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

Erythropoietin is a glycoprotein hormone that plays a vital role in erythropoiesis. It is mainly produced in the fetal liver till the third trimester of pregnancy. At that point, the kidney interstitium takes over this function and becomes the main source of erythropoietin. Hypoxia stimulates erythropoietin production by a mechanism that may require a heme protein as a second messenger. Erythropoietin stimulates the maturation of erythroid precursors (colony-forming unit-erythroid and burst-forming unit-erythroid) via at least two types of cell surface receptors. The higher-affinity receptors appear to be more important in modulating the effects of erythropoietin in vivo. Changes in intracellular calcium may ultimately mediate the action of erythropoietin on erythroid precursors. A specific and sensitive radioimmunoassay is now available for accurately measuring erythropoietin levels. All forms of erythrocytosis except polycythemia vera are associated with elevated erythropoietin levels. Levels are also high in cord blood obtained following fetal asphyxia. Reduced levels are seen in patients with anemia due to renal diseases. The response of erythropoietin to the degree of anemia appears to be attenuated in patients with cancer, chronic diseases, and human immunodeficiency virus (HIV) infection. Erythropoietin has been successfully used for treating patients with anemia due to renal failure. Its use has also been approved for the treatment of anemia patients receiving zidovudine for HIV infection. Encouraging results have been observed when erythropoietin was used to treat anemia due to rheumatoid arthritis, hematological malignancies, and prematurity. It has also been used to increase the yield of autologous blood collected prior to an elective surgical procedure. However, it has not proved to be useful in sickle cell anemia and myelodysplastic syndromes.
 ...
PMID:Erythropoietin. Biology and clinical applications. 178 66

A 23-year-old man with severe sickle cell disease and a chronic non-healing left leg ulcer was entered into a study in which he received hydroxyurea (HU) and recombinant human erythropoietin (r-HuEPO) in order to modify the severity of his disease. HU 20 mg/kg/day effectively prevented vaso-occlusive crises and improved hematological parameters, but the chronic leg ulcer and chronic mild bone pains remained. Six months later, r-HuEPO 600-800 IU/kg subcutaneously was added at weekly intervals. This led to a rapid and complete healing of the chronic leg ulcer, further improvement in hematological parameters and relief from chronic pains. We conclude that treatment with r-HuEPO may provide an effective therapy for chronic leg ulcers in patients with sickle cell disease.
 ...
PMID:Recombinant human erythropoietin induced rapid healing of a chronic leg ulcer in a patient with sickle cell disease. 195 Mar 63

Erythroid progenitors circulating in peripheral blood and their response to erythropoietin (EPO), interleukin-3 (IL3), and phytohemagglutinin-stimulated, lymphocyte-conditioned medium (PHALCM) were assessed in sickle cell anemia (SCA) patients and controls. SCA patients have significantly higher numbers of circulating burst-forming unit-erythroid (BFU-E) compared with controls (mean +/- SEM, 940.27 +/- 129.11 per ml and 86.56 +/- 19.74 per ml, respectively; P less than 0.0001). At low doses of EPO, BFU-E-derived colonies were significantly increased in SCA patients compared with controls (each P less than 0.05). The EPO dose required to produce 50% of maximum colony numbers was 47 times greater in control subjects than in SCA patients. Moreover, in 11 of 17 patients with SCA, spontaneous BFU-E-derived colonies were formed without added erythropoietin. This phenomenon was not observed in control subjects (P = 0.035). PHALCM developed from mononuclear cells of SCA patients had significantly greater stimulatory effect than did that derived from controls regardless of the source of target cells (each P less than 0.05). A two-step study of IL3 sensitivity of erythroid progenitors was conducted. First, in a liquid culture system, circulating erythroid progenitors of SCA patients and controls were incubated in the presence of varying doses of IL3. During a second step, CFU-E-like colonies were observed in methylcellulose cultures of these cells. The mean numbers of colony-forming unit-erythroid (CFU-E)-like colonies was significantly higher in SCA patients compared with control subjects at low doses of IL3 (each P less than 0.02). The increased response of erythroid progenitors to IL3 and the increased production of hemopoietic growth factors (IL3 or non-IL3) contribute to the hemopoietic response in SCA patients. These mechanisms and increased sensitivity of the BFU-E to EPO may explain lower than expected EPO levels in SCA patients.
 ...
PMID:Increased response of erythroid progenitors to interleukin-3 in sickle cell anemia: CFU-E-like behavior of circulating erythroid progenitors in liquid culture. 195 Dec 99

