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)

The long-term efficacy and toxicity of hydroxyurea for infants are undefined, and its role in preventing organ dysfunction is unknown. Short-term feasibility of hydroxyurea administration, toxicities, hematologic effects, and effect on spleen function in infants with sickle cell anemia (SCA) were reported (Hydroxyurea Safety and Organ Toxicity [HUSOFT] trial). These infants completing 2 years of hydroxyurea therapy (20 mg/kg/d) were offered study extension with dose escalation to 30 mg/kg/d. Patients were monitored with laboratory tests and biannual imaging studies. Hematologic indices were compared with predicted age-specific values and event rates compared with historic rates. All 21 subjects completing the original trial enrolled in the extension study: median age, 3.4 years old (range, 2.6 to 4.4 years); 12 females; 20 with Hb SS, 1 with Hb S/beta0-thalassemia. Seventeen patients completed 4 years of hydroxyurea, and 11 completed 6 years. After 4 years, hydroxyurea was associated with increased hemoglobin concentration, percentage of fetal hemoglobin (Hb F), and mean corpuscular volume (MCV) and decreased reticulocytes, white blood cells (WBCs), and platelets (P < .01). Patients experienced 7.5 acute chest syndrome (ACS) events per 100 person-years, compared with 24.5 events per 100 person-years among historic controls (P = .001). Treated patients had better spleen function than expected and improved growth rates. Infants with SCA tolerate prolonged hydroxyurea therapy with sustained hematologic benefits, fewer ACS events, improved growth, and possibly preserved organ function.
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PMID:Long-term hydroxyurea therapy for infants with sickle cell anemia: the HUSOFT extension study. 1617 53

Patients with E/beta(0) thalassaemia, the most common haemoglobinopathy in many Asian countries, might benefit from drugs that increase fetal and total haemoglobin and thereby decrease the need for transfusions. The long-term clinical efficacy and safety of such therapy is unknown, limiting its use in countries where resources for safe and regular transfusion are scarce. In this study, 45 patients were treated with hydroxyurea (18-20 mg/kg) for 24+/-9 months, hydroxyurea with sodium phenyl butyrate (n=8) and hydroxyurea with erythropoietin (n=9), each for approximately 6 months, and followed for 3 years from study exit. Hydroxyurea had minimal toxicity, resulted in a mean 1.3 g/dl steady-state increase in haemoglobin in 40% of patients, and a milder response (<OR=1 g/dl) in the others. Baseline haemoglobin F was significantly associated with an increase in haemoglobin (P<0.001). Combined treatment with erythropoietin benefited selected patients, but the addition of sodium phenyl butyrate had no effect. Of the 27/45 patients who discontinued regular transfusions before the study, 13 remained transfusion independent during long-term follow-up, 6/13 continued hydroxyurea. Hydroxyurea moderately increased steady-state haemoglobin in a sub-group of E/beta(0) thalassaemia patients and can be considered for patients with intermediate severity disease, thus delaying or avoiding the need for life-long transfusions. Continuous monitoring of toxicity and growth is required.
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PMID:Fetal haemoglobin augmentation in E/beta(0) thalassaemia: clinical and haematological outcome. 1622 58

Patients with hemoglobin E (Hb E)-beta 0-thalassemia, one of the most common hemoglobinopathies worldwide, could benefit from drugs that increase fetal and total hemoglobin levels and thereby decrease the need for transfusions. The long-term clinical outcome of such therapy, its hematologic effects, and which patients are likely to benefit from treatment are unknown. Consequently, the use of such drugs for Hb E-beta 0-thalassemia is limited, and countries where resources for safe and regular transfusion are scarce cannot benefit from them. In a multicenter trial of 42 patients treated with hydroxyurea for two years, almost half the patients demonstrated a significant increase in steady-state hemoglobin level. Drug toxicity was minimal. Combined treatment of hydroxyurea with erythropoietin benefited selected patients, but the addition of sodium phenyl butyrate was ineffective. After 5 years of follow-up, a subset of patients remained off transfusions. Hydroxyurea should be considered for a subset of Hb E-beta 0-thalassemia patients.
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PMID:Single and combination drug therapy for fetal hemoglobin augmentation in hemoglobin E-beta 0-thalassemia: Considerations for treatment. 1633 72

