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Query: UMLS:C0039730 (thalassemia)
 10,305 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Red blood cell (RBC) membranes from patients with the thalassemic and sickle hemoglobinopathies carry abnormal deposits of iron presumed to mediate a variety of oxidative-induced membrane dysfunctions. We hypothesized that the oral iron chelator deferiprone (L1), which has an enhanced capacity to permeate cell membranes, might be useful in chelating these pathologic iron deposits from intact RBCs. We tested this hypothesis in vitro by incubating L1 with RBCs from 15 patients with thalassemia intermedia and 6 patients with sickle cell anemia. We found that removal of RBC membrane free iron by L1 increased both as a function of time of incubation and L1 concentration. Thus, increasing the time of incubation of thalassemic RBCs with 0.5 mmol/L L1 from 0.5 to 6 hours, enhanced removal of their membrane free iron from 18% +/- 9% to 96% +/- 4%. Dose-response studies showed that incubating thalassemic RBC for 2 hours with L1 concentrations ranging from 0.125 to 0.5 mmol/L resulted in removal of membrane free iron from 28% +/- 15% to 68% +/- 11%. Parallel studies with sickle RBCs showed a similar pattern in time and dose responses. Deferoxamine (DFO), on the other hand, was ineffective in chelating membrane free iron from either thalassemic or sickle RBCs regardless of dose (maximum, 0.333 mmol/L) or time of incubation (maximum, 24 hours). In vivo efficacy of L1 was shown in six thalassemic patients whose RBC membrane free iron decreased by 50% +/- 29% following a 2-week course of L1 at a daily dose of 25 mg/kg. As the dose of L1 was increased to 50 mg/kg/d (n = 5), and then to 75 mg/kg/d (n = 4), 67% +/- 14% and 79% +/- 11%, respectively, of their RBC membrane free iron was removed. L1 therapy--both in vitro and in vivo--also significantly attenuated the malondialdehyde response of thalassemic RBC membranes to in vitro stimulation with peroxide. Remarkably, the heme content of RBC membranes from L1-treated thalassemic patients decreased by 28% +/- 10% during the 3-month study period. These results indicate that L1 can remove pathologic deposits of chelatable iron from thalassemic and sickle RBC membranes, a therapeutic potential not shared by DFO. Furthermore, membrane defects possibly mediated by catalytic iron, such as lipid peroxidation and hemichrome formation, may also be alleviated, at least in part, by L1.
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PMID:Deferiprone (L1) chelates pathologic iron deposits from membranes of intact thalassemic and sickle red blood cells both in vitro and in vivo. 765 28

In summary, it has been shown that orally administered HBED causes enhanced excretion of iron in all of the thalassemia major patients studied and that both urinary and stool iron are increased in the process. Increasing the dose from 40 to 80 mg/kg divided t.i.d. caused iron balance to increase from 38% to 50%. While this is significantly less than that expected based on our preclinical studies in animals, the potential usefulness of this chelator has been demonstrated. Efforts to increase its oral bioavailability are now in progress. Lending further support to the effort is the fact that no evidence of toxicity has been observed in the studies performed to date and that negative iron balance was achieved in the one thalassemia intermedia patient studied. The results also reinforce the conclusion that DFO causes the excretion of substantially more iron than would be predicted by an assessment of serum ferritin levels or past compliance with chelation therapy. In patients with thalassemia major, serum ferritin levels relate more to tissue damage than to body iron load. Effective chelation therapy can diminish the former much faster than it can remove storage iron. Hence, in cases of iron overload, aggressive chelation therapy should not be tapered off until a significant reduction in iron excretion can be demonstrated. Routine measurements of urinary iron excretion should now be considered essential in the management of beta-thalassemia. Finally, two more patients with thalassemia intermedia will be studied in an effort to substantiate that net negative iron balance can be achieved in this subgroup of patients. We also plan to study several transfused patients in whom the dose of HBED will be increased to 120 mg/kg divided t.i.d. While the chances of achieving net negative iron balance in these patients seems remote, we hope to further demonstrate the safety of this drug with an eye toward the development of an effective prodrug.
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PMID:Results from a phase I clinical trial of HBED. 788 41

Desferal, a siderophore of microbial origin is the only drug currently used for clinical treatment of a genetic disorder, thalassemia. By using a combination of HPLC and 31P-NMR, it is demonstrated that the Cu complex of desferal cleaves DNA, the primary site of hydroxyl radical attack being the sugar C1' in the minor groove, which leads to production of 5-methylene furanone. While no C5'-oxidation was observed, a minor process involving C4'-attack accompanies the above cleavage path. The oxidative cleavage of DNA observed with CuDFO may have implications in the emerging applications of desferal as a drug delivery agent and an antimalarial.
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PMID:DNA cleavage by Cu(II)-desferal: identification of C1'-hydroxylation as the initial event for DNA damage. 816 67

