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A J Erslev

Publications and source records attributed to A J Erslev.

At least 19 recordsLinked to original sources
PubMed1992

Clinical pharmacology and economics of recombinant human erythropoietin in end-stage renal disease: the case for subcutaneous administration.

The clinical pharmacology of human recombinant erythropoietin (epoetin) was studied in order to compare the effectiveness of various routes and dosing schedules in dialysis patients. Thirty-six patients received epoetin beta three times a week i.v. for at least 12 wk. The mean dose needed to achieve target hemoglobin was 225 +/- 36 U/kg per week (median dose, 180 U/kg per week). Twenty-eight of 36 patients who were converted to a once-a-week i.v. schedule increased their requirements to 429 +/- 50 U/kg per week in order to maintain a target hematocrit of 33 to 40 vol%. Twelve of 28 patients could maintain their target hematocrit when dosed once a week s.c. at 84 +/- 10 U/kg. The other 16 patients required 137 +/- 15 U/kg per week divided into two doses. In the entire group of 28 patients, the weekly requirement for epoetin was reduced by 50% when the s.c. route was used two or three times a week. Pharmacokinetic studies performed during chronic therapy indicated rapid clearance of erythropoietin (t1/2 of 6.8 +/- 0.3 h). Single i.v. doses greater than 150 U/kg were required to increase basal erythropoietin by 30 mU/mL at 44 h postdosing. With s.c. dosing, such increments in erythropoietin levels frequently persisted beyond 60 h because of prolonged and slow absorption. Pharmacokinetic simulations in conjunction with clinical correlation of the erythropoietic response suggest that the duration that the erythropoietin levels are maintained, and not the absolute peaks, is the primary determinant of efficacy. This may result from nonlinearity in the dose response. Pharmacokinetic simulation also indicated that i.v. dosing could not maintain adequate interdialytic erythropoietin levels, whereas s.c. dosing could. Cost analysis indicated that the use of s.c. dosing two or three times a week at an average total weekly dose of 110 to 120 U/kg is effective treatment of anemia in most dialysis patients.

Adolescent↗
PubMed1992

The therapeutic role of recombinant erythropoietin in anemic patients with intact endogenous production of erythropoietin.

Recombinant human erythropoietin (r-HuEPO) has been shown to be remarkably effective in raising the hemoglobin concentrations and improving the quality of life of patients with chronic renal disease. It is currently under investigation for treatment of patients with nonrenal anemias associated with cancer chemotherapy, acquired immunodeficiency syndrome, rheumatoid arthritis, and other chronic illnesses. To date, investigators have shown that patients with mild anemia and low endogenous erythropoietin (EPO) production may be good candidates for such treatment. Conversely, studies have shown that patients with severe anemia and serum EPO concentrations of above 500 mU/mL apparently do not respond to doses used for patients with mild anemia or chronic renal disease. Large doses of r-HuEPO may be of use in such patients, and clinical trials are in progress to determine if it is at least possible to make these patients transfusion-independent.

Anemia↗
PubMed1991

Erythropoietin.

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Anemia↗
PubMed1991

Erythropoietin life span in rats with hypoplastic and hyperplastic bone marrows.

The metabolic fate of erythropoietin (EPO) remains unknown. Urinary excretion does not appear to play a major role and liver catabolism has been shown to occur only after terminal sugars on the hormone have been removed. However, it has been proposed that EPO is eliminated by consumption in the bone marrow. In order to examine the extent of such consumption we measured the half-life of radioidinated recombinant EPO injected intravenously (IV) to rats with bone marrows suppressed by cyclophosphamide or hypertransfusion and marrows stimulated by phenylhydrazine or bleeding. The mean half-life or erythropoietin in normal rats was 179 +/- 16 min, with similar half-lives found in the other rats regardless of decreased or increased bone marrow activity. The results indicate that it is unlikely that erythroid activity determines EPO life span and catabolism.

Animals↗
PubMed1990

Erythropoietin.

The remarkable capacity of the bone marrow to compensate for blood loss and for reduced atmospheric oxygen tension has been found to be mediated by a renal hormone, named erythropoietin. It is produced by peritubular interstitial cells in response to renal hypoxia, but molecular engineering has permitted large scale production of an identical recombinant erythropoietin in vitro. When used as a replacement hormone in patients with impaired endogenous production it has been found to be capable of improving or eliminating the anemia of chronic kidney disease and the anemia of prematurity. In the future it may also be used as a pharmacologic agent and possibly be able to control the anemia of patients with bone marrow failure and make them transfusion-independent.

Anemia↗
PubMed1989

Inappropriate increase in erythropoietin titers during chemotherapy.