Reactivation of fetal hemoglobin (HbF) expression is an important therapeutic option in patients with hemoglobin disorders. In sickle cell disease (SCD), an increase in HbF would interfere with the polymerization of sickle hemoglobin while in beta-thalassemia, an increase in gamma-globin chain synthesis would decrease non-alpha:alpha chain imbalance. Hydroxyurea, an inducer of HbF, is the only currently approved agent for the treatment of patients with moderate and/or severe SCD. However, about one third of patients with SCD do not respond to HU, and in beta-thalassemia, the clinical response is unimpressive. The last decade has seen a renewed interest in the use of inhibitors of DNA methylation in the treatment of patients with hemoglobin disorders. In this review, we discuss the role of DNA methylation in gamma-globin gene regulation, describe clinical trials with agents that hypomethylate DNA and speculate about the future role of DNA hypomethylation therapy in patients with SCD and beta-thalassemia.
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PMID:DNA hypomethylation therapy for hemoglobin disorders: molecular mechanisms and clinical applications. 1651 30

beta-thalassemia major is the most common monogenic hereditary blood disease in children. beta+-thalassemia major gene frequency in Georgia averages 0,019 (3,79% gene carriers). Hydroxyurea (HU) has been known to cause induction of fetal hemoglobin (HbF), but the efficacy of this treatment in beta-thalassemia patients is still unclear. This study was undertaken to evaluate the clinical and hematologic responses in patients with beta+-thalassemia to treatment with HU during 5 years in Georgia. Six children, aged 8 years to 13 years with transfusion-dependent beta+-thalassemia phenotype were enrolled in a trial to assess the response to HU therapy. Hemoglobin, reticulocyte count, HbF and ferritin were evaluated. The starting dose of HU was 5 mg/kg per day (5 days week) given orally once a day. Response to therapy was evaluated at 1, 2, and 5 years of treatment. Clinical improvement and rise in the HbF levels was observed in all patients. We report three cases of a remarkable response to treatment with HU in which the red cell transfusion was stopped after 1 year of treatment, and the patients became completely transfusion-free for more than 5 years. A moderate response was seen in two patients, who remained transfusion-dependent, but at longer intervals. There was no serious complication of treatment with HU. Long-term HU therapy may correct the anemia and can eliminate or minimize the transfusional needs in children with beta+-thalassemia major in cases, when the patient's baseline HbF level is > or =15% and its increase during the treatment is up to 20%.
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PMID:Hematologic response to hydroxyurea therapy in children with beta-thalassemia major. 1840 19

For the majority of children with beta- hemoglobinopathies and -thalassemias who do not have a transplant donor, survival is shortened and morbidity is high. Hydroxyurea, EPO preparations, sodium phenylbutyrate, arginine butyrate, and 5-azacytidine/decitabine have shown efficacy in approximately 40% to 70% of sickle cell and beta-thalassemia patients. Many responses, although significant, were not completely ameliorating of symptoms or pathology, and trials of new agents with dual actions, or drug combinations, are needed. Ideally, limiting chemotherapeutic exposure is desirable for long-term treatment of children, and an oral therapeutic at tolerable doses is necessary for practical use. A new oral therapeutic candidate that induces fetal hemoglobin production and also stimulates erythropoiesis is entering clinical evaluation. Use of agents that should have additive or synergistic effects in combination, such as EPO and hydroxyurea or a short-chain fatty acid derivative (SCFAD), offer better therapeutic potential than hydroxyurea alone. Childhood is an optimal time to introduce such therapies, particularly the non-mutagenic SCFADs, while the erythroid marrow reserve is preserved and before organ damage has become widespread. A challenge for successful application of these therapies is to define patient subsets that are most likely to respond to a particular agent, or which require combination therapies, and to develop optimal dose regimens in thalassemias with rapid erythroid apoptosis. Development of this therapeutic avenue will require close collaboration among treating and academic physicians, families and patients, funding agencies, and researchers.
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PMID:Fetal globin stimulant therapies in the beta-hemoglobinopathies: principles and current potential. 1854 45

Hydroxycarbamide (HC), although a key drug therapy in sickle cell disease (SCD), does not result in a clinical response in all patients. Increases in fetal haemoglobin (HbF) and mean corpuscular volume of erythrocytes are standard clinical measures of HC efficacy in SCD. Genetic studies have determined that the majority of HbF regulation occurs outside the beta-globin locus. Approximately 30% of SCD patients have co-inherited alpha-thalassaemia resulting in hypochromic and microcytic erythrocytes. We provide data from 30 SCD patients (10 with alpha-thalassaemia) demonstrating that co-existing alpha-thalassaemia significantly affects several standard measures of HC efficacy in SCD.
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PMID:The presence of alpha-thalassaemia trait blunts the response to hydroxycarbamide in patients with sickle cell disease. 1876 67

There is clinical variability in the presentation of sickle cell disease among Indians. Vaso-occlusive crisis is common among non-tribal patients. Hydroxyurea, induces fetal hemoglobin (HbF) synthesis and reduces the clinical severity of sickle cell disease but individual patients have a variable response. This study was undertaken to investigate the efficacy and safety of hydroxyurea in Indians with severe manifestations where the beta(s) gene is linked to the Arab-Indian haplotype and is associated with higher HbF levels. Seventy-seven patients (29 adult sickle homozygous, 25 pediatric sickle homozygous, 23 adult sickle beta-thalassemia) selected for hydroxyurea therapy were evaluated for clinical, hematological, biochemical and genetic parameters and were followed for 24 months. Ninety-eight point seven percent of the sickle chromosomes were linked to the Arab-Indian haplotype, 27% of patients had associated alpha thalassemia and 65% were Xmn I +/+. Seventy-eight percent of the patients had no further crises after starting hydroxyurea. This effect was accompanied by a significant increase in HbF (p<0.001), but this increase was variable in individual cases. There was also an increase in gamma gene mRNA expression in the few cases so studied. Hemoglobin levels increased significantly (p<0.001) resulting in the cessation of blood transfusions. Leucopoenia was observed in one patient. Hydroxyurea was effective in reducing the clinical severity in Indian patients who initially had higher HbF levels and the presence of ameliorating factors, such as alpha-thalassemia and the Xmn I polymorphism. Hydroxyurea therapy with careful monitoring can thus change the quality of life of Indians with sickle cell disease.
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PMID:Hydroxyurea in sickle cell disease--a study of clinico-pharmacological efficacy in the Indian haplotype. 1895 99

