Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P02794 (ferritin)
 17,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Eleven patients with beta thalassemia major were entered into the trial of the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1). Their ages ranged from 17 to 26 years (mean +/- SD, 22.3 +/- 2.7). Six were male and five were female. L1 was administered at an initial daily dose of 42.5 to 60 mg/kg as a single dose. After 4 weeks, the dose was increased to 85 to 119 (102 +/- 10.7) mg/kg for 191 to 352 days divided into either two or four doses daily, except for one patient who developed agranulocytosis after 11 weeks and was taken off the trial. Initial serum ferritin values in the remaining 10 patients ranged between 1,000 and 9,580 (5,549 +/- 3,333) micrograms/L and at end of the trial their mean serum ferritin was significantly lower (4,126 +/- 2,278; P less than .05 using the paired t-test). Urinary iron excretion at a daily dose of 85 to 119 mg/kg administered as two divided doses ranged between 0.14 and 0.82 (0.44 +/- 0.26) mg/kg/24 h. In three patients, the four doses per day schedule caused substantially more iron excretion than the same total dose divided into two. During the course of the trial, several possible adverse effects have been encountered. One patient (female, aged 20) developed agranulocytosis 11 weeks after starting treatment and 6 weeks after beginning treatment with a daily dose of 105 mg/kg. This patient's neutrophil count recovered spontaneously 7 weeks after the discontinuation of L1. A decrease in serum zinc levels to subnormal levels was observed in four patients with symptoms of dry skin, with an itchy scaly rash in two that was associated with low serum zinc levels that responded to zinc therapy. Urinary zinc levels ranged from 4.7 to 23.4 (13 +/- 5.5) mumol/24 h and were above 9 mumol/24 h (upper limit of normal) in eight patients. Mild nausea occurred in three patients and transient diarrhea in a fourth. Mild musculoskeletal symptoms occurred in three patients but settled without discontinuation of L1 therapy in two and with temporary discontinuation of L1 in the third. A transient increase in serum aspartate transaminase was also noted in five patients, but serum aspartate transaminase levels subsequently decreased in all of them. No cardiovascular, neurologic, renal, or retinal toxicities were demonstrable. These results confirm that L1 is an effective oral iron chelator. Further clinical trials are needed to determine the incidence and severity of adverse effects.
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PMID:Efficacy and possible adverse effects of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) in thalassemia major. 846 82

A new oral iron chelator, L1, was given for 14 to 16 months to four patients with transfusion haemosiderosis. These patients could no longer be treated with deferoxamine because of allergic reactions or psychological problems. Serum ferritin values at the start of the treatment ranged from 2220 to 4530 microgram/l. L1 was given in a total daily dose of 3 g, at first in a single dose, later 3 times 1 g daily. The 24-hour urinary excretion of iron varied greatly from day to day. The mean urinary iron excretion of the four patients ranged from 19.3 to 45.7 mg/day. In two patients an important decrease of ferritin was found. These patients had been given no more or only sporadic transfusions. In one patient transient agranulocytosis was seen which was probably not caused by L1.
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PMID:[Long-term treatment of patients with transfusion hemosiderosis using oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1)]. 194 90

This report updates the combined experience of four centres involved in the long-term treatment of transfusional iron overload in 84 patients with the oral iron chelator deferiprone (L1) over 167 patient-years. The source of L1 was variable, including two university research laboratories and three pharmaceutical firms. Compliance was rated as excellent in 48%, intermediate in 36%, and poor in 16% of patients. On a mean L1 dose of 73-81 mg/kg/d, urinary iron excretion was stable, at around 0.5 mg/kg/d, with no indication of a diminishing response with time. Serum ferritin showed a very steady decrease with time from an initial mean +/- 1 SD of 4207 +/- 3118 to 1779 +/- 1154 micrograms/l after 48 months (P < 0.001). 17 patients abandoned L1 therapy. Major complications of L1 requiring permanent discontinuation of treatment included agranulocytosis (three), severe nausea (four), arthritis (two) and persistent liver dysfunction (one). The remaining patients abandoned treatment because of low compliance (three) and conditions unrelated to L1 toxicity (four). Lesser complications permitting continued L1 treatment included transient mild neutropenia (four), zinc deficiency (12), transient increase in liver enzymes (37), moderate nausea (three) and arthropathy (17). There was no treatment-related mortality. Although the complications associated with L1 treatment are significant and require close monitoring, they do not preclude effective long-term therapy in the vast majority of patients. Further well-controlled prospective studies of L1 are required in order to enable proper judgement of its suitability for general long-term clinical use.
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PMID:Results of long-term deferiprone (L1) therapy: a report by the International Study Group on Oral Iron Chelators. 757 38