Serial erythropoietin measurements by RIA were performed in six patients with acute leukemia treated by intensive chemotherapy. In all cases erythropoietin titers increased after the onset of treatment, although the hemoglobin concentration remained at stable values. Subsequently the erythropoietin titers gradually returned to baseline levels. In same patients this reduction occurred at the end of chemotherapy, in others coincident with infections and antibiotic therapy. In four patients this decrease occurred at the time of bone marrow recovery. The explanation for this inappropriate increase in erythropoietin titers is not clear but may be related to a direct or indirect effect of a suppressed marrow on sites of erythropoietin production or catabolism.

Adult↗
PubMed1989

Stimulation of erythropoietin gene transcription during hypoxia and cobalt exposure.

Erythropoietin, a plasma glycoprotein produced primarily by the kidney, is a growth and differentiation factor for erythroid progenitor cells. Production of renal erythropoietin is regulated by modulation of mRNA levels in response to changes in tissue oxygenation. Exposure to cobalt, a nonphysiologic stimulus for erythropoietin production, also acts by inducing mRNA accumulation. To determine whether variations in erythropoietin mRNA levels result from enhanced transcription of the erythropoietin gene, in vitro transcription reactions were performed using isolated rat kidney cell nuclei. Quantitation of specific nuclear RNAs labeled during in vitro transcription revealed active erythropoietin gene transcription in kidney nuclei from anemic-hypoxic and cobalt-treated animals while erythropoietin transcriptional activity was undetectable in normal kidney nuclei. Time course studies showed that stimulation of transcription begins between two and four hours following cobalt treatment and parallels the kinetics of mRNA and plasma erythropoietin accumulation. These results indicate that tissue hypoxia and cobalt exposure specifically enhance erythropoietin gene expression. This increase in erythropoietin production is regulated at least in part at the level of gene transcription.

Animals↗
PubMed1988

Erythropoietin-beta-D-galactosidase. The generation, purification and use of a fusion protein.

A human erythropoietin (Epo) cDNA fragment encoding the complete erythropoietin peptide sequence was fused to the 3'-end of the lacZ gene in the polylinker region of the high expression vector, pUR 278. Escherichia coli bacteria were transformed with the recombinant plasmid harboring the hybrid Epo-beta-D-galactosidase gene. After induction with isopropyl-thiogalactoside large amounts of the fusion protein, Epo-beta-D-galactosidase were synthesized in the transformed bacteria. The fusion protein was partially purified and shown to exhibit intact galactosidase enzymatic activity. Although no biological activity of the Epo counterpart of the fusion protein was detected both in an in vivo and in an in vitro bioassay, the fusion protein served as an effective antigen for the production of anti-erythropoietin antibodies. Antifusion protein antibodies raised in rabbits were shown to react with the intact human Epo molecule from erythropoietin producing culture supernatants. The affinity of these anti-fusion protein antibodies was sufficiently high to permit the development of a sensitive radioimmunoassay for human Epo. This fusion protein approach is a relatively straightforward and rapid method of generating antibodies with specificity for any protein encoded by a cloned eukaryotic gene.

Animals↗
PubMed1987

Dynamics of erythropoiesis following renal transplantation.

We examined the temporal dynamics of the correction of anemia following renal transplantation in 65 recipients using a sensitive radioimmunoassay for erythropoietin to determine the effects of modern immunosuppressive agents, delayed graft function, and early acute rejection. Pretransplant mean erythropoietin (25.6 +/- 3.3 mU/ml) was only 25% of the expected value at the mean hematocrit of 27.2 +/- 0.7, and erythropoietin correlated positively with hematocrit (r = 0.37, P less than 0.05). Following onset of graft function, erythropoietin increased to 109 +/- 13 mU/ml and then decreased in a negative feedback fashion over the next several months. Delayed graft function was associated with delay in the assumption of this orderly process irrespective of the immunosuppressive regimen used. Cyclosporine A produced a biphasic response despite delayed graft function in recipients with underlying adult polycystic kidney disease. Correction of anemia required resumption of graft function. Onset of acute graft rejection within the first month posttransplantation (14 episodes in 11 patients) abrogated the hematopoietic response until the rejection was successfully reversed. We conclude that a major cause for the anemia of renal failure is subnormal production of erythropoietin. Following transplantation, anemia corrects in an orderly manner with restoration of the normal biofeedback process between erythropoietin and red cell mass. This process is delayed by failure of graft to function initially and interrupted by acute early rejection, re-commencing following successful reversal.

Adolescent↗
PubMed1987

Regulation of erythropoietin production in a human hepatoblastoma cell line.

Production of immuno and biologically active erythropoietin was documented to occur in the human hepatoblastoma cell line HepG-2. The expression of the erythropoietin gene was further verified by Northern blot analysis using a single stranded RNA probe. In vitro studies showed that erythropoietin production by these cells was not stimulated by hypoxia or cobalt chloride, but was related to the proliferative activity of the cells in culture. In addition it was found that the secretion of erythropoietin was almost completely abrogated by tunicamycin, an inhibitor of N-linked glycosylation. This effect of tunicamycin was also observed in a permanently transfected cell line that secretes erythropoietin in large quantities.

Animals↗