Major thalassemia is one of the most common hemoglobinopathies in many Asian countries including Iran. Pharmacologic agents such as hydroxyurea have been known to enhance the production of fetal hemoglobin, and also an increase in total hemoglobin level has been repeatedly reported during hydroxyurea treatment in patients with sickle cell disease and in several patients with intermediate beta-thalassemia. We evaluated the long-term efficacy and safety of hydroxyurea in major beta-thalassemic patients. Forty-nine beta-thalassemic patients enrolled in the study. The mean follow-up time was 60 months. The mean dose of hydroxyurea was 10 mg/kg per day (8-15 mg/kg). Before starting hydroxyurea, all patients underwent routine biochemical laboratory tests. Patients with low platelet count (<100,000/mm3), neutropenia (polymorphonuclear neutrophil<1,200/mm3), pregnancy, and on interferon treatment were excluded.Twenty-eight out of 49 enrolled patients were females with the mean age of 18.38 years (10-40 years). The mean packed red cell transfusions during one year before starting of hydroxyurea was 22.75 units which decreased to 6.02 units after treatment (P<0.01). The mean ferritin level during the first period was 2751.44 ng/mL, but decreased to 1594.20 ng/mL after one year of hydroxyurea therapy (P<0.001).We observed a substantial and persistent increase in hemoglobin level and a significant decrease in blood transfusion. Hydroxyurea treatment was well-tolerated and it did not cause any hematopoietic suppression except in one patient who developed transient thrombocytopenia which resolved after short period of hydroxyurea cessation. We did not encounter any malignancies including leukemia in the five-year follow-up.
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PMID:Hydroxyurea therapy in 49 patients with major beta-thalassemia. 1940 Jun 8

The National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (CERHR) conducted an evaluation of the potential for hydroxyurea to cause adverse effects on reproduction and development in humans. Hydroxyurea is a drug used to treat cancer, sickle cell disease, and thalassemia. It is the only treatment for sickle cell disease in children, aside from blood transfusion and, in severe cases, hematopoietic stem cell transplantation. Hydroxyurea is FDA-approved for use in adults with sickle cell anemia to reduce the frequency of painful crises and the need for blood transfusions. Hydroxyurea may be given to children and adults with sickle cell disease for an extended period of time or for repeated cycles of therapy. Treatment with hydroxyurea is associated with known side effects such as cytotoxicity and myelosuppression, and hydroxyurea is genotoxic (can damage DNA). CERHR selected hydroxyurea for evaluation because of: its increasing use for treatment of sickle cell disease in children and adults, knowledge that it inhibits DNA synthesis and is cytotoxic, and published evidence of reproductive and developmental toxicity in rodents. The results of this evaluation are published in the NTP-CERHR Monograph on Hydroxyurea, which includes the NTP Brief and Expert Panel Report on the Reproductive and Developmental Toxicity of Hydroxyurea. Additional information related to the evaluation process, including public comments received on the draft NTP Brief and the final expert panel report, are available on the CERHR website (http:// cerhr.niehs.nih.gov/). See hydroxyurea under "CERHR Chemicals" on the homepage or go directly to http://cerhr.niehs.nih.gov/chemicals/hydroxyurea/hydroxyurea-eval.html). The NTP reached the following conclusions on the possible effects of exposure to hydroxyurea on human reproduction or development. The possible levels of concern, from lowest to highest, are negligible concern, minimal concern, some concern, concern, and serious concern. The NTP expresses serious concern that exposure of men to therapeutic doses of hydroxyurea may adversely affect sperm production. This level of concern is for all males who have reached puberty. The NTP concurs with the Expert Panel that there is concern that exposure of pregnant women to hydroxyurea may result in birth defects, abnormalities of fetal growth, or abnormal postnatal development in offspring. The NTP concurs with the Expert Panel that there is minimal concern that exposure of children to therapeutic doses of hydroxyurea at 5 -15 years of age will adversely affect growth. NTP will transmit the NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Hydroxyurea to federal and state agencies, interested parties, and the public and make it available in electronic PDF format on the CERHR web site (http://cerhr niehs nih gov) and in printed text or CD from CERHR.
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PMID:NTP-CERHR monograph on the potential human reproductive and developmental effects of hydroxyurea. 1940 58


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