Recombinant human erythropoietin represents a potential therapeutic alternative to red blood cell transfusions in a number of pediatric anemias. It is effective in correcting anemia associated with chronic renal failure and may significantly reduce the morbidity associated with childhood CRF. Most exposures to allogeneic blood products in pediatrics for treatment of anemia with blood transfusions occur in neonatal intensive care units. If proven effective in treating anemia in premature babies, r-HuEPO will be responsible for a major reduction in the use of blood transfusions in clinical neonatology. Carefully designed, placebo-controlled clinical trials will be required to establish the role of r-HuEPO in anemia of prematurity. Recombinant human erythropoietin also may be useful to increase the amount of blood that can be collected before elective surgical procedures. Another potential indication is to raise the hematocrits of infants with large intracardiac shunts who develop congestive heart failure coincident with the developmental fall in hemoglobin concentration after birth. Finally, r-HuEPO may one day play a role in modifying the expression of globin genes and, thereby, ameliorate the course of sickle cell disease and beta thalassemia. Many questions surrounding the use of r-HuEPO in infancy and childhood are being addressed in ongoing clinical trials.
 ...
PMID:Recombinant erythropoietin in pediatrics: a clinical perspective. 218 91

The effects of prostaglandin E2 (PGE2) in association with erythropoietin on the synthesis of fetal and adult hemoglobin in peripheral blood-derived erythroid burst colonies from normal adults and from patients with sickle cell anemia were investigated. The synthesized hemoglobin at the end of 8, 14 or 18 days in culture was separated by DEAE-cellulose chromatography of 35S-methionine labelled hemoglobin. Quantitative estimation of the synthesized hemoglobin phenotypes, for the three indicated culture periods, showed preferential synthesis of Hb F in addition to an overall increase in hemoglobin synthesis in PGE2 treated colonies. Furthermore, the reactivation of fetal hemoglobin production by PGE2 was more pronounced when the adherent cells were included in the culture dishes. These results indicate that the addition of PGE2 to culture dishes presumably constitutes an environmental change to promote the functional changes seen in the blood erythroid bursts in terms of Hb synthesis and switching.
 ...
PMID:Prostaglandin E2 mediated effects on the synthesis of fetal and adult hemoglobin in blood erythroid bursts. 240 99

Stimulating the production of fetal hemoglobin may benefit patients with sickle cell anemia by inhibiting sickling. We gave pulsed treatments with high doses of recombinant human erythropoietin to baboons in order to test the hypothesis that the resultant rapid erythroid regeneration would stimulate F cells--i.e., cells that contain fetal hemoglobin. In normal animals, this treatment caused sharp increments in F-reticulocyte levels, which rose from 1 to 2 percent before treatment to 40 to 50 percent afterward. In two animals with chronic anemia and high levels of endogenous erythropoietin, recombinant human erythropoietin induced further increments in F-reticulocyte levels, which rose in one animal from 6 to 8 percent before treatment to 23 percent after treatment, and in the other from 20 percent before to 50 percent afterward. The time course of F-reticulocyte stimulation suggested that these cells were the products of mobilized early erythroid progenitors. These results raise the possibility that pulses of erythropoietin could be used to stimulate F-cell formation in patients with sickle cell disease.
 ...
PMID:Stimulation of fetal hemoglobin synthesis by erythropoietin in baboons. 244 Dec 58

Reactivation of fetal hemoglobin (HbF, alpha 2 gamma 2) synthesis was previously reported in normal human adult erythroblast colonies ("bursts") generated by erythroid progenitors (BFU-E) in fetal calf serum-supplemented (FCS+) semisolid cultures stimulated with erythropoietin (Ep). Our studies focused on the reactivation of HbF synthesis in normal adult erythroid bursts generated by peripheral blood mononuclear cells (PBMCs) seeded in FCS+ methylcellulose culture. Reactivation is almost totally suppressed when (a) PBMCs are grown in optimized FCS- culture, or (b) PBMCs are first stringently depleted of monocytes and then plated in FCS+ medium (ie, BFU-E growth in FCS+ Mo- culture). In both experimental conditions, the proliferation of lymphocytes and macrophages interspersed among colonies is drastically reduced, and the cloning efficiency of granulocyte-macrophage (GM) progenitors is sharply diminished. In either case, addition of biosynthetic GM colony-stimulating factor (GM-CSF) induces a dose-related increase of HbF synthesis up to the level in FCS+ culture, with even more elevated values on delayed addition of Ep. A dose-related increase was also observed in erythroblast clones generated by highly purified BFU-E. These results suggest that reactivation of HbF synthesis in normal adults is at least in part mediated by GM-CSF. Furthermore, they imply intriguing hypotheses on the mechanism(s) of perinatal Hb switching. Finally, they raise the possibility of reactivation of HbF synthesis in beta-thalassemia and sickle cell anemia by GM-CSF therapy.
 ...
PMID:Granulocyte-macrophage colony-stimulating factor reactivates fetal hemoglobin synthesis in erythroblast clones from normal adults. 247 26

