Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002895 (sickle cell disease)
 11,747 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fetal hemoglobin (Hb F) levels in the peripheral blood of baboons (Papio cynocephalus) increased from an average value of 0.78% to 18.1% during the recovery phase from phenylhydrazine-induced hemolytic anemia. A similar increase was observed in animals exposed to hypobaric hypoxia. Large individual variations in the maximal Hb F levels were observed which could not be correlated with the ages of the animals. Reinduction of hemolysis in two fully recovered animals resulted in Hb F levels that were of similar magnitude as in the preceding episode, suggesting the possibility of genetically determined individual variations in the rate of Hb F synthesis under the same conditions of erythropoietic stimulation. Reticulocytes from the animals subjected to hemolysis of hypobaric hypoxia synthesized similar absolute quantities of Hb F in vitro. The results of the present studies indicate that the physiological switch from the synthesis of Hb F to that of Hb A during ontogeny can be reversed in adult nonhuman primates by conditions of erythropoietic stress known to be associated with high erythropoietin levels. These findings open the possibility that Hb F synthesis in adult humans may be therapeutically modulated in individuals who might benefit from increased levels of Hb F, such as patients with sickle cell anemia.
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PMID:Stimulation of fetal hemoglobin synthesis in baboons by hemolysis and hypoxia. 9 44

By using a methylcellulose clonal assay, we cultured peripheral blood erythropoietic precursors from a patient with sickle cell anemia, a patient with sickle cell hemoglobin C disease, and a normal volunteer. We then analyzed the synthetic rates of adult and fetal hemoglobins (Hb) in individual erythropoietic bursts. Bb were labeled with 14C-amino acids in culture, separated by slab gel isoelectric focusing techniques, and quantitated by fluorographic methods. All bursts exhibited both fetal and adult Hb in varying ratios. Frequency distributions of the individual burst differing in percentage of BbF biosynthesis approached normal distributions. Further stimulation of HbF synthesis by higher erythropoietin in culture was associated with increased HbF biosynthesis in individual bursts. Augmentation of human HbF synthesis in culture appears to be controlled by qualitative intracellular changes rather than by changes in cellular population.
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PMID:Hemoglobin biosynthesis in individual erythropoietic bursts in culture. Studies of adult peripheral blood. 43 39

Erythropoiesis was evaluated in 37 patients with sickle cell anaemia, 26 of them children under 12 years of age. Mean haemoglobin, haematocrit, reticulocyte, and erythropoietin levels were similar for 11 who were asymptomatic, 11 with infections, and 12 in vaso-occlusive crisis. Mean haemoglobin, haematocrit, and reticulocyte values were significantly lower and the mean erythropoietin level significantly higher for three patients in aplastic crisis. Reticulocyte counts reflected erythropoietic activity during the asymptomatic state but were variable during infection and crisis. No erythropoietic inhibitory activity was found in any of the four clinical states. It has been suggested that erythropoietin production decreases during infection. Patients in this study responded appropriately to stress, showing no decrease in erythropoietic activity during acute infection or crisis.
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PMID:Erythropoiesis in sickle cell anaemia during acute infection and crisis. 47 53

A child with homozygous sickle cell disease and transposition of the great vessels had erythrocytosis associated with markedly increased plasma erythropoietin activity. Her clinical course was complicated by neurologic manifestations but not by recurrent sickle cell vasooculsive episodes. The fetal hemoglobin level which had been greater than 25% during the first two years of life gradually decreased to less than 10%. She died at 3 years of age of congestive heart failure and severe anemia. The only sickle cell painful crisis occurred during her terminal illness. It is likely that the high levels of fetal hemorglobin decreased sickling and thus allowed erythrocytosis to develop. Fetal hemoglobin may also have prevented frequent vaso-occlusive events despite the high hematocrit level.
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PMID:Sickle cell anemia and transposition of the great vessels. 62 79

We cultured marrow and peripheral blood erythropoietic precrusors in methylcellulose clonal assay and measured the synthetic rates of HbA, A2, F, and S in patients with and without sickle cell anemia. Hb was labeled with 14C-amino acid in culture, separated by slab gel isoelectric focusing techniques, and quantitated by autoradiographic methods. Comparison of marrow late (CFU-E) and early (BFU-E) precursors from patients without hemoglobinopathies showed that preferential synthesis of HbF is limited to early precursors. Simultaneous examinations of Hb synthesis by blood and marrow early erythropoietic precursors confirmed the similarity of the biosynthetic capabilities of the precursors from the two sources. Increasing concentrations of erythropoietin (Ep) in culture corresponded with increases in the percentages of HbF synthesized by blood BFU-E of normal individuals. HbF biosynthesis by blood BFU-E from sickle cell anemia patients was significantly higher than that synthesized by nonanemic individuals and showed significant individual variations. HbF synthesis in patients with sickle cell anemia was partially dependent on Ep concentrations in culture. Cell culture of circulating erythropoietic precursors in man appears to provide a unique tool for studying the control mechanisms of Hb synthesis in man.
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PMID:Augmentation of fetal hemoglobin (HbF) synthesis in culture by human erythropoietic precursors in the marrow and peripheral blood: studies in sickle cell anemia and nonhemoglobinopathic adults. 71 66

Seven patients with sickle cell anemia were treated with oxymetholone for at least 2 mo. Markedly increased basal rates of hemolysis and erythropoiesis were confirmed. The urinary erythropoietin excretion was either normal or lower than expected for the red cell mass, and an expanded blood volume was due primarily to an increased plasma volume. After androgen therapy, six patients demonstrated more than a fivefold increase in urinary erythropoietin, with an increase in red cell mass ranging from 17%-75% above the control value. All showed a decline in serum iron level to the 25-75 mug/100 ml range within 4 wk after the start of therapy. Less marked changes followed lower oxymetholone doses. Reversible hepatic toxicity, with a serum bilirubin concentration exceeding 50 mg/100 ml, occurred in one patient. Androgenic hormone therapy may be useful for selected adult patients with sickle cell disease when severe anemia contributes to disease morbidity.
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PMID:Oxymetholone treatment for sickle cell anemia. 112 26

