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)

Given the mortality and morbidity associated with acute iron intoxication, effective iron chelation which is easily administered in an emergency situation would be ideal. The pharmacokinetics of L1 were examined in 5 healthy adult male volunteers to assess its potential for use in acute iron overload. Ferrous sulfate (600 mg), L1 (900 mg), and ferrous sulfate and L1 were administered on three separate days, each one week apart. On each test day, blood samples were collected at regular intervals for the measurement of plasma L1 and total iron. Pharmacokinetic values were calculated. The data were also compared to that obtained in 10 patients with beta-thalassemia and chronic iron overload. In the normal volunteers, a 20% decrease in the area under the concentration time curve of plasma iron and of plasma L1 was demonstrated when they were co-administered. There was no change in urinary iron excretion when L1 was given with iron (p = 0.414). The elimination half-life of L1 in the thalassemia patients (137.65 +/- 48.65 min) was significantly longer than that in the healthy volunteers (77.56 +/- 13.0) (p = 0.0047) due to larger apparent volume of distribution. In all of the iron-overloaded individuals L1 resulted in increased urinary iron excretion. None of the other pharmacokinetic variables compared were significantly different between these two groups. These studies indicate that at levels below saturation, transferrin does not allow L1 to remove absorbed iron in healthy volunteers, whereas in thalassemia patients, who are beyond saturation of their iron binding capacity, the drug binds iron and promotes its excretion.
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PMID:Comparison of the pharmacokinetics of 1,2-dimethyl-3-hydroxypyrid-4-one (L1) in healthy volunteers, with and without co-administration of ferrous sulfate, to thalassemia patients. 831 62

Fifteen thalassemia intermedia patients were considered, whose clinical and radiological findings were examined and compared. Eight patients underwent regular transfusion therapy. All patients underwent total body CT: the volume of ectopic erythropoiesis foci was calculated by a digital calculation algorithm (ROI volume). This work was aimed at correlating the quantitative measures of ectopic erythropoiesis assessed by CT with serum level of erythropoietin (EPO) and of trasferrin-free receptors (TfR) in both transfused and non-transfused patients, also considering the volume changes of ectopic erythropoiesis and bone changes over 36 months' follow-up. A direct correlation was demonstrated between serum transferrin and ectopic erythropoietic masses in transfusion-dependent patients: in fact, increased values of serum transferrin correspond to the enlargement of these masses and to bone lesion worsening.
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PMID:[Clinico-radiological correlation in thalassemia intermedia]. 832 57

High total haemoglobin levels in homozygous sickle cell (SS) disease are a risk factor for painful crises, avascular necrosis of the femoral head, proliferative sickle retinopathy, and the acute chest syndrome. Since lowering the haemoglobin level may ameliorate these features, understanding the determinants of total haemoglobin may be of practical importance. A range of possible determinants including red cell characteristics, reticulocytes, serum iron, transferrin saturation, serum ferritin, alpha thalassaemia status, red cell mass and plasma volume, oxygen affinity, red cell survival, transferrin receptor and erythropoietin levels have been measured in 62 patients selected to provide a range of total haemoglobin and fetal haemoglobin levels. There were weak negative associations of haemoglobin with mean cell volume and mean cell haemoglobin concentration, strong negative associations with proportional reticulocyte counts, oxygen affinity, plasma volume, serum transferrin receptors, and erythropoietin levels and strong positive associations with red cell mass. Weighted analysis suggested that the statistically independent determinants of haemoglobin level were alpha thalassaemia, sex, red cell mass/body weight, plasma volume/body weight, fetal haemoglobin, and red cell count. The apparent contributions of red cell survival, P50, reticulocyte count, serum transferrin receptor and erythropoietin levels were explained by the effects of these other variables. The independent determinants as a group explained 91% of the variation in haemoglobin level.
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PMID:Determinants of haemoglobin level in steady-state homozygous sickle cell disease. 856 87

