (GAPD) step do not rise in the first 24 hr of life, possibly due to insufficient inorganic phosphate (Pi), a substrate of GAPD; (5) plasma Pi increases from about 7 mg/dl at birth to 11 mg/dl at 72 hr, activates the GAPD, and FDP levels decline; and (6) the in vitro activity of the DPG synthetic enzyme, DPG mutase, is increased 12-fold in neonatal compared to adult RBC. We conclude that the postnatal rise in DPG is explained at least in part by the sequential effects of these metabolic changes.

scholarly journals Modification of hemoglobin by ninhydrin

Blood ◽  
1980 ◽  
Vol 56 (4) ◽  
pp. 701-705 ◽  
Author(s):  
G Kokkini ◽  
VJ Stevens ◽  
CM Peterson ◽  
A Cerami
Keyword(s):  
Carbonyl Compounds ◽  
Oxygen Affinity ◽  
Equal Degree ◽  
Isoelectric Points ◽  
Degradation Reaction ◽  
Hemoglobin Variants ◽  
Oxygen Affinity Of Hemoglobin ◽  
And Function ◽  
Guanidino Group

Abstract The Strecker degradation reaction was evaluated as a means of modifying hemoglobin in vitro, utilizing ninhydrin as a model compound. Ninhydrin led to modification of hemoglobin (when incubated with hemoglobin or red cells) at physiologic temperature and pH. Isoelectric focusing documented the formation of new hemoglobin bands, all with decreased (more negative) isoelectric points that hemoglobin A. Both alpha and beta chains were modified to an equal degree, although electrophoretic studies documented two modified species of alpha-chains and three modified species of beta-chains. Amino acid analysis of modified hemolysate following NaB3H4 reduction revealed peaks that coeluted with deaminated valine, epsilon-deaminated lysine, and a product with the guanidino group of arginine. The oxygen affinity of hemoglobin increased following its incubation with increasing concentrations of ninhydrin. These studies suggest that ninhydrin is representative of a class of carbonyl compounds that could be utilized to specifically modify that structure and function of hemoglobin variants.

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