Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002874 (aplastic anemia)
 5,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In a dose escalation study we tested the feasibility and tolerance of high-dose recombinant human erythropoietin (r-HuEPO) therapy in four patients with ineffective erythropoiesis due to myelodysplastic syndromes (MDS) or paroxysmal nocturnal hemoglobinuria (PNH). Recombinant human EPO was administered i.v. with an initial dose of 50 U/kg body weight (BW) three times per week. The dose was increased by steps of 25 or 50 U/kg bW with intervals of 1-4 weeks up to a maximum dose of 500 U/kg BW three times per week. All patients were treated as outpatients. Pre-study treatment with cyclosporin A and/or Danazol was continued in three patients. In one patient r-HuEPO was discontinued after 20 weeks because of relapse of severe aplastic anemia. No major side effects were observed even at the maximum dose. One patient with PNH showed an increase of hemoglobin from 89 to 139 g/liter that permitted monthly phlebotomies to reduce his iron overload. In one patient with MDS the reticulocyte count increased from 2.5 to 50 x 10(9)/liter, and the transfusion requirement decreased to 2 U every 3-4 weeks instead of every 2 weeks. Two patients did not complete the whole treatment period and showed no rise in reticulocyte count. We conclude that high dose r-HuEPO therapy is feasible in patients with anemia due to MDS or PNH. High-dose r-HuEPO appears to have some effect on anemia due to ineffective erythropoiesis in a subgroup of patients. Further studies are needed to identify potential responders and to define the optimal administration of r-HuEPO.
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PMID:High-dose recombinant human erythropoietin for treatment of anemia in myelodysplastic syndromes and paroxysmal nocturnal hemoglobinuria: a pilot study. 222 80

Physicochemical and biological properties of recombinant human erythropoietin (rhEPO) were compared with human urinary erythropoietin (uEPO). uEPO and rhEPO were purified to apparent homogeneity from the urine of patients with aplastic anemia and from the conditioned medium of Chinese hamster ovary (CHO) cells transfected with a cDNA clone for human EPO, respectively. The microheterogeneous nature of both factors, observed on isoelectric focusing, is derived from the difference of the number of terminal sialic acid residues bound to the carbohydrate chains of the EPO molecule. The primary structure of rhEPO, consisting of 165 amino acid residues, was determined, and the C-terminal arginine predicted from the cDNA sequence was confirmed to be missing, as described previously (Recny et al. (1987) J. Biol. Chem. 262, 17156). Three N-glycosylation and one O-glycosylation sites of both factors were determined as Asn24, Asn38, and Asn83 and Ser126, respectively. Two disulfide linkages are located between Cys7 and Cys161, and between Cys29 and Cys33, in both EPOs. Hematogenic potencies of rhEPO and uEPO compared in normal and in partially nephrectomized rats were approximately the same. Both factors also stimulated the colony formation of CFU-E, BFU-E, and CFU-Meg in a dose-dependent manner. From these results, it is concluded that rhEPO produced in CHO cells transfected with cDNA clone for human EPO is indistinguishable from uEPO physicochemically and biologically, and is valuable for further research and for clinical use.
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PMID:Physicochemical and biological comparison of recombinant human erythropoietin with human urinary erythropoietin. 234 70

Serum erythropoietic activity was determined in 32 patients with beta thalassemia major and intermedia. Quantitation was performed by an in vitro bioassay using rabbit erythroid precursor cells (CFU-E) either by colony assay or by 3H-thymidine uptake. 20 polytransfused beta-thalassemic major patients had erythropoietic activity (mean 89.3 +/- 36 milliunits/ml) which was not significantly different (p greater than 0.2) from normal individuals (51.3 +/- 32 milliunits/ml). 12 untransfused patients with beta thalassemia intermedia were found to have comparable serum erythropoietic activity (p greater than 0.01). These levels were much lower than those found in patients with aplastic anemia who had a comparable degree of anemia. We have shown that the low EPO activity in thalassemic patients was not due to experimental conditions (excess of ferritin, low transferrin) nor to specific inhibitors appearing in this disease. No correlation was found between the erythropoietic activity and sex or other clinical parameters of the patients such as severity of the anemia, splenectomy, iron chelation or transfusion therapy. 4 young thalassemic children (1-2 yr of age) studied had high erythropoietic activity ranging from 661 to 5793 milliunits/ml--significantly different from normal children of the same age. It is suggested, therefore, that a decrease in serum erythropoietin levels develops during the course of the disease.
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PMID:Erythropoietin activity in the serum of beta thalassemic patients. 378 74

