Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0039730 (thalassemia)
 10,305 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hydroxyurea (HU), a widely used cytostatic, has been given over a long period of time to 14 adult Caucasian compound heterozygotes for beta s and various beta-thalassaemia genes. All patients had severe pain crises and other complications prior to receiving the drug. After 4-8 weeks on high 'sub-toxic' doses of HU all patients responded with a multifold increase of fetal haemoglobin (HbF) and a marked increase of MCV and MCH; they also felt significantly better and ceased having pains or other complaints. Haematological toxicity was minimal and rapidly reversible. Follow-up of the patients has now exceeded 100 weeks and goes up to 180 weeks in two of them. Pain crises have never recurred. Maintenance of high levels of HBF requires continuous administration of high doses of HU; whenever the latter were decrease in various attempts to avoid potential long-term toxicity, the observed changes gradually faded. The effect of HU in HbS/beta-thalassaemia may be better than that reported for homozygous HbS disease because the synthesized gamma-chains not only inhibit the sickling process but they also neutralize the noxious effects of the excess alpha-chains and cut down the ineffective erythropoiesis of the patients.
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PMID:Clinical and laboratory effects of long-term administration of hydroxyurea to patients with sickle-cell/beta-thalassaemia. 753 27

The beta-thalassaemias represent a heterogenous group of diseases resulting from decreased erythroid beta-globin mRNA expression and imbalanced alpha/beta-globin chain synthesis which are manifest clinically by ineffective erythropoiesis and excessive haemolysis. Increasing levels of haemoglobin F (HbF) by pharmacological agents has been proposed to ameliorate the severity of the disease by improving the balance in globin chain synthesis. Hydroxyurea (HU), as an effective agent with low toxicity for activating gamma-globin gene, has been shown to enhance HbF synthesis in experimental animals and in patients with sickle cell anaemia. However, previous trials of HU in beta-thalassaemia patients are ambiguous, with a small number having increased HbF synthesis. In a recent study of HU effects in Chinese beta-thalassaemia patients we unexpectedly found that two unrelated patients with beta-thalassaemia intermedia demonstrated an improvement in the effectiveness of erythropoiesis reflected by an increase in haemoglobin concentration (from 4.1 to 6.3 g/dl, patient 1; from 6.5 to 9.7 g/dl, patient 2) and in red cell volume (from 68 to 104 fl, patient 1; from 68 to 85 fl, patient 2) after a period of excess of 300d of low-dosage HU treatment. These effects, however, appear to be due to increased beta-globin biosynthesis, because the percentage of HbF decreased in each patient as total Hb increased. This was reflected by changes in the beta/alpha ratio (from 0.301 to 0.581, patient 1; from 0.348 to 0.487, patient 2) with minimal changes in gamma-globin biosynthesis. We conclude that in addition to its known effects in stimulating gamma-globin production, hydroxyurea may have a more general role in augmenting globin synthesis, including beta-globin in some thalassaemia intermedia patients who maintain the capacity to express normal beta-globin chains.
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PMID:Hydroxyurea therapy in beta-thalassaemia intermedia: improvement in haematological parameters due to enhanced beta-globin synthesis. 764 94

Hydroxyurea (HU), an inhibitor of DNA synthesis, has been shown to increase fetal hemoglobin (HbF) levels in patients with sickle cell anemia and in some patients with beta-thalassemia. However, until now there have not been good in vitro model systems that simulate this effect for study of the molecular and cellular mechanism(s) involved in perturbing the normal ontogeny of the globin genes. We analyzed the cellular effects of HU using a two-phase liquid culture procedure (Fibach et al: Blood 73:100, 1989) in which human peripheral blood-derived progenitor cells undergo proliferation and differentiation. HU was found to have multiple effects on these cultured cells: (1) an increase in the proportion of HbF produced; (2) a decrease in cell number due to inhibition of cell proliferation; (3) an increase in hemoglobin content per cell (mean corpuscular hemoglobin [MCH]); and (4) an increase in cell size (mean corpuscular volume). The extent of these effects was related to the HU dose and time of addition. When added to cell cultures from normal individuals, 4 days following their exposure to erythropoietin (EPO), 100 mumol/L HU caused a 1.3- to 3.5-fold increase in the proportion of HbF, from 0.4% to 5.2% (mean 1.6) in untreated to 1.5% to 8.2% (mean 3.1) in HU-treated cultures and a 45% +/- 10% increase in MCH but only a 25% +/- 7% decrease in cell number on day 13. Cultures of cells derived from five patients with sickle cell anemia have shown a twofold to fivefold increase in the percentage of Hb F following addition of HU while four patients with beta-thalassemia showed a 1.3- to 6.2-fold increase. We believe that this primary cell culture procedure should prove useful in studying the cellular and molecular mechanisms of pharmacologic induction of HbF and might provide a valuable predictive assay system for evaluation of the response of individual patients with hemoglobinopathies to HU and similar agents.
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PMID:Hydroxyurea increases fetal hemoglobin in cultured erythroid cells derived from normal individuals and patients with sickle cell anemia or beta-thalassemia. 768 Sep 23