Patients with sickle cell anemia were treated with daily doses of hydroxyurea, to assess pharmacokinetics, toxicity, and increase in fetal hemoglobin (Hb) production in response to the drug. Plasma hydroxyurea clearances were not a useful guide to maximum tolerated doses of the drug. The mean daily single oral dose that could be maintained for at least 16 weeks was 21 mg/kg (range, 10 to 35 mg/kg). Among 32 patients, last HbF levels were 1.9% to 26.3% (mean, 14.9%) with increases in HbF over initial values of 1.4% to 20.2% (mean, 11.2%). The most significant predictors of last HbF were last plasma hydroxyurea level, initial white blood count and initial HbF concentration. Last HbF was not related to beta globin haplotype or alpha globin gene number. No serious toxicity was encountered. Clinically significant bone marrow depression was avoided, and chromosome abnormalities after 2 years of treatment were no greater than those observed before treatment. The period of observation has been too short to evaluate the risk of carcinogenesis. Patient's red cells developed striking macrocytosis. Median red cell Hb concentrations did not change. Hb concentrations increased, on average 1.2 g/dL, but serum erythropoietin levels increased. Patients' body weights increased, and some returned to work or school, but no conclusions regarding therapeutic efficacy could be drawn from this uncontrolled open-label study.
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PMID:Hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia. 137 2

Hydroxyurea has been shown to increase fetal hemoglobin (Hb F) production in patients with sickle cell disease and therefore has the potential to alleviate both the hemolytic and vaso-occlusive manifestations of the disease. Preliminary evidence indicates that recombinant human erythropoietin (rhEpo) may also induce Hb F. Three sickle cell anemia patients were treated with escalating doses of intravenous rhEpo and, subsequently, with daily oral hydroxyurea. After the optimal hydroxyurea dose was attained, rhEpo was added again. Two additional patients were treated with hydroxyurea alone. Treatment with rhEp, either alone or in combination with hydroxyurea, had no significant effect on the percentage of F reticulocytes or F cells. In contrast, hydroxyurea treatment was associated with a 1.5-fold to sevenfold increase in F cells and a 2.3- to 27-fold increase in the percentage of Hb F. In the three patients whose response reached a plateau, hydroxyurea treatment was associated with lessened hemolysis, decreased serum bilirubin and lactate dehydrogenase levels, and prolonged 51chromium-labeled RBC survival. Hydroxyurea treatment also resulted in decreased numbers of irreversibly sickled cells and in decreased sickling at partial oxygen saturation, increased oxygen affinity, increased total RBC cation content, and diminished potassium:chloride co-transport. All five patients treated with hydroxyurea experienced a decrease in severity and frequency of painful sickle crises. This study confirms that hydroxyurea therapy increases Hb F production and provides objective evidence of a significant reduction in hemolytic rate and intracellular polymerization. In contrast, rhEpo, either alone or in combination with hydroxyurea, offered no measurable benefit. Based on these encouraging preliminary data, large-scale, controlled clinical trials are warranted to study the safety and efficacy of hydroxyurea in the treatment of sickle cell disease.
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PMID:Hydroxyurea and erythropoietin therapy in sickle cell anemia. 137 76

Hydroxyurea, a cell-cycle-specific cytotoxic agent, has been shown to increase fetal hemoglobin (HbF) production. This property makes it an attractive drug for treatment of sickle cell disease and severe beta thalassemia. Its potential efficacy is limited because of a variable and often suboptimal response. Combinations of hydroxyurea and other drugs may induce more clinically significant increases in HbF. We have utilized chronically phlebotomized rhesus monkeys, treated with oral hydroxyurea, to investigate the capacity of several other agents to further augment HbF synthesis. Recombinant human erythropoietin, in super-pharmacologic doses, increased F-reticulocyte production when given on a weekly sequential schedule (3 of 7 days) with hydroxyurea (4 of 7 days), but it was less effective on an alternate day schedule when hydroxyurea was given daily. Neither recombinant human interleukin 3 (IL-3) nor recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF), when infused individually, increased F-reticulocytes in animals receiving daily hydroxyurea. Sequential, overlapping infusions of IL-3 and GM-CSF produced a small but statistically significant increase in F-reticulocytes in one of two hydroxyurea-treated animals. Infusions of sodium butyrate produced a substantial augmentation in F-reticulocyte production in animals chronically treated with hydroxyurea. Thus, our studies have identified several agents that may prove useful in combination with hydroxyurea to achieve clinically beneficial levels of HbF.
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PMID:Hydroxyurea-induced HbF production in anemic primates: augmentation by erythropoietin, hematopoietic growth factors, and sodium butyrate. 138 93

Between 1981 and 1990, the American Red Cross Rare Donor Registry supplied 9,872 units of red cell components with rare phenotypes to blood centers in the United States and abroad. Approximately 51% were from donors with high-frequency antigen-negative phenotypes and 49% were from donors with multiple antigen-negative phenotypes. Since 1989, the disease category requiring the largest number of units has been sickle cell disease. Strategies to ensure that the Registry will have adequate resources to meet future requirements include testing selected donors for rare phenotypes and blood conservation programs, such as intraoperative salvage and the treatment of anemia of chronic renal failure with recombinant erythropoietin.
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PMID:A decade of rare donor services in the United States. Report of the American Red Cross Rare Donor Registry (1981-1990). 144 63


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