The rapidity and duration of the response of non-transferrin-bound iron (NTBPI) to chelation therapy are largely unknown and have important implications for the design of optimal chelation regimens. Methodology was developed to measure simultaneously NTBPI, deferoxamine (DFO), and its major metabolite. NTBPI was present in all but 2 of 28 thalassaemia major (TM) patients who had received conventional subcutaneous DFO the previous night, suggesting a short duration of NTBPI clearance by DFO. The detailed kinetics of NTBPI were therefore studied in response to intravenous DFO at 50 mg/kg/27 h for 48 hours and compared in 17 regularly transfused TM and 8 untransfused thalassaemia intermedia (TI) patients to determine the influence of hypertransfusion and iron overload on NTBPI response. Before DFO infusion, NTBPI was present in all patients and was significantly higher in TI (4.52 +/- 0.53 mumol/L) than TM (2.92 +/- 0.03 mumol/L; P = .03). NTBPI values in TM correlated with transferrin saturation (r = .6, P = .03) but not with serum ferritin. Removal of NTBPI by intravenous DFO is in a biphasic manner. The initial rapid rate constant (alpha) was similar in TI (1.5 hour-1) and TM (1.6 hour-1), but the subsequent beta phase was slower (0.04 hour-1) in TI when compared with TM (0.4 hour-1, P = .002). Detectable NTBPI persisted during the beta phase, particularly in TI, despite an excess of plasma DFO also being present (steady state 8 mumol/L). On cessation of DFO infusion, NTBPI reappearance was rapid; the kinetics also being biphasic. The rapid initial rate constant (alpha = 2.5 hour-1) lasted less than 30 minutes and was approximately equal to the summation of the initial rate constant for removal of DFO (1.8 hour-1) and its major metabolite (0.6 hour-1). This was followed by a slower return to pretreatment levels, usually between 6 and 12 hours, which was faster in TI than in TM. This marked NTBPI lability supports the use of continuous rather than intermittent DFO in high risk patients.
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PMID:Kinetics of removal and reappearance of non-transferrin-bound plasma iron with deferoxamine therapy. 869 19

Microcytosis is a highly prevalent finding during blood examination. This study investigates the causes of microcytosis (defined as mean corpuscular volume (MCV) < 82 fl) in 466 patients referred to our laboratory for suspected hemoglobinopathy. The following data were obtained: Hb, MCV, serum iron, transferrin, ferritin, HbA2, HbF, isoelectric focusing of the Hb, gene mapping of chromosome 16 with Xba I and Bgl II and hybridization with an alpha- and a zeta-probe, inflammatory status. Results show that iron deficiency remains the first cause of microcytosis (35.2% of our patients), even in a selected population such as ours. Deletional alpha-thalassemia, probably the most frequent hemoglobinopathy throughout the world, represents the second most frequent cause of microcytosis (31.1%), followed by beta-thalassemia heterozygous state (18.9%). Of our patients, 1.3% had microcytosis due to the presence of an abnormal hemoglobin (HbC, Hb S/C, HbE). Three cases (0.6%) had other possible causes of microcytosis. Of the remaining 60 cases, 28 had an inflammatory state. Finally, 32 cases (6.9%) remain unexplained; taking into consideration the origin of these cases, their hematological parameters and their family history, we postulate that these cases are at high risk for non-deletional alpha-thalassemia.
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PMID:Investigation of microcytosis: a comprehensive approach. 869 32

Fifteen iron-overloaded thalassaemia major (TM) patients and two homozygous sickle cell patients (SCD) were treated continuously for 7d each week with the novel 48 h continuous subcutaneous (s.c.) desferrioxamine (DFX) delivery device (code C1083, Baxter) and 10 TM patients received the 24 h continuous intravenous (i.v.) DFX delivery device (code C1071). The 27 patients had previously received conventional s.c. DFX for 8-10h on 5 or more days each week. The serum non-transferrin bound iron (NTBI) levels fell significantly in both groups within 12h of commencing the continuous infusion. In the s.c. group the mean level fell from 4.2 to 2.0 mumol/l (P = 0.001), whereas in the i.v. group the mean level fell from 3.6 to 0.1 mumol/l (P = 0.006) the initial levels being measured 12h after stopping conventional s.c. DFX. After 4 weeks there was a significant fall in serum ferritin in both groups (P = 0.009). The new DFX delivery device is effective at removing toxicfree iron from plasma and reducing body iron. Moreover, it is preferred by patients with much improved compliance compared to the conventional s.c. DFX pump.
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PMID:A novel delivery system for continuous desferrioxamine infusion in transfusional iron overload. 870 13