The introduction of oral chelation therapy with the alpha-ketohydroxypyridine chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1, INN/BAN: deferiprone) in iron- and aluminium-overloaded patients has been initiated in over 15 countries in the last 7 years. Over 600 patients with various conditions, in 26 centres have received L1, in some cases daily for over 5 years. In the vast majority of iron-loaded patients, doses of 55-100 mg kg-1 of L1 resulted in urinary iron excretion levels greater than those accumulating from transfusions (15-35 mg d-1) and also reduction in serum ferritin and liver iron to near normal levels. Urinary iron excretion was related to the iron load of the patients, as well as the dose and frequency of administration of L1. The L1 appears to mobilize iron mainly from a serum iron pool in excess of transferrin saturation, transferrin-bound iron and tissue iron, mainly but not exclusively from the liver. The order of metal binding by L1 at pH 7.4 is Fe > Cu > A1 > Zn. Aluminium removal from aluminium-loaded renal dialysis patients by L1 was also effective at doses similar to those used for iron-loaded patients. Overall toxic side effects include six cases of reversible agranulocytosis, 0-30% incidence of transient musculoskeletal and joint pains, 0-6% of gastric intolerance and 0-2% zinc deficiency. Deferiprone appears to be as effective as desferrioxamine in iron and aluminium removal and has low toxicity. Its oral efficacy and low cost make it more accessible than desferrioxamine for the vast majority of patients needing iron chelation worldwide. The development of other alpha-ketohydroxypyridines is currently in progress.
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PMID:New concepts of iron and aluminium chelation therapy with oral L1 (deferiprone) and other chelators. A review. 774 Dec 39

Nine iron overloaded patients were treated with L1--Deferiprone (1,2-dimethyl-3-hydroxypyrid-4-one) in daily dose 3 g (40-50 mg/kg) for 12 weeks. In 7 patients the efficiency of L 1 treatment was compared to the therapeutic effect of the same dose of desferrioxamine (Desferal). A significant increase in urinary iron excretion was observed after administration of both chelating agents. Iron excretion after L 1 treatment was approximately 65% of that obtained with Desferal. The amount of excreted iron correlated with the amount of iron stores before chelation. A significant decrease in transferrin saturation, serum and red cell ferritin was observed after treatment with Desferal, L 1 administration caused a significant decrease only in serum ferritin level. However, all the parameters reflecting iron stores remained increased when compared to normal values after 12 weeks of chelation therapy. An incomplete absorption from gut and some reutilization of chelated iron may be responsible for less potent iron chelation by L 1 in comparison to Desferal. A low tolerance of the drug together with repeated nausea and vomiting were the most frequent adverse effects observed in the course of L1 administration. L 1 treatment had to be discontinued due to repeated vomiting in one patient and due to progressive granulocytopenia and thrombocytopenia in another patient. Because of the side effects more clinical studies with L 1 are needed before its introduction in wide clinical practice.
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PMID:[Treatment of iron overload states with oral administration of the chelator agent, L1 (Deferiprone)]. 797 62

Are there enough mast cells in denervated skeletal muscle to account for autopharmacological mediation of the antigen potentials (APs) elicited by microtaps? Through rough qualitative estimations, some authors have suggested a positive answer to this question. However, in view of measurements performed in this investigation of both the density of mast cells and the diffusion coefficient of antigens, the probability of such mediated effects was found to be relatively low: P = 0.016 for egg albumin and P = 0.004 for ferritin. Therefore, most APs induced by microtaps should be attributed to the direct effect of antigen over the sensitized muscle fibers. Yet, both the density of mast cells found in this work and the known amount of histamine they are capable of releasing when challenged with antigen, support the hypothesis regarding the involvement of these cells when antigen is massively superfused so as to induce Schultz-Dale reactions in muscle strips. Under this circumstance, the direct and mediated mechanisms may coexist.
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PMID:Probability of mast cells to mediate anaphylaxis in skeletal muscle. 811 17

