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At least 127 records · Page 7Linked to original sources

PubMed1982

Mouse hemoglobin during gestation. Absence of fetal hemoglobin.

A "fetal hemoglobin' has been reported to exist during mouse gestation, Investigations using CMC chromatography, starch gel electrophoresis or isoelectric focusing have shown a hemoglobin band from fetal tissues, and blood was obtained which was different from the adult hemoglobin and designated a "fetal hemoglobin'. In the current study isoelectric focusing was used to study the hemoglobins existing in the tissues and blood during fetal and neonatal development and the results suggest there is no "fetal hemoglobin' present during gestation. It appears that the hemoglobin designated as "fetal' in our laboratory was a methemoglobin formed by an incomplete reaction of KCN with the hemoglobin. The additional hemoglobin bands which were obtained from fetal liver or neonatal spleen tissues appeared to be a modified adult hemoglobin.

Animals↗

PubMed2007

The prevalence of low hemoglobin values among new infantry recruits and nonlinear relationship between hemoglobin concentration and physical fitness.

There is limited information regarding the optimal hemoglobin level for physical activity and most studies followed relatively few participants. The object of this study was to assess iron storage levels in a population of healthy young males and their impact on physical fitness. Blood samples were drawn from 358 consenting infantry recruits for hemoglobin, iron, ferritin, transferrin, folic acid, and B(12) levels. A detailed medical and nutritional history was noted. Recruits performed a field fitness test including a 2,000-m run. Mean hemoglobin was 13.8 +/- 1.0 g/dl. Level of hemoglobin lower than 14 and 12 g/dl were found in 53.6% and 4.5% of the recruits, respectively. Mean ferritin was 57 +/- 34 ng/ml, with 15% of the recruits under 25 ng/ml. On multivariate analysis, after adjusting for pre-induction sports activity (P < 0.001), intermediate pre-induction hemoglobin level (12-14 g/dl) was associated with significantly faster 2,000-m running time (530 +/- 69 s, n = 176) than both the lower hemoglobin group (570 +/- 77 s, n = 16) and the higher hemoglobin group (552 +/- 86 s, n = 166, P < 0.05). The subjects in this study were non-athletic healthy young men. The high rate of abnormally low hemoglobin and ferritin values probably indicates a nutritional deficit in this population. The slower running results in the group with hemoglobin below 12 g/dl are in line with previous work, indicating the need for iron supplementation. The decrease in running ability with increased hemoglobin above 14 g/dl is surprising and will need further evaluation.

Adolescent↗

PubMed2001

Occurrence of two architectural types of hexagonal bilayer hemoglobin in annelids: comparison of 3D reconstruction volumes of Arenicola marina and Lumbricus terrestris hemoglobins.

A 3D reconstruction at 25 A resolution of native hemoglobin of the polychaete worm Arenicola marina was carried out from frozen-hydrated specimens examined in the electron microscope. The reconstruction volume of this large extracellular multimeric respiratory pigment appears as a hexagonal bilayer structure with eclipsed vertices in its upper and lower hexagonal layers. Conversely, in hemoglobins of oligochaetes, achaetes, and vestimentiferans and in chlorocruorins of the Sabellidae (polychaete) family, the vertices of the upper layer are 16 degrees clockwise rotated with respect to those of the lower layer. The fact that two other polychaete hemoglobins (Alvinella pompejana and Tylorrhynchus heterochaetus) have the same architecture as Arenicola led us to define two types of hexagonal bilayer hemoglobins/chlorocruorins: (i) type-I present in oligochaete, achaete, and vestimentiferan hemoglobins and in Sabellidae chlorocruorins; and (ii) type-II present in polychaete hemoglobins. A comparative study of the hemoglobins of Lumbricus terrestris (type-I) and Arenicola marina (type-II) showed that only two small differences located in the c4 and c5 linking units are responsible of the important architectural difference present in oligomers. A likely scheme proposed to explain the phylogenic distribution of the two types suggests that Clitellata, Sabellida (polychaete), and vestimentiferan hemoglobins and chlorocruorins derive from a type-I ancestral molecule, while Terebellida (Alvinella), Phyllodocida (Tylorrhynchus), and Scolecida (Arenicola) and possibly other polychaetes derive from an ancestor molecule with type-II hemoglobin. The architectures of the hollow globular substructures are highly similar in Arenicola and Lumbricus hemoglobins, with 12 globin chains and three linking units (c3a, c3b, and c4). The central piece of Arenicola hemoglobin is an ellipsoid while that of Lumbricus is a toroid. No phylogenic correlation could be found between the structure of the central pieces and the architecture type.