In summary, long-term studies of DFO therapy in multiply-transfused patients with beta-thalassemia major have clearly shown it to be generally safe and effective. Appropriate use of DFO can remove excess iron, prevent iron-induced organ damage, and improve survival in thalassemia patients. Patients who begin treatment at a young age can be protected from the lethal complications of iron overload for at least two decades, but chelation therapy may not always prevent or ameliorate late growth failure and/or delayed or absent puberty. Those with iron damage to the heart and possibly other organs may experience stability or improvement in function with intense chelation. High-dose intravenous DFO produces a rapid decrease in hepatic iron content and improved cardiac function but can also cause severe toxicity, as can normal doses in patients with a low iron burden. Continuing studies of DFO are necessary to help further define its long-term efficacy and toxicity. In particular, significant attention should be paid to new strategies aimed at fostering improved compliance with its use.
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PMID:Chelation therapy in beta-thalassemia: the benefits and limitations of desferrioxamine. 856 Feb 88

Desferrioxamine is produced by a type of actinomycetes. It reacts with trivalent iron ions and forms a hydrosoluble complex called ferrioxamine B. This complex is able to remove iron from ferrous protein, but not from hemoglobin. This feature permits its use for the treatment of chronic iron accumulation such as that which occurs in thalassemia. Only two cases of successful desensitization to desferrioxamine hypersensitivity have been previously described. This paper describes a case of desensitization in a six-year-old girl with desferrioxamine hypersensitivity. She suffered from Cooley's disease and had received blood transfusions since the age of three months. From the age of four years, the patient was treated with desferrioxamine, which was interrupted after the occurrence of urticaria-angioedema. Skin and patch tests an in vitro lymphocyte transformation test were negative, indicating a pseudoallergic reaction. The desensitization treatment lasted twenty-one days and, afterwards, the patient was able to tolerate desferrioxamine therapy at the dose previously administered (400 mg/day, subcutaneously).
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PMID:Successful desensitization of a child with desferrioxamine hypersensitivity. 857 39

Deferoxamine chelation therapy (widely used to reduce iron overload in hypertransfused thalassemic patients) has been implicated in causing skeletal growth abnormalities (rachitic-like changes in the long bones and vertebral body flattening), particularly when used in early infancy and at high dose levels. Radiographs of seven hypertransfused and well-chelated patients with thalassemia were reviewed. For two patients, serial films of the spine from the early 1970s to the present revealed a sequence of changes in the vertebral bodies, beginning with normal bodies that became bulbous and subsequently flattened. These two patients had begun deferoxamine chelation therapy early in infancy. The bone changes, though slightly reminiscent of post-radiation changes, are milder and result in a final Scheuermann-like picture.
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PMID:Deferoxamine-induced platyspondyly in hypertransfused thalassemic patients. 857 2

Red blood cells (RBCs) from patients with sickle cell anemia and thalassemia carry abnormal accumulations of molecular Fe(III) at the cytosol/membrane interface. The avidity of the red cell membrane for this iron has not been defined. Using open ghost membranes prepared from sickle RBC, we examined the ability of membrane-associated Fe(III) to resist removal by 15 chelators representing a 40-log range of affinities for Fe(III). Efficacy of chelators was compared with literature values for their idealized affinity for iron as represented by the cummulative stability constant (beta n), their effective stability constant reflecting affinity under biologic conditions (Keff), and an indicator of their ability to chelate Fe(III) in the presence of an insoluble phase of iron (Ksol). Deferoxamine, a very high affinity chelator having log beta n = 30.6, was found to be the lowest affinity chelator able to remove RBC membrane Fe(III). Regardless of chelator beta n, only those agents able to preserve log Keff > or = 12 were able to do so, indicating that the membrane's effective avidity for Fe(III) is on the order of 10(12). Additional confirmation that membrane avidity for Fe(III) is extremely high is found in the observation that only chelators having log Ksol > 0 were effective. Potential physiologic iron chelators in cytoplasm of pathologic red cells are unable to prevent or reverse iron accumulation on the membrane because they do not have sufficiently high affinity for iron. These data argue that RBC membrane Fe(III) is truly pathologic.
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PMID:Extremely high avidity association of Fe(III) with the sickle red cell membrane. 870 94