Cytokine is a generic term of biologically active molecules which are mainly produced by the immune-competent cells and regulate the immune response, inflammation and hematopoiesis. This includes interleukins (IL), colony-stimulating factors (CSF), interferons (IFN), tumor necrosis factors (TNF) and so on. These cytokines are glycoproteins with a molecular weight of 20,000-40,000 kD and work at very low concentrations of pM order. ILs and CSFs transduce their signal via specific cell-membrane receptors which usually consist of at least two subunits and belong to a newly identified superfamily of cytokine receptors. Characterization of cytokine/receptor system has had a considerable impact on many clinical fields including pathophysiology of diseases and therapy. For example, IL-4 and IL-5 has been revealed to play essential roles in IgE production in allergic diseases and eosinophilia in a hypereosinophilic syndrome, respectively. Receptor abnormality has also been proven to cause diseases; patients for X-linked severe combined immunodeficiency (X-SCID) have a specific defect in the gamma chain of the IL-2 receptor which is critical for thymic maturation of T cells. EPO, G-CSF, M-CSF, IFN, and IL-2 are already commercially available for therapeutic use. IL-1, IL-3, IL-6, and TNF may also be useful for mycosis fungoides, aplastic anemia, thrombocytopenia, and malignant melanoma, respectively. On the other hand, it is possible to modulate the immune response by using the monoclonal antibody directed to the cytokine receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Cytokine and disease]. 752 45

A 23-year-old male patient developed aplastic anemia and was treated with cyclosporin A and rhG-CSF. Bone marrow biopsy showed an improvement in cellularity with a recovery of all hematopoietic precursors after nine weeks of therapy. WBC increased after two weeks of treatment, mostly due to an increase in the absolute granulocyte cell count. Hb, RBC, Plts and reticulocytes showed an increase six weeks after the beginning of therapy. Of the serum cytokines, EPO levels progressively decreased, while sTfR increased in peripheral blood. A reverse correlation between blood neutrophil count and serum levels of G-CSF was observed, indicating an increased clearance of G-CSF. Finally, sIL-2R showed a rapid increase in the first week of treatment and prior to the increase in PMN cells. Thus, the use of cyclosporin A and rhG-CSF in our patient induced a complete recovery of hemopoiesis, and this may be explained by a synergic effect induced by the capacity of cyclosporin A to remove inhibitory factors and the stimulatory activity of rhG-CSF.
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PMID:Response to cyclosporin A and rhG-CSF in a case of aplastic anemia. 767 15

With a newly developed enzyme linked immunosorbent assay kit TOYOBO Co. in which 2 anti-EPO monoclonal antibodies were used, we assayed EPO concentration in sera from normal adults, 168 patients with renal failure and 333 patients with hematological disorders. In the patients with renal failure, serum EPO level was normal (52.9%) or reduced (42.9%), and there was no correlation to their hematocrits. However, there was an increment in EPO concentration correlated to their severity of anemia in the most patients with hematological disorders, such as iron deficiency anemia (correlation coefficient r = -0.74), aplastic anemia (r = -0.89), leukemia (r = -0.81), and MDS (r = -0.65). On the other hand, EPO concentration in sera from all the untreated patients with polycythemia vera were significantly low level. But the concentrations of EPO from the patients successfully treated, with normal hematocrit were recovered to normal level. In the patients with secondary polycythemia, there were much varieties in EPO level. Assay of EPO in blood is important not only for diagnosis of polycythemia but also for the analysis of anemia and clinical use of EPO in vivo. The method described here is accurate and technically not complicated, and could be widely induced in most laboratories.
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PMID:[Assay of erythropoietin in serum with short term enzyme linked immunosorbent assay method--the clinical significance, Part 1: Relation to anemia in renal failure and hematological disorders]. 834 55

With a newly developed short term enzyme linked immunosorbent assay kit (TOYOBO Co.), in which 2 kinds of anti-EPO monoclonal antibodies were used, we assayed EPO concentration in sera from patients with renal failure and hematological disorders. In this report, the EPO data were analysed in relation to serum iron concentrations, with ferritin and UIBC. In the patients with renal failure, there was no significant correlation between EPO concentration and serum iron, ferritin, nor UIBC concentration. On the other hand, in the patients with hematological disorders, there were two types. One was in patients with iron deficiency anemia, whose serum EPO was negatively correlated to serum iron (r = -0.64) and ferritin (r = -0.59), but positively related to UIBC (r = 0.27). The another was the pattern in patients with aplastic anemia, leukemia and MDS, whose serum EPO positively correlated to iron and ferritin but negatively correlated to UIBC. In the patients with aplastic anemia serum EPO had good correlation to serum iron (r = 0.62), ferritin (r = 0.60) and UIBC (r = -0.46). The relationship of EPO to iron in the patients with leukemia (r = 0.54), and EPO to ferritin in the patients with MDS (r = 0.42) show significantly positive correlation coefficient.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Assay of erythropoietin in serum with short term enzyme linked immunosorbent assay method--the clinical significance: Part 2--:Relation to serum iron, UIBC and ferritin in renal failure and hematological disorders]. 835 May 9