Animals↗

PubMed1981

Development of in vivo somatic mutation system using antibody against hemoglobin: preparation and use of an anti-hemoglobin antibody for identifying C57BL/6 red cells in artificial mixture of DBA/2 and C57BL/6 red cells.

A cellular specific-locus mutation test is described for detecting mutant cells in mammals. The test is based upon the use of specific anti-C57BL/6J mouse hemoglobin antibody that binds hemoglobin "single" (hemoglobin s, present in C57BL/6J mouse) and not hemoglobin "diffuse" (hemoglobin d, present in DBA/2J mouse). Attempts to purify such antibody from pony and rabbit anti-sera through cross-absorption were unsuccessful. Immunization of LP/J mouse with C57BL/6J hemoglobin produced antiserum that reacted with s hemoglobin but not with a d hemoglobin. In a fluorescent antibody technique, this antibody was found to label fixed red blood cells from C57BL/6J mice but not from DBA/2J mice. In a mixture of C57BL/6J and DBA/2J red cells, the C57BL/6J cells could be differentiated by their bright fluorescence from the non-fluorescent DBA/2J cells. Reconstruction experiment with artificial mixtures of DBA/2J and C57BL/6J cells showed that s hemoglobin bearing cells could be detected in DBA/2J red cells at frequencies as small as 0.4 X 10(-6). Thus, the system is sensitive enough to detect d leads to s mutation in DBA/2J mice. Amino acid comparison of the globin chains of s and d hemoglobins shows that our antibody can probably detect mutations leading to a substitution of serine or proline by alanine at beta 20 position and/or a substitution of threonine by alanine at beta 139 position.

Animals↗

PubMed1991

Hemoglobin Columbia Missouri or alpha 2[88 (F9) Ala----Val]beta 2: a new high-oxygen-affinity hemoglobin that causes erythrocytosis.

A previously undescribed hemoglobin variant, hemoglobin Columbia Missouri, alpha 88 (F9) Ala----Val, was detected in a 22-year-old white man who was undergoing assessment for erythrocytosis. This new hemoglobin variant does not separate from hemoglobin A by electrophoresis in conventional media, by isoelectric focusing, or by electrophoresis of purified globin chains in 8 M urea. It exhibits a high oxygen affinity, with a P50 (oxygen tension at 50% saturation) of 19.3 torr for the patient's whole blood. The substitution of hemoglobin Columbia Missouri is an internal residue near the end of the F helix of the alpha chain. Hemoglobin Okazaki has an arginyl residue substitution for a cysteinyl residue at F9 (beta 93) in the beta chain. In comparison with hemoglobin Okazaki, the substitution in hemoglobin Columbia Missouri has a more pronounced effect on oxygen affinity. Consequently, hemoglobin Columbia Missouri is associated with erythrocytosis, whereas hemoglobin Okazaki is not.

Adolescent↗

PubMed1974

Regulation of hemoglobin synthesis in a murine erythroblastic leukemic cell: the requirement for replication to induce hemoglobin synthesis.

The induction of hemoglobin synthesis by dimethylsulfoxide in cells infected with Friend leukemia virus has been shown to depend on the number of cell divisions after the addition of the inducing agent. In asynchronous cultures the cells have a generation time of 24 hr, and hemoglobin synthesis occurs after 48 hr in the presence of dimethylsulfoxide. Generation times were extended by lowering the serum content of the medium. In 7.5% and 2.5% fetal calf serum, the generation time was increased to 36 hr and 48 hr, respectively, and hemoglobin synthesis began at 72 hr and 96 hr, respectively. In the presence of N(6),O(2)'-dibutyryladenosine 3':5'-cyclic monophosphate the generation time was extended to 38 hr, and hemoglobin synthesis began after 72 hr in dimethylsulfoxide. The number of cell doublings, under conditions where the generation time was 24 hr, was regulated by the size of the initial cell concentration. When a low inoculum (1.5 x 10(5) cells per cm(3)) was used, the culture was still in log phase after two doublings and hemoglobin appeared in log phase; a moderate initial inoculum (4.2 x 10(5) cells per cm(3)) took the culture into stationary phase after two doublings, and hemoglobin synthesis was induced in stationary-phase cells. Heavy inocula (3.7 x 10(6) cells per cm(3)) maintained the cells in stationary phase, and under these conditions no induction of hemoglobin synthesis occured. We conclude from these studies that the initiation of hemoglobin synthesis required two rounds of mitosis after treatment with dimethylsulfoxide.In studies with synchronized cultures of cells infected with Friend leukemia virus, two mitoses were required for the initiation of hemoglobin synthesis. We conclude that two rounds of DNA synthesis and/or mitosis are also required for the dimethylsulfoxide-mediated induction of erythroid differentiation and hemoglobin synthesis in these cells.