The objective of this study was to determine the prevalence and possible pathogenesis of scoliosis in beta-thalassemia in our country, and to compare its characteristics to those of patients with idiopathic scoliosis from the same geographic area. Twenty-four [13 male and 11 female thalassemic patients aged 16 +/- 7 years (range 7-32 years)] of 115 examined patients with beta-thalassemia showed scoliosis of 14 degrees +/- 11 (range 10-65 degrees) radiologically. The prevalence of scoliosis in the thalassemic population was 21% in this series, whereas the overall prevalence of scoliosis in the general Greek population was 6% (Smyrnis PN, Valavanis J, Alexopoulos A, Siderakis G, Giannestras NJ: School screening for scoliosis in Athens, J Bone Joint Surg 61B:215-217, 1979). The scoliosis prevalence in the general population was significantly higher in the females (5%) than in the males (1%), whereas no difference in prevalence was found between the two sexes in the thalassemic population. The most common curve pattern in thalassemia was the left lumbar (38%) followed by the right lumbar (21%), whereas in patients with idiopathic scoliosis the left thoracolumbar most commonly appeared (25%) followed by the left lumbar (14%). No patient with thalassemia showed radiographic signs of congenital spinal deformities and spinal fractures, whereas all patients showed a significant retardation of their skeletal maturation. The age of the thalassemic patients with scoliosis was significantly (p = 0.0003) higher than in patients without scoliosis. The hematocrit of the thalassemic patients with scoliosis was significantly (p = 0.0012) lower than in those without scoliosis, whereas the rate of transfusions was not correlated with the magnitude of the scoliosis. The level of ferritin was significantly (p = 0.025) higher in the thalassemic patients with scoliosis than in those without scoliosis. The duration of Desferal treatment was significantly (p = 0.0357) longer in thalassemic patients with scoliosis when compared with those without scoliosis. Thus, the prevalence, curve pattern, and etiology of scoliosis in beta-thalassemia differ from those of idiopathic scoliosis, indicating that the spinal deformities in thalassemia represent a distinct type of scoliosis.
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PMID:Prevalence of scoliosis in beta-thalassemia. 879 87

We investigated the effects of deferoxamine on the differentiation of embryonal carcinoma F9 cells. Deferoxamine, a widely used therapeutic agent for thalassemia and iron overload, was found to induce F9 cell differentiation and to have some unique characteristics compared with other chelators, hinokitiol and dithizone, which were previously reported to induce differentiation of these cells. This hydrophilic agent induced reversible differentiation as did sodium butyrate, whereas other chelators did not. However, morphological features of the cells after deferoxamine-induced differentiation were similar to those of cells incubated with the other chelators. The differentiation-inducing activity of deferoxamine was abolished by preincubation with Fe3+ ions, similarly to the other chelators examined. Moreover, cell proliferation was inhibited by treatment with this agent, and the numbers of cells in the colonies were reduced by apoptosis. Based on these results, we conclude that deferoxamine induces differentiation and apoptosis of F9 cells via chelation of extracellular and/or intracellular Fe3+ ions.
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PMID:Induction of embryonal carcinoma cell differentiation by deferoxamine, a potent therapeutic iron chelator. 920 79

Desferrioxamine (DFX) remains the most effective and safe iron chelator for treatment of patients with transfusional iron overload. It is usually given by intermittent subcutaneous infusions for 8-12 h on 4-6 days weekly using a battery-driven pump. Disposable balloon infusers provide a suitable method of giving continuous subcutaneous infusions with improved patient compliance. For patients with cardiac abnormalities due to iron overload, continuous intravenous desferrioxamine is essential to eliminate toxic plasma non-transferrin bound iron and to reduce body iron stores. Deferiprone (L1, l-2 dimethyl-3hydroxy-pyrid-4-one) is a less effective iron chelator but has the advantage of being orally active. Long-term trials in which patients have taken 75 mg/kg/day have shown that deferiprone is capable of maintaining body iron stores at safe levels in a proportion of thalassaemia major patients but body iron stores, assessed by liver biopsy remain at high levels (> 15.0 mg/g dry weight) in a substantial number of patients. These concentrations have been associated with tissue damage. Trials of increased doses of deferiprone (up to 100 mg/kg/day) or of combined therapy with daily deferiprone and DFX or 1 or 2 days each week are being carried out in an attempt to achieve lower body iron burden in these patients. Preliminary results show that the drugs can be given safely together and urine iron excretion produced is additive, implying that the drugs chelate different body iron pools. Patients previously well chelated with serum ferritin levels less than 2500 micrograms/L have the fewest side-effects from deferiprone and usually may be kept at the same level of body iron for periods of at least 4 years, assessed by serum ferritin and urine iron excretion. The side-effects of deferiprone result in some patients discontinuing therapy. These side-effects, especially arthropathy, mainly occur in previously poorly chelated and so the most heavily iron-loaded patients. Nausea and other gastrointestinal symptoms, agranulocytosis or milder degrees of neutropenia account with arthropathy for nearly all the withdrawals from deferiprone therapy. Patients with cardiomyopathy due to iron overload should be given intravenous DFX rather than deferiprone. Deferiprone, licensed for pharmaceutical use in India, awaits official approval for widespread clinical use in Western Europe and North America. Meanwhile, attempts to find new orally active iron chelators and improved methods of administration of desferrioxamine are in progress.
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PMID:Iron chelation therapy. 935 Jan 80


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