In thalassemia after successful bone marrow transplantation (BMT), iron overload remains an important cause of morbidity. After BMT, patients have normal erythropoiesis capable of producing a hyperplastic response to phlebotomy so that this procedure can be contemplated as a method of mobilizing iron from overloaded tissues. A phlebotomy program (6 mL/kg blood withdrawal at 14-day intervals) was proposed to 48 patients with prolonged follow-up (range, 2 to 7 years) after BMT. Seven patients were not submitted to the program (five because of refusal and two because of reversible side effects). The remaining 41 patients (mean age, 16 +/- 2.9 years) were treated for a mean period of 35 +/- 18 months. All were evaluated before and after 3 +/- 0.6 years of follow-up. Values are expressed as mean +/- standard deviation (SD) or as median with a range (25 to 75 percentile). Serum ferritin decreased from 2,587 (2,129 to 4,817) to 417 (210 to 982) microg/L (P < .0001), total transferrin increased from 2.34 +/- 0.37 to 2.7 +/- 0.58 g/L (P = .0001), transferrin saturation decreased from 90% +/- 14% to 50% +/- 29% (P < .0001). Liver iron concentration evaluated on liver biopsy specimens decreased from 20.8 (15.5 to 28.1) to 4.2 (1.6 to 14.6) mg/g dry weight (P < .0001). Aspartate transaminase decreased from 2.7 +/- 2 to 1.1 +/- 0.6 (P < .0001) and alanine transaminase from 5.2 +/- 3.4 to 1.7 +/- 1.2 (P < .0001) times the upper level of normality. The Knodell score for liver histological activity decreased from 6.9 +/- 3 to 4.9 +/- 2.8 (P < .0001). These data indicate that phlebotomy is safe, efficient, and widely applicable to ex-thalassemics after BMT.
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PMID:Phlebotomy to reduce iron overload in patients cured of thalassemia by bone marrow transplantation. Italian Cooperative Group for Phlebotomy Treatment of Transplanted Thalassemia Patients. 924 28

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

Serum transferrin receptors (TfR) are a sensitive index of tissue iron availability, increasing progressively in response to functional iron deficiency. Unlike conventional laboratory tests of iron status, serum TfR are unaffected by underlying acute or chronic infection. Therefore, serum TfR measurement is particularly promising for evaluation of iron status when iron deficiency is simultaneously present with overt or subclinical infection or inflammation--a scenario often seen in patients seeking medical care, in elderly persons, and in persons living in developing countries. This test is also promising for assessment of iron status in pregnancy because it is not confounded by gestational effects. With the exception of conditions associated with markedly enhanced erythropoiesis which can increase TfR independently (e.g., megaloblastic anemia, thalassemia), serum TfR determination is a specific test of iron status. Serum TfR measurement is also reliable; a single, small amount of blood sample is adequate for its accurate determination. These sensitivity, specificity, and reliability characteristics of serum TfR measurement enable it to enhance confidence in iron status assessment in complex situations with the standard repertoire of laboratory tests.
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PMID:Diagnostic utility of serum transferrin receptors measurement in assessing iron status. 962 83

In thalassemia, iron overload is the joint outcome of excessive iron absorption and transfusional siderosis. While iron absorption is limited by a physiologic ceiling of about 3 mg/d, plasma iron turnover in thalassemia may be 10 to 15 times normal, caused by the wasteful, ineffective erythropoiesis of an enormously expanded erythroid marrow. This outpouring of catabolic iron exceeds the iron-binding capacity of transferrin and appears in plasma as non-transferrin-plasma iron (NTPI). The toxicity of NTPI is much higher than of transferrin-iron as judged by its ability to promote hydroxyl radical formation resulting in peroxidative damage to membrane lipids and proteins. In the heart, this results in impaired function of the mitochrondrial respiratory chain and abnormal energy metabolism manifested clinically in fatal hemosiderotic cardiomyopathy. Ascorbate increases the efficacy of iron chelators by expanding the intracellular chelatable iron pool, but, at suboptimal concentrations is a pro-oxidant, enhancing the catalytic effect of iron in free radical formation. NTPI is removed by i.v. DFO in a biphasic manner and reappears rapidly upon cessation of DFO, lending support to the continuous, rather than intermittent, use of chelators. Unlike DFO and other hexadentate chelators, bidentate chelators such as L1 may produce incomplete intermediate iron complexes at suboptimal drug concentrations.
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PMID:Pathophysiology of iron overload. 966 40


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