Animals↗

PubMed1984

A high-resolution proton nuclear-magnetic-resonance investigation of carp hemoglobin. Conformational differences between carp and human normal adult hemoglobins in solution.

The high-resolution proton nuclear magnetic resonance spectra of carp hemoglobin have been compared to those of human normal adult hemoglobin. Carp deoxy and carbonmonoxy hemoglobins in the deoxy-type quaternary state exhibit two downfield exchangeable proton resonances as compared to four seen in human normal adult deoxyhemoglobin. This suggests that two of the hydrogen bonds present in human normal adult deoxyhemoglobin are absent or occur in very different environments in carp hemoglobin. One of the exchangeable proton resonances of carp hemoglobin, while present in the deoxy-type quaternary state of the carbonmonoxy and deoxy derivatives, is absent in the oxy-type quaternary state of both, in agreement with the assignments of these quaternary structures by other methods. The ring-current-shifted proton resonances (sensitive tertiary structural markers) of carp carbonmonoxyhemoglobin are substantially different from those of human normal adult hemoglobin. The aromatic proton resonance region of carp hemoglobin has fewer resonances than that of human normal adult hemoglobin, consistent with its much reduced histidine content. The hyperfine-shifted proximal histidyl NH-exchangeable proton resonances of carp hemoglobin suggest that during the transition from the oxy to the deoxy quaternary structure, there is a greater alteration in the heme pocket of one type of subunits (presumably the beta chain) than that in the other subunit. The present results suggest that there are differences in both tertiary and quaternary structures between carp and human normal adult hemoglobins which could contribute to the great differences in the functional properties between these two proteins.

Adult↗

PubMed1970

Nature of fetal hemoglobin in the Greek type of hereditary persistence of fetal hemoglobin with and without concurrent beta-thalassemia.

The fetal hemoglobin in the affected members of three Greek families with the hereditary persistence of fetal hemoglobin has only gamma-chains of the type with alanine in position 136. Although certain Negro families had been considered to have only this type of gamma-chains in their fetal hemoglobin, further studies required that they be reclassified. Consequently, the Greek cases are the sole examples of this class among the heterozygotes for the hereditary persistence of fetal hemoglobin. In Greek double heterozygotes for beta-thalassemia and the hereditary persistence of fetal hemoglobin, fetal hemoglobin is increased above the level of hemoglobin F in simple heterozygotes and gamma-chains with glycine in position 136 become apparent. In these individuals, gamma-chains with alanine in position 136 apparently derive from the chromosome for the hereditary persistence of fetal hemoglobin and are present in the hemoglobin F with gamma-chains of both types from the chromosome for beta-thalassemia. When these data are correlated with earlier knowledge of the genetic state of the Greek individuals, modifications of our previous ideas about deletions as the genetic basis of the hereditary persistence of fetal hemoglobin must be considered.

Alanine↗

PubMed1986

Limited synthesis of labile hemoglobin A1 in vivo and in vitro by the preexisting hemoglobin A1 in diabetic subjects.

The synthesis of labile hemoglobin A1 in vivo was studied in subjects with non-insulin dependent diabetes mellitus, impaired and normal glucose tolerance. The labile hemoglobin A1 index defined as delta labile hemoglobin A1 divided by delta plasma glucose at 30 min after oral glucose load, representing the rate of labile hemoglobin A1 synthesis in vivo, was low in diabetic subjects and high in normal subjects, showing an inverse correlation with the amount of preexisting hemoglobin A1. The study on the synthesis of labile hemoglobin A1 in vitro showed a lower initial rate of synthesis and a smaller increase in labile hemoglobin A1 at saturation in red blood cells from diabetic subjects with a relatively large amount of preexisting hemoglobin A1, as opposed to red blood cells from normal subjects. Although the further study is necessary in which delta plasma glucose levels are kept relatively constant in each of 3 groups by glucose-clamp methods, our data suggest that the synthesis of labile hemoglobin A1 is limited in vivo and in vitro in diabetic subjects by the preexisting hemoglobin A1 due to the saturability of its synthesis.