We examined the pharmacokinetics of recombinant human erythropoietin (rh-EPO) in genetically anemic mice (W/Wv genotype) to clarify its disposition mechanism in hematopoietic injury such as occurs in aplastic anemia. After rh-EPO was administered to W/Wv and control (+/+ genotype) mice once a day for 1 week at different doses, both the hematocrit (Hct) and tissue uptake clearance (CLup) of 125I-rh-EPO by spleen and bone marrow in the femur were estimated on the eighth day. The hematocrit increased on eighth day, depending on the dose administered. Compared with +/+ mice 10 times more rh-EPO was needed in W/Wv mice to produce an almost equivalent pharmacological effect. In +/+ mice, the CLup of 125I-rh-EPO by spleen increased to 4-fold that of controls after treatment with rh-EPO, 4.8 microg/kg, whereas that by bone marrow remained unchanged, irrespective of the dose administered. On the other hand, the increase in both the Hct and CLup in spleen was minimal in W/Wv mice. The CLup by bone marrow and spleen in both types of mice showed saturation with similar Km values (389-619 pM), comparable with the dissociation constant of the EPO receptor. In addition, the Hct correlated with the sum of the CLup by bone marrow and spleen in both types of mice, and the correlation lines were superimposable. These results suggest that the pharmacological receptors govern the saturable tissue uptake not only in normal mice but also in those that are anemic.
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PMID:Pharmacokinetics of erythropoietin in genetically anemic mice. 945 98

We reviewed clinical and molecular data of 23 consecutive unrelated patients affected by paroxysmal nocturnal hemoglobinuria (PNH) (19 with hemolytic PNH, 3 with aplastic anemia/PNH, and 1 with myelodysplasia/PNH syndrome) with a mean follow-up of 11.8 years. Five patients had thrombotic episodes, and 10 needed regular blood transfusions; 2 died for cerebral hemorrhage and kidney failure, and 2 spontaneously recovered from PNH. Twenty different PIG-A gene mutations were detected in 21/23 patients: 15 frameshift, 1 splicing, 2 nonsense, and 2 missense mutations. Two mutations (DelG341 and IVS2 +1g-a) were detected twice. A PIG-A mutated clone was also revealed in the two patients in complete clinical remission. One patient with aplastic anemia/PNH syndrome was treated with two courses of antilymphocyte globulin and cyclosporin with partial sustained response. Six patients were given rHu-EPO 150 U/kg/day s.c. for at least 6 months: one became transfusion-independent for 8 months and then discontinued treatment for clinical complications; one displayed a mean rise of Hb of 1.5 g/dL and is currently maintaining Hb levels higher than 9 g/dL after 54 months of therapy. Mutation specific quantitative-competitive PCR showed that the rise of hemoglobin was related to an increase of PIG-A negative molecules, suggesting that the efficacy of rHu-EPO therapy may be due to the stimulation of the abnormal clone.
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PMID:Clinical and molecular aspects of 23 patients affected by paroxysmal nocturnal hemoglobinuria. 1530 4

Antithyreoid drugs are known causative agents of agranulocytosis and, in rare cases, aplastic anaemia as well. This is a case report of a female patient with secondary aplastic anaemia developed two years after continual use of thiamazole. She suffered from exhaustion and massive epistaxis. Physical examination revealed pale skin and mucous membranes, skin hematomas (body and legs) and high body temperature--39 degrees C. At admission, her blood film revealed pancytopaenia with 75 g/l hemoglobin concentration, 1.0 x 10(9)/l leukocytes and severe thrombocytopaenia--7.0 x 10(9)/l. Differential count showed 91% of lymphocytes, 1% of monocytes and only 8% of neuthrophils. Bone marrow cytology and pathohistologic findings revealed severe hypocellularity, replaced with fat cells and only 10% of active hematopoietic tissue. In the acute phase of illness, in vitro growth of bone marrow progenitors was completely absent. Treatment was initiated with prednisone and danazol. During that time, she suffered from epistaxis, gastro-intestinal bleeding and herpes infection. Due to therapeutic failure cyclosporine A was added after 21 days. There upon, slow recovery ensued. After two months, she was discharged from hospital with stable blood film findings (HB 83 g/l, WBC 4.6 x 10(9)/l, and PLT 30.0 x 10(9)/l). She was forbidden thiamazole for her life time. After recovery from the acute phase of illness, in vitro haematopoietic precursor cells examination was repeated. The number of CFU-E colonies stimulated with 1 IU EPO was decreased in comparison with the control values. Upon adding 100 micro/l of thiamazole (5 mg/ml concentration e.g. 500 mg per culture), the growth of CFU-E was completely prevented, followed by marked cytotoxicity signs. The treatment including low doses (5 mg/ kg body weight daily) of cyclosporine A administration was continued on outpatient basis. After one year, blood film showed almost normal results with 120 g/l hemoglobin concentration, 4.3x10(9)/l leukocytes and mild thrombocytopaenia 72.0 x 10(9)/l. She was transfusion free.
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PMID:[Aplastic anaemia caused by thiamazole--a case report]. 1549 89


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