Hydroxyurea (HU) is one of several agents that have been shown to enhance hemoglobin (Hb) F levels in patients with sickle cell disease and may be useful as a therapy for beta-globinopathies. However, limited information exists on the effects of HU in patients with thalassemia. Accordingly, we examined the hematologic effects of orally administered HU in 13 patients with beta-thalassemia/Hb E, including four patients who had been splenectomized. These patients were treated with escalating doses (final range, 10 to 20 mg/kg/d) for 5 months and were observed in the outpatient hematology clinic every 2 to 4 weeks. Complete blood counts including reticulocyte counts, amounts of Hb E and Hb F, G gamma:A gamma and alpha:non-alpha globin biosynthetic ratios were evaluated before and during treatment. Almost all patients responded with an average increase of 33% in Hb F levels, from a mean (+/- SD) of 42% +/- 11% to 56% +/- 8% (P < .0001), and a reciprocal decline in the percentage of Hb E from 59% +/- 9% to 49% +/- 8% (P < .001). Reticulocytosis was decreased from a mean (+/- SD) of 18.0% +/- 15.6% to 11.7% +/- 9.1% (P < .05); there was also a slight (10%) but statistically significant increase in hemoglobin levels and an improved balance in alpha:non-alpha globin chains ratios. The side effects were minimal in most patients, although these patients tended to tolerate a lower dose of HU before significant myelosuppression than has been our previous experience in sickle cell disease. One splenectomized patient died of sepsis during the trial. We conclude that increased Hb F production in beta-thalassemia/Hb E patients, with an improvement in the alpha:non-alpha globin ratios and, probably, the effectiveness of erythropoiesis, can be achieved using HU. Longer trials of HU in this population, including at other doses and in combination with other agents, appear warranted.
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PMID:Hydroxyurea increases hemoglobin F levels and improves the effectiveness of erythropoiesis in beta-thalassemia/hemoglobin E disease. 856 58

Hydroxyurea (HU) is the first widely used treatment to have an impact on the severity of disease in adult patients with sickle cell anemia, but limited data are available for younger patients or those with variant genotypes. We reviewed 324 months of experience with HU in 16 patients from 5.3 to 18.4 years of age treated for 6 to 50 months. The major toxicity was reversible neutropenia. Linear growth continued unchanged, and all patients gained weight. Hematologic results were similar to those reported in adults with increases in mean corpuscular volume (MCV) and total and fetal hemoglobin (HbF). We noted that the maximal hematologic effects occurred at less than the maximum dose. Clinically, patients experienced an 80% reduction in episodes of acute chest syndrome and a reduced need for blood transfusion, as well as a 30% decrease in the number of hospitalizations for painful events during HU therapy compared with an equivalent number of months before HU. These highly statistically significant results confirmed the value of HU in ameliorating the severe clinical course of pediatric patients. Similar effects were observed in three patients with sickle beta degrees-thalassemia, sickle beta+-thalassemia, and S-O Arab. Recurrent acute splenic sequestration and progressive symptomatic osteonecrosis were observed during HU. Thus, HU may not prevent the development of complications once organ damage is present. The challenge remains to determine when and to which pediatric patients with sickle cell disease HU should be offered.
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PMID:Hydroxyurea therapy for diverse pediatric populations with sickle cell disease. 931

Hydroxyurea increases fetal haemoglobin in many patients with sickle cell anaemia, but its effectiveness in thalassaemia appears to be less consistent. We describe the response to hydroxyurea in an adult male with homozygous beta thalassaemia, symptomatic paraspinal extramedullary haemopoiesis, bone pain, and progressive tissue iron loading. Prior to therapy with hydroxyurea the circulating haemoglobin (Hb) concentration was 7.0 g/dl and absolute fetal haemoglobin concentration was 5.0 g/dl. Administration of sodium phenylbutyrate had induced no increase in either parameter. Subsequent therapy with hydroxyurea was associated with increases in total haemoglobin to 9.0 g/dl, and in fetal haemoglobin to 7.6 g/dl. Ineffective erythropoiesis was reduced and extramedullary haemopoiesis regressed during therapy.
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PMID:Regression of extramedullary haemopoiesis and augmentation of fetal haemoglobin concentration during hydroxyurea therapy in beta thalassaemia. 963 80