In the last few years we have witnessed the emergence of oral chelation which is a new form of therapy for transfusional iron-loaded patients in thalassaemia and other refractory anaemias. The need for a cheap, non-toxic, orally effective iron chelator is paramount because it could potentially save the lives of many thousands of patients. At present, less than 10% of the patients requiring iron chelation therapy worldwide receive the widely used chelating drug desferrioxamine (DF) because of its high cost, oral inactivity and toxicity. The most promising oral iron chelator is 1, 2-dimethyl-3-hydroxypyrid-4-one (L1 or INN: Deferiprone), which has so far been taken by over 450 patients in 15 countries, and in some cases daily for over 4 years with very promising results. L1 was shown at 50-100 mg/kg/day to be effective in bringing patients to negative iron balance. It increases urinary iron excretion, decreases serum ferritin levels and reduces liver iron in multi-transfused iron-loaded patients. Toxic side effects were mainly encountered at high doses (80-100 mg/kg/day) and include transient agranulocytosis (5 cases), transient musculoskeletal and joint pains (10-20%), gastric intolerance (2-6%) and zinc deficiency (1%). The incidence of these toxic side effects was reduced by using lower doses of 50-75 mg/kg/day. The overall efficacy and toxicity of L1 is comparable to that of DF in animals and humans. Further work is required for identifying susceptible individuals to L1 toxicity, and also optimum dose protocols of L1 which can maximise iron excretion and minimise the incidence of toxic side effects.
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PMID:Present status and future prospects of oral iron chelation therapy in thalassaemia and other diseases. 826 86

We performed an open, nonrandomized, multicenter phase-II trial to evaluate the efficacy and toxicity of 1 year of treatment with the oral iron chelator deferiprone in 38 mainly nonthalassemic patients with transfusional iron overload. Initial serum ferritin varied between 996 and 11.644 micrograms/l. Patients were treated with 3-6 g of deferiprone daily. Mean urinary iron excretion (UIE) in 36 evaluable patients was 21.0 mg/24 h and was significantly higher in the patients with thalassemia than in those with myelodysplasia. Negative iron balance was achieved in 20 patients (56%). The median duration of treatment was 10 months; due to side effects and other causes only 20 patients completed 1 year of treatment. Mean serum ferritin levels decreased from 3563 micrograms/l at the start of the trial to 2767 micrograms/l at 6 months (26 patients, p < 0.004) and to 2186 micrograms/l at 12 months (20 patients, p < 0.005). Serum ferritin levels normalized in two patients who were no longer transfusion dependent. Deferiprone was clearly not effective in three patients (two with myelofibrosis, one with myelodysplasia). One patient with myelodysplasia developed agranulocytosis after 12 months of treatment; this was rapidly reversible after stopping deferiprone. Three patients had a mild and transient decrease in white blood cell count. Other side effects leading to withdrawal from the trial consisted mainly of nausea (3 patients), arthralgia (2), and skin rash (1). No clinical signs of zinc deficiency were seen, although zinc excretion was increased in three patients. No changes were seen in liver enzymes, creatinine, antinuclear factor, T-cell subsets, cardiac function, visual acuity, and audiogram. Although our results confirm deferiprone as an effective iron chelator in patients with thalassemia and in some patients with other forms of iron overload, there is still some concern about the safety of this drug, which therefore, at this time, should be used exclusively in well-controlled clinical trials.
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PMID:Long-term treatment of transfusional iron overload with the oral iron chelator deferiprone (L1): a Dutch multicenter trial. 895 43

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

Fifty-one transfusion-dependent iron-loaded adult patients (38 with thalassemia major) were treated with the orally active iron chelator deferiprone (1,2 dimethyl-3-hydroxypyrid-4-one, L1) at a dose of 75 mg/kg/d (range, 50 to 79). Twenty patients discontinued the drug and five died after a mean of 18.7 months (range, 4 to 35). Of the 20, 5 had arthropathy, 5 had gastrointestinal symptoms, 4 had a rising serum ferritin, 3 had agranulocytosis or neutropenia, 1 had tachycardia, 1 had renal failure, and 1 went abroad. Twenty-six patients continued deferiprone for a mean of 39.4 months (range, 12 to 49). Among these patients, there was no overall significant change in serum ferritin (initial mean, 2,937 microg/L; range, 980 to 5,970; final mean, 2,323 microg/L; range, 825 to 5,970) or in urine iron excretion (initial mean, 31.2 mg/24 h; range, 16.3 to 58. 2; final mean, 32.1 mg/24 h; range, 9.4 to 75.8), implying no overall change in iron stores. When the patients who had received deferiprone for longer than 3 years were considered separately, there was also no significant change in serum ferritin or urinary iron excretion. The initial serum ferritin levels in the 26 patients who continued deferiprone treatment were significantly lower than in those who discontinued the drug (P < .01). The liver iron content in 17 patients who had received deferiprone for 24 to 48 months ranged from 5.9 to 41.2 mg/g dry weight, 50% having levels above 15.0 mg, a level associated with a high risk of cardiac disease due to iron overload. In this study the drug caused fewer side effects and was more effective at maintaining iron status among patients previously well chelated and with lower initial serum ferritin levels.
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PMID:Long-term trial of deferiprone in 51 transfusion-dependent iron overloaded patients. 941 97


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