Adult↗

PubMed1985

Glycated hemoglobin. Reaction and biokinetic studies. Clinical application of hemoglobin A1c in the assessment of metabolic control in children with diabetes mellitus.

The introduction briefly describes the necessity of maintaining a good metabolic control in children with diabetes mellitus. Thereupon, the object of the study is defined, viz. the wish to elucidate glycation of hemoglobin by means of reaction and biokinetic studies and to evaluate the applicability of the glycated hemoglobin fraction HbA1c in the clinical control of children with diabetes mellitus. In the subsequent historical section the most important studies on glycated hemoglobin are reviewed, with a particular view to the formation of this hemoglobin fraction and its clinical applicability. A brief description follows of the pathway in which hemoglobin A, via condensation with glucose, first forms a labile intermediate adduct, designated HbA1d, which is thereafter rearranged to the more stable HbA1c form. The methods used for determining glycated hemoglobin are described and their specificity assessed. In addition, an account is given of the reasons for choosing isoelectric focusing for a further elucidation of the glycation of hemoglobin. Among the results of the present studies it may be mentioned that by using the method of isoelectric focusing for separation of hemoglobin it is possible to: separate HbA1d and HbA1c and to determine the rate and equilibrium constants for the formation and dissociation of these glycated hemoglobin fractions; calculate, by the use of a biokinetic model, that HbA1c reflects the mean blood glucose concentration of the preceding 4 weeks; ascertain that HbA1c is preferable to HbA1 as a parameter for assessing the glycemic control; demonstrate that in children with newly diagnosed diabetes mellitus HbA1c is a useful index for defining the start and cessation of the remission period and for predicting the length of this period; demonstrate that HbA1c in children with diabetes mellitus is positively correlated to the clinical control and negatively correlated to linear growth; demonstrate a seasonal variation in the HbA1c substance fraction which shows the lowest level in the months of June and July; demonstrate that the transport of glucose across the erythrocyte membrane in children with diabetes mellitus is not notably affected by the glycemic control. The final section deals with the possibility whether glycation of hemoglobin and of other proteins can be a contributory cause of long-term diabetic complications.

Blood Glucose↗

PubMedDate not supplied

Evolution of cooperativity in hemoglobins: what can invertebrate hemoglobins tell us?

While vertebrate hemoglobins typically are tetrameric and show highly regulated and cooperative ligand binding, little is known of the evolution of these properties. We are studying the structural and functional properties of the hemoglobins from Caudina arenicola, an echinoderm. The echinoderms are in the lineage most closely related to the vertebrates to express hemoglobin. C. arenicola has three sets of red cells, in the water vascular system, the coelomic cavity, and in an intestinal vein. Each of these expresses a distinct array of globins. The hemoglobins are cooperative and exhibit unusual ligand-linked associative properties, being dimeric when oxygenated and forming tetramers and higher aggregates on deoxygenation. The major coelomic hemoglobins have been subjected to a detailed examination by a combination of ligand binding analyses and protein and DNA sequencing, as well as X-ray crystallography. Two typical globin introns were identified, along with a unique intron that bisects an N-terminal extension of the globin from the remainder of the gene. X-ray crystallographic analysis shows that the subunit interfaces of C. arenicola hemoglobins differ radically from those of vertebrate hemoglobins and indeed from some other invertebrate hemoglobins, but closely resemble the packing arrangements found in a clam hemoglobin (Scapharca). However, the residues implicated in cooperativity in these two types of hemoglobins differ substantially.

Animals↗

PubMed1976

Surface activity of hemoglobin S and other human hemoglobin variants.

The kinetics of surface pressure change (deltapi vs. t isotherms) were determined for several single point mutations of the human hemoglobin system. It was observed that hemoglobin S and hemoglobin CHarlem (both containing beta6 Glu leads to Val substitutions) have a specific behavior at the water-air interface: their extent of surface pressure change is larger than for hemoglobin A, hemoglobin C and hemoglobin Korle Bu (beta73 Asp leads to Asn). In addition, hemoglobin S seems to occupy a larger area per molecule than hemoglobin A. The conformational requirements for this property, in addition to the beta6 Val substitution, appear to be the liganded state of the betas chain in the tetramer. Electrostatic, hydrogen bonding and hydrophobic interactions are involved in determining the surface activity of a hemoglobin molecule. The differences between the surface activity of oxyhemoglobin S and oxyhemoglobin A could be the basis for their differences in mechanical precipitability, although other factors may play a role.