Extramedullary hematopoiesis (EMH) is observed in people suffering from severe anemia of prolonged duration and appears to be a compensatory mechanism for disturbed medullary hematopoiesis. The hemoglobinopathies (such as thalassemia, spherocytosis, and sickle cell disease), neoplastic diseases such as leukemia and lymphoma, and others, including myelofibrosis and osteitis fibrosa cystica, are associated with EMH. These diseases and their resultant anemia have in common the ability to stimulate erythropoietin production, which in turn may stimulate hematopoiesis in organs of mesenchymal origin. The liver and spleen are the most common sites of EMH; however, other sites, including the falx cerebri, thoracic cavity, retroperitoneal area and pelvis have been reported. When present, intrathoracic EMH is most frequently associated with thalassemia. Spinal cord compression and hemothorax have also been reported as complications of intrathoracic EMH.
 ...
PMID:Asymptomatic intrathoracic extramedullary hematopoiesis: a report of three cases. 262 Nov 1

Erythropoietin is produced mainly by the kidneys and stimulates erythropoiesis in the bone marrow. Chronic renal failure is characterized by anemia, which is principally caused by erythropoietin deficiency. Recombinant human erythropoietin (r-hEPO) corrects the anemia of chronic renal disease and improves patient well-being, exercise tolerance, and cognitive function. The clinical pharmacology, efficacy, safety, and tolerance of r-hEPO are presented. Four major studies attest to r-hEPO's efficacy in the treatment of anemia of chronic renal disease and document potential toxicities of hypertension, iron deficiency, thrombosis, and bone pain. Careful attention to the extent of correction of the hematocrit, increased heparinization during hemodialysis therapy, and compliance with dietary restrictions may minimize the incidence and severity of adverse reactions. Resistance to r-hEPO may be due to iron deficiency, aluminum toxicity, or inflammation, including infection. Potential future uses of r-hEPO include the treatment of various other anemias, such as those seen in sickle cell anemia, rheumatoid arthritis, and autologous blood donation. Controlled clinical studies in these areas have not been reported.
 ...
PMID:Recombinant human erythropoietin. 266 69

The chemistry, pharmacology, pharmacokinetics, clinical uses and efficacy, adverse effects, drug interactions, dosage and administration, and formulary considerations of epoetin are described. Erythropoietin, a glycoprotein hormone primarily synthesized in the kidney, is the chief regulator of red blood cell production. Erythropoietin concentrations increase in response to a hypoxic state, resulting in increased red blood cell formation, accelerated hemoglobin production, and premature movement of reticulocytes into the circulation. The human gene responsible for the production of erythropoietin recently was cloned, and the recombinant product--epoetin--has been made available through mass production. The apparent volume of distribution of i.v. epoetin approximates the assumed plasma volume both in healthy volunteers and in patients with chronic renal failure. Little is known about the metabolism and route of elimination of epoetin and erythropoietin. Epoetin recently was approved by the FDA for treatment of anemia associated with chronic renal failure. Clinical trials in patients receiving hemodialysis or peritoneal dialysis and in predialysis patients with renal dysfunction demonstrate epoetin's efficacy. Other potential indications include augmentation of blood production in patients enrolled in autologous blood donation programs and treatment of anemias associated with rheumatoid arthritis, sickle cell disease, acquired immunodeficiency syndrome, cancer, and premature birth. The most frequent adverse effect associated with epoetin therapy is the worsening or development of hypertension. Other adverse effects include thrombocytosis, hyperkalemia, rise in serum urea concentration, iron deficiency, and flu-like symptoms. No drug interactions with epoetin have been reported in humans. The recommended starting epoetin dosage in patients with chronic renal failure is 50-100 IU/kg three times weekly. Epoetin is available only as an injection for i.v. or s.c. administration. Epoetin provides a new therapeutic approach to the treatment of anemia associated with chronic renal failure in hemodialysis, peritoneal dialysis, and predialysis patients. Benefits of epoetin therapy include reduced need for blood transfusions, the amelioration of anemic symptoms, and an improved quality of life.
 ...
PMID:Epoetin: human recombinant erythropoietin. 268 Feb 41


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>