The clinical effectiveness of Hydroxyurea in thalassemia is still controversial. The present paper puts together the authors' experience in two groups of patients with thalassemia intermedia and sickle cell/beta-thalassemia treated with varying dosages of hydroxyurea over several months. A third group received hydroxyurea along with recombinant human erythropoietin. Our observations are summarized in that treatment with hydroxyrea results in a significant increase of fetal hemoglobin with no change of the total hemoglobin levels. The drug causes also a considerable increase of the erythrocyte volume and hemoglobin content while the MCHC values remain unchanged. As a rule, and without objective criteria so far, patients state feeling better and having more energy. The authors postulate that this feeling may reflect the significant decrease of ineffective erythropoiesis resulting by the replacement of the poorly hemoglobinized, prematurely dying erythroid progenitor and red cell population by another population of cells with higher hemoglobin content and longer survival, the regeneration of which requires less energy and consumption. As expected, patients with sickle cell/beta-thalassemia have also fewer crises and painful episodes. The above findings are in keeping with the few available reports in the literature.
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PMID:Hydroxyurea therapy in thalassemia. 966 34

Hydroxyurea (HU) and sodium phenylbutyrate (SPB) have been shown to increase fetal hemoglobin (Hb F) levels in patients with thalassemia intermedia. The reported effects of these agents in increasing total Hb, however, have been inconsistent and there have been no studies on the combination of these medications. We describe the clinical response, as determined by increases in total Hb and decreased transfusion needs, in five patients with thalassemia intermedia treated with HU alone or in combination with SPB. All of the patients responded with increased levels of Hb F, but the responses in total Hb varied. Of the five patients, two had a marked response in total Hb in excess of 3 g/dl, two responded modestly with an increase in total Hb of 1-2 g/dl, and one did not respond. Prolonged responses were achieved with low doses of HU (3-10 mg/kg/day) and higher doses were associated with mild reversible hematologic or hepatic toxicity and no further increases in Hb. Sodium phenylbutyrate was added to treatment with HU in two patients, but failed to produce an increase in total Hb despite increasing Hb F levels. Of the four patients who responded to HU with an increase in total Hb, all reported symptomatic improvement and three have not required further transfusions. We conclude that low-dose HU therapy in patients with thalassemia intermedia may increase total Hb levels sufficiently to eliminate the need for transfusions. We, therefore, recommend a trial of HU for thalassemia intermedia patients in whom chronic transfusion therapy is being contemplated.
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PMID:Hydroxyurea and sodium phenylbutyrate therapy in thalassemia intermedia. 1058 77

Collectively sickle cell disease and beta-thalassaemia are the most commonly inherited single-gene defects world-wide and were the first group of diseases for which DNA-based detection strategies were utilized. Although genotypically distinct, these two groups of diseases exhibit several common clinical features: moderate-to-severe haemolytic anaemia, acute and progressive tissue damage, disease- or treatment-related organ failure and premature death. Within the last two decades, a striking improvement in life expectancy in the two patient populations has been observed, by dint of primary and secondary prevention strategies. However, apart from bone marrow transplantation, a generally applicable, specific and non-toxic form of treatment remains unavailable for these disorders. Nonetheless, a greater appreciation of the developmental control of human globin gene expression coupled with observations of the effects of certain classes of agents to 'reverse' erythroid cellular phenotype in in vitro and animal models have led to pharmacological trials to obtain meaningful increases in haemoglobin F production in patients affected by these two severe beta-globin disorders. Contemporary understanding of the quantitative relationship between the abnormal molecules in the red cells (aggregates of sickle haemoglobin) in the sickle cell syndromes and aggregated alpha-globin polypeptides in the beta-thalassemia syndromes, and the extent of the red cell and/or organ involvement, has now enabled investigators to predict how much inhibition of these intracellular pathogenic processes might be necessary to achieve partial or total abrogation of disease manifestations. The results of the Multicenter Study of Hydroxyurea and other controlled trials now bear out these predictions.
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PMID:Pharmacological therapy. 1087 80

Hydroxyurea (HU) is an oral drug that ameliorates the clinical course of sickle cell anemia by increasing the levels of fetal hemoglobin and decreasing the adhesion of red cells to endothelium. Although HU has minimal short-term toxicity, few data are available about the long-term safety and the potential risk for carcinogenesis or leukemogenesis. An 8-year-old child with sickle cell/beta 0-thalassemia who received HU treatment for painful crises is described. Six months after the initiation of the HU treatment he developed Hodgkin's disease, lymphocyte predominance subtype. Chemotherapy induced a complete remission. After discontinuation of chemotherapy the painful crises recurred and bone marrow transplantation was decided at the age of 12 years. Two years after the bone marrow transplantation, the child is in complete remission without painful crises. Although the authors suggest that the development of Hodgkin's disease is a coexisting event, questions arise about the safety of HU treatment in childhood.
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PMID:Hodgkin's disease in a child with sickle cell disease treated with hydroxyurea. 1155 31


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