Asparagine↗

PubMed1970

Electron paramagnetic resonance studies of spin-labeled hemoglobins and their implications to the nature of cooperative oxygen binding to hemoglobin.

The spin label technique has been used to study human hemoglobins A, F, Zürich, and Chesapeake as a function of carbon monoxide saturation. The experimental results suggest that the changes in the electron paramagnetic resonance spectra of hemoglobin labeled with N-(1-oxyl-2,2,6,6-tetramethyl-4-piperidinyl)iodoacetamide depend on the state of ligation of more than one heme group. For those hemoglobins with full or large cooperative ligand binding (such as A, F, and Zürich), there is a lack of isosbestic points in the spectra as a function of CO saturation. However, for those hemoglobins with little or no cooperative ligand binding (such as Chesapeake and methemoglobins), there is a sharp set of isosbestic points. These findings confirm and extend the early work of McConnell and co-workers. The absence of a set of isosbestic points in those hemoglobins with full cooperative ligand binding is consistent with the sequential model of Koshland, Némethy, and Filmer for cooperative oxygen binding to hemoglobin. The present results, with hemoglobin variants having known amino acid substitutions, also focus on the importance of the interactions among the amino acid residues located at alpha(1)-beta(2) or alpha(2)-beta(1) subunit contacts for the functioning of hemoglobin as an oxygen carrier. In addition, the resonance spectra of the spin label are very sensitive to small structural variations around the heme groups in the beta- or gamma-chains where the labels are attached. The results of the spin label experiment are discussed in relation to recent findings on the mechanism of oxygenation of hemoglobin from the nuclear magnetic resonance studies of this laboratory and the x-ray crystallographic analysis of Perutz and co-workers.

Amides↗

PubMed1976

Association of hemoglobin Saint Etienne (alpha2beta295F8 His replaced by G1n) with hemoglobins A and F. Synthesis and subunit exchange in vitro.

The unstable hemoglobin (Hb) Saint Etienne (alpha2beta295F8 His replaced by G1n) (betaSE) was found in the red blood cells of an 8-year-old boy. The composition of this hemoglobin was 26% Saint Etienne, 52% A, 3% A2 and 19% HbF. Studies of hemoglobin synthesis indicate: a) a balanced synthesis of alpha and non-alpha chains (alpha=betaA + betaSE + gamma), b) an increased pool of free alpha hemoglobin chains, and c) a rapid exchange of alpha chains between this pool and HbSE. The alpha chain pool resulted from the dissociation of HbSE and the greater instability of betaSE chains than alpha chains upon heating. Hemoglobin F is of the fetal type and is heterogeneously distributed among the red cells. Furthermore, two populations of red blood cells could be separated according to their i antigen content. Analysis of the hemoglobins revealed a heterogeneous distribution. Thus, F hemoglobin was preferentially associated with cells having low i antigen level, while Saint Etienne hemoglobin was increased in cells having a high i antigen level. HbF and HbSE were not present in the parents of the propositus. Study of the genetic markers confirmed the filiation. The parents were normal upon clinical and hematological examination; they exhibited a normal pattern and synthesis of hemoglobin. The Hb Saint Etienne case is compared with Hb Istanbul, which in spite of the same amino acid substitution is not associated with increased HbF level.

Adult↗

PubMed1983

Relation between variations in the phenotypic expression of an unstable hemoglobin disorder (hemoglobin Zürich) and carboxyhemoglobin levels.

Longitudinal studies in a group of 15 asymptomatic subjects with hemoglobin Zürich from two unrelated families indicated marked variation in the clinical and hematologic expression of the hemoglobinopathy, even within the same family. Carbon monoxide bound to normal hemoglobin stabilized the molecule when exposed to a variety of denaturing procedures. The marked increase in the affinity of hemoglobin Zürich for carbon monoxide, approximately 65 times that of normal hemoglobin, led to a study of carboxyhemoglobin levels in smoking and nonsmoking subjects with hemoglobin Zürich and their relation to the phenotypic expression of the hemoglobinopathy. The carboxyhemoglobin content in whole blood from persons with hemoglobin Zürich ranged from 3.9 to 6.7 percent in nine nonsmokers and from 9.8 to 19.7 percent in six smokers. Rates of hemolysis as determined by values for hematocrit, reticulocyte count, and haptoglobin and hemopexin levels were less in smokers than in nonsmokers. Also, rates of Heinz body formation in intact red cells and isopropanol-induced precipitation of the abnormal hemoglobin in hemolysates were less in smokers than in non-smokers. These observations suggest that variability in the phenotypic expression of hemoglobin Zürich is a post-translation event secondary to stabilization of the abnormal hemoglobin by carbon monoxide.

