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PubMedDate not supplied

[New therapeutic trends in thalassemia: oral chelating agents].

The future therapeutic strategy for decreasing iron overload in poly-transfused patients will include oral chelation. The product currently undergoing the most intensive experimentation is Ll (1,2-dimethyl-3-hydroxypyrid-4-one). We report here a short-term efficacy study carried out in 10 thalassemic transfusion-dependent pediatric volunteer patients, already closely followed in our Day Hospital, after having provided their informed consent. In our study Ll, when compared to Desferrioxamine, was clearly efficacious and safe.

Administration, Oral↗
PubMed1992

A comparison of the iron-clearing properties of 1,2-dimethyl-3-hydroxypyrid-4-one, 1,2-diethyl-3-hydroxypyrid-4-one, and deferoxamine.

A comparative study of the iron-clearing properties of subcutaneously (SC) administered deferoxamine (DFO) with those of orally administered 1,2-dimethyl-3-hydroxypyrid-4-one (CP20) and 1,2-diethyl-3-hydroxypyrid-4-one (CP94) is presented. The studies were performed in both a non-iron-overloaded, bile duct-cannulated rat model and an iron-loaded Cebus monkey model. All three drugs performed well in the rodent, promoting the excretion of iron in both the urine and the bile, with total iron output efficiencies of 2.8%, 1.2%, and 7.1%, respectively. The efficiency of DFO increased slightly in the Cebus model, while that of the hydroxypyridones was essentially the same in the monkey, with total iron output efficiencies of 5.5%, 2.1%, and 7.4%, respectively. Iron balance studies showed that both DFO and CP94 were able to maintain the animals in a negative iron balance, while CP20 had little impact.

Animals↗
PubMed1992

Complexation of iron with the orally active decorporation drug L1 (3-hydroxy-1,2-dimethyl-4-pyridinone).

The stability constants for the Fe(III) complexes of the orally active iron decorporation drug L1 (3-hydroxy-1,2-dimethyl-4-pyridinone) have been determined by potentiometric titration [glass electrode, 25.0 degrees C, mu = 0.15 mol/L (isotonic) NaCl]. A simple computer model of blood plasma (citrate 100 mumol/L, transferrin 37 mumol/L) has been used to compare the Fe(III) binding efficacies in blood of L1 and the clinically used intravenously administered chelating agent deferoxamine.

Chelating Agents↗
PubMed1992

Reduction of tissue iron stores and normalization of serum ferritin during treatment with the oral iron chelator L1 in thalassemia intermedia.

In patients with thalassemia intermedia in whom hyperabsorption of iron may result in serious organ dysfunction, an orally effective iron-chelating drug would have major therapeutic advantages, especially for the many patients with thalassemia intermedia in the Third World. We report reduction in tissue iron stores and normalization of serum ferritin concentration after 9-month therapy with the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) in a 29-year-old man with thalassemia intermedia and clinically significant iron overload (SF 2,174 micrograms/L, transferrin saturation 100%; elevated AST and ALT, abnormal cardiac radionuclide angiogram) who was enrolled in the study with L1 75 mg/kg/day after he refused deferoxamine therapy. L1-Induced 24-hour urinary iron excretion during the first 6 months of therapy was (mean +/- SD, range) 53 +/- 30 (11 to 109) mg (0.77 mg/kg), declining during the last 3 months of L1 to 24 +/- 14 (13-40) mg (0.36 mg/kg), as serum ferritin decreased steadily to normal range (present value, 251 micrograms/L). Dramatic improvement in signal intensity of the liver and mild improvement in that of the heart was shown by comparison of T1-weighted spin echo magnetic resonance imaging with images obtained immediately before L1 administration was observed after 9 months of L1 therapy. Hepatic iron concentration decreased from 14.6 mg/g dry weight of liver before L1 therapy to 1.9 mg/g liver after 9 months of therapy. This constitutes the first report of normalization of serum ferritin concentration in parallel with demonstrated reduction in tissue iron stores as a result of treatment with L1. Use of L1 as a therapeutic option in patients with thalassemia intermedia and iron overload appears warranted.

Adult↗
PubMed1992

Efficacy and possible adverse effects of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) in thalassemia major.

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.

Adult↗
PubMed2004

Glucose metabolism disorders improvement in patients with thalassaemia major after 24-36 months of intensive chelation therapy.

Thalassaemic patients with haemocromatosis often present with metabolic disturbances such as diabetes mellitus. A group of adult thalassaemic patients who received intensive oral and subcutaneous chelation therapy (Defferiprone/Ferriprox and Desferioxamine/Desferal) for a period of 24-36 months was studied for the presence of glucose metabolism disturbances (GMD). Investigation of the prevalence of diabetes mellitus (DM) and impaired glucose tolerance (IGT) was carried out by yearly oral glucose tolerance tests (OGTT). Results showed that GMD (DM and IGT) improved in 1/3 of the patients after the intensive combined chelation treatment, a finding that we attributed to a reduction in liver iron deposits. Although this study is still in progress we believe that intensive combined chelation therapy may have a positive effect on glucose metabolism.

Adult↗
PubMed1992

Origin and fate of iron mobilized by the 3-hydroxypyridin-4-one oral chelators: studies in hypertransfused rats by selective radioiron probes of reticuloendothelial and hepatocellular iron stores.

The mechanism of in vivo iron chelation by 3-hydroxypyridin-4-ones (CP compounds) was studied in hypertransfused rats in which the major storage iron pools in hepatocytes and in the reticuloendothelial (RE) system have been labeled by selective radioiron probes. Both dimethyl-3-hydroxypyridin-4-one (CP 20 or L1) and diethyl-3-hydroxypyridine-4-one (CP 94) have an identical and very high (log beta 3 36) binding constant and selective affinity to iron(III), but the lipid solubility of CP 94 is considerably higher than that of CP 20. Both chelators induced an increase in the fecal excretion of hepatocellular iron with no effect on urinary excretion. In contrast, about one third to one half of the iron mobilized from RE cells was excreted in the urine. The chelating efficiency of CP 20 was comparable with that of deferoxamine (DF), whereas CP 94 was up to eight times more effective than DF. Unlike DF, which had no effect by the oral route, the oral and parenteral effectiveness of both CP compounds was identical. These findings indicate that: (1) lipid solubility is an important determinant of in vivo chelating efficiency; (2) urinary iron excretion induced by the CP compounds is derived from RE cells; (3) part of the iron mobilized from RE cells and all of the iron derived from hepatocytes is excreted through the bile; and (4) contrary to previous observations in cell cultures, there is no in vivo evidence for a diminishing chelating efficiency at the lowest doses used.

Animals↗
PubMed1991

Iron chelation.

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Chelation Therapy↗
PubMed1991

Efficacy and safety of 1-2, dimethyl-3-hydroxypyrid-4-one (L1) as an oral iron chelator in patients of beta thalassaemia major with iron overload.

Twenty-four patients with beta thalassaemia major, aged 8-22 years (mean 15.3 +/- 8.1) were given 1-2, dimethyl-3-hydroxypyrid-4-one (L1) orally for a period of three months. The drug was given in the dose of 25 mg/Kg/day for the first week and gradually increased to 100 mg/Kg/day which was continued until 3 months. The mean urinary iron excretion was 5.73 +/- 3.648 mg/day on 25 mg/Kg/day of L1; 15.2 +/- 11.225 mg/day on 50 mg/Kg/day; 24.2 +/- 12.69 mg/day on 75 mg/Kg/day and 36.3 +/- 19.4 mg/day on 100 mg/Kg/day of L1. Serum ferritin estimated by ELISA before and 3 months after L1 therapy in 21 patients showed significant drop in levels, the mean drop being 964.3 +/- 844.4 (P less than 0.001). The only side-effects noted were transient gastrointestinal symptoms in 5 patients and skeletomuscular pain in 3 patients. Both these groups of symptoms were of transient nature. The efficacy of L1 appears to be excellent and equivalent to the standard iron chelation therapy available at present i.e. desferrioxamine. It appears to be free of major toxicity. L1 is also a specific chelator for iron as it does not deplete trace metals. L1 appears to be a cheap and effective oral alternative to desferrioxamine for treating iron overloading.

Adolescent↗
PubMed1991

[Long-term treatment of patients with transfusion hemosiderosis using oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1)].

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.

Adolescent↗
PubMed1991

Comparative iron mobilizing actions of deferoxamine, 1,2-dimethyl-3-hydroxypyrid-4-one, and pyridoxal isonicotinoyl hydrazone in iron hydroxamate-loaded mice.

A comparison was made of the actions of deferoxamine (DFX), 1,2-dimethyl-3-hydroxypyrid-4-one (L1), and pyridoxal isonicotinoyl hydrazone (PINH) in mobilizing and promoting excretion of iron in mice loaded with iron-acetohydroxamic acid complex. DFX was given ip, while L1 and PINH were given po. Each was given daily for four days at 300 mg/kg/day, and total excreta were collected 24 hr after each administration. Total iron excreted over the 4-day period, expressed as micrograms/mouse, were: Controls, 26; PINH-treated, 31; DFX-treated, 162; and L1-treated, 208. Measurements of iron in selected organs 96 hr after the last administration of each compound revealed that treatment with L1 and DFX induced significant reductions of iron concentrations in kidneys (16% and 17%, respectively) and in pancreas (18% and 19%, respectively). In addition, L1 treatment led to a significant reduction in the liver iron burden (11%), an action not seen after treatment with DFX. None of the compounds reduced iron concentrations in heart, the most critical organ for toxicity of transfusional siderosis. The synthetic routes for preparation of L1 and PINH are described in detail.

Animals↗
PubMedDate not supplied

Impaired erythropoietin responsiveness to the anaemia in rheumatoid arthritis. A possible inverse relationship with iron stores and effects of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one.

We investigated the serum erythropoietin (Epo) response in 11 rheumatoid arthritis (RA) patients without anaemia, 7 with RA and iron deficiency (ID) and 12 with RA and anaemia of chronic disease (ACD). In all patients the serum Epo was higher than in healthy subjects. Apparently this increase was insufficient to prevent anaemia in ID and ACD. Serum Epo correlated negatively with serum ferritin. Ten RA patients with ACD were treated with the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1). No obvious toxicity signs occurred after one week of treatment. It effectively released iron from iron stores. The Hb rise (in 70% of the patients) was correlated positively with an Epo increase and negatively with a serum ferritin decrease. We conclude that a serum Epo increase does not overcome ACD. Epo response might correlate inversely with iron stores. L1 treatment effectively chelates iron from iron stores. The effects of L1 on erythropoiesis and serum Epo and its safety need further substantiation after prolonged treatment in more RA patients.

Aged↗