Adolescent↗

PubMed1983

Dielectric constant of sickle cell hemoglobin. Dielectric properties of sickle cell hemoglobin in solution and gel.

The dielectric constants of sickle cell hemoglobin were determined before and after gelation. The dielectric properties of oxy and deoxy sickle cell hemoglobin in solution are nearly identical to those of oxy and deoxy hemoglobin A. Only in the gel state did deoxy sickle cell hemoglobin display dielectric behavior different from that in solution. Upon gelation of deoxy sickle cell hemoglobin, the dielectric constant showed a marked decrease, and the relaxation frequency shifted towards higher frequencies. This result suggests that dielectric constant measurement can be used for the investigation of the kinetics of polymerization of sickle cell hemoglobin molecules. Despite the marked decrease in the dielectric constant, deoxy sickle cell hemoglobin still showed a well-defined dielectric dispersion even in the gel state. This indicates that individual molecules have considerable freedom of rotation in gels. It was observed that the dielectric properties of gelled deoxy sickle cell hemoglobin were affected by electrical fields at the level of 10 to 20 V/cm. This observation suggests that electrical fields of moderate strengths are able to perturb the gel structure if the system is near the transition region. The non-linear electrical behavior of gelled sickle cell hemoglobin will be discussed further in subsequent papers.

Electric Conductivity↗

PubMed1981

Agar gel electrophoretic determination of glycosylated hemoglobin: effect of variant hemoglobins, hyperlipidemia, and temperature.

We investigated the effect of temperature, variant hemoglobins, and hyperlipidemia on determination of glycosylated hemoglobin by an electrophoretic method (Clin. Chem. 26: 1598-1602, 1980). We found that: (a) temperature variations ranging from 4 to 30 degrees C were without effect on results obtained by electrophoresis; (b) concurrent determination of glycosylated hemoglobin by electrophoresis and column-chromatography in blood specimens from 150 diabetic patients yielded almost identical mean values for both procedures when operations were carried out at 22 degrees C; (c) electrophoretic determination of glycosylated hemoglobin in whole-blood hemolysate was not affected by concentration of triglycerides; and (d) unlike column-chromatographic procedures, which underestimate the percentage of glycosylated hemoglobin in patients with hemoglobin S and C, the electrophoretic method accurately determined the proportion of glycosylated hemoglobin in these hemoglobinopathies. Evidently, electrophoresis on agar gel is an excellent alternative to cation-exchange column-chromatographic methods for glycosylated hemoglobin.

Chromatography, Ion Exchange↗

PubMed2004

Pharmacokinetics of PEG-hemoglobin SB1, a hemoglobin-based oxygen carrier, after its intravenous administration in beagle dogs.

The purpose of the present study was to investigate the pharmacokinetics of PEG-hemoglobin SB1, a modified bovine hemoglobin with polyethylene glycol, after its single and multiple administration in beagle dogs. For this purpose, the analytical method of free hemoglobin in the plasma was developed and validated. Excellent linearity (r2=0.999) was observed in the calibration curve data, with the limit of quantification of 0.005 g/dL. The precision and the deviation of the theoretical values for accuracy were always within +/-15% in both the between- and the within-day results. The method was tested by measuring the plasma concentrations following intravenous administration to beagle dogs and was shown to be suitable for pharmacokinetic studies. In a single dose study, the plasma half-life (t1/2) increased and the total body clearance (CLt) decreased with the dose (i.e., 0.017 to 0.75 gHb/kg as PEG-hemoglobin SB1) in both sexes. The volume of distribution at steady-state (Vd(ss)) showed no difference with the dose. In contrast, the values of t1/2, CLt and the area under the plasma concentration-time curve (AUC) after the multiple dose were significantly different from those of the single dose administration. The values of t1/2 in the multiple administration were about two times higher than that of the single dose. As a result, t1/2 of hemoglobin after the administration of PEG-hemoglobin SB1 was about 15-30 h, indicating the PEG modification of the hemoglobin lead to a prolongation of plasma concentration of the protein. Therefore, these observations suggested that the PEG modification of hemoglobin is potentially applicable in the hemoglobin-based therapeutics.

Animals↗