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PubMed1991

Relationship between the pharmacokinetics and iron excretion pharmacodynamics of the new oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one in patients with thalassemia.

Single-dose and steady-state pharmacokinetics of the new oral iron chelator, 1,2-dimethyl-3-hydroxypyrid-4-one (L1) were studied in 14 patients with thalassemia and correlated with iron excretion. Food prolongs the rate of absorption of L1, but it does not affect significantly the extent of absorption measured by the area under the plasma concentration-time curve. Similarly, it does not affect the chelation potential of the drug. The mean elimination half-life of the drug is 3 hours, suggesting that a divided dose every 8 hours may assure better chelation. Our steady-state studies reveal that urinary iron excretion is independently influenced by body iron load (measured by ferritin levels) and by steady-state trough concentrations of the drug. While patients were receiving an unchanged regimen of 75 mg/kg/day, we have detected a gradual and significant decrease in trough concentrations in the presence of unchanged patients' compliance monitored by the Medication Event Monitoring System, diaries, and pill count. These findings suggest self-induction of L1 metabolism or decreased absorption during long-term therapy. Because of the concentration-dependent iron excretion, patients may need increasing doses to achieve negative iron balance.

Adolescent↗

PubMed1994

Urinary iron excretion depends on the mode of administration of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one in patients with homozygous beta-thalassemia.

OBJECTIVE: To examine the effect of frequency of oral administration of 1,2-dimethyl-3-hydroxypyrid-4-one (L1) on urinary iron excretion. HYPOTHESIS: Sustained serum concentrations of L1 will cause more iron chelation than the same daily dose given in larger but less frequent amounts. PATIENTS AND METHODS: Ten patients with thalassemia with a mean age of 20.9 +/- 4.7 years (range, 13 to 27 years), who were receiving regular treatment with 75 to 100 mg/kg/day oral L1, received 75 mg/kg/day L1 orally in equally divided doses: every 6 hours for 3 days and every 12 hours for 3 days. The two study periods occurred 1 month apart immediately after the monthly blood transfusions. Urine was collected for two consecutive 24-hour periods during each of the different schedules. Serial blood samples were collected from six patients over a 6-hour period and analyzed for total L1 and the L1 glucuronide metabolite concentrations. RESULTS: The patient's mean hemoglobin levels (138.8 +/- 12.5 and 139.0 +/- 11.6 gm/L) and ferritin levels (2856.4 +/- 2207.8 and 2890.0 +/- 2264.4 micrograms/L) were similar during the every-6-hour and every-12-hour L1 administrations, respectively. There was significantly more urinary iron excretion when L1 was administered every 6 hours (0.59 +/- 0.29 mg/kg/day) versus every 12 hours (0.40 +/- 0.26 mg/kg/day; p = 0.0129). Calculated 24-hour area under the plasma concentration-time curve of L1 was similar during the every-6-hour (7023.9 +/- 2637.8 mg.min/L) and every-12-hour (7050.1 +/- 1668.8 mg.min/L) experiments. CONCLUSIONS: These data suggest that the sustained presence of L1 in the blood results in greater chelation of iron than that observed with larger, less frequent doses.

Administration, Oral↗

PubMed1994

Deferoxamine augments growth and pathogenicity of Rhizopus, while hydroxypyridinone chelators have no effect.

Deferoxamine (DFO), when used in dialysis patients, is a well recognized risk factor for the development of mucormycosis caused by Rhizopus. This study compares, both in vivo and in vitro, the effects produced on Rhizopus by DFO and by two chelators of the hydroxypyridinone class, L1 and CP94. Experimental systemic mucormycosis was induced in the guinea pig by an i.v. injection of two different strains of Rhizopus: R. microsporus and R. arrhizus. Concomitant i.p. administration of DFO for four days shortened animal survival (P < 0.05), whereas concomitant administration of either L1 or CP94 did not. In vitro radioiron uptake by R. microsporus was 100-fold higher from the 55ferric complex of DFO than of L1 or CP94. In vitro fungal growth was stimulated sevenfold by the ferric complex of DFO (P < 0.0001) but not significantly by the ferric complex of either L1 or CP94. These results indicate that the ferric complex of DFO but not that of L1 or CP94 specifically stimulates both the iron uptake and the growth of Rhizopus. They suggest that the risk of developing mucormycosis should be minimal with L1 or CP94, as opposed to DFO.

Animals↗

PubMed2002

Protein kinases--the major drug targets of the twenty-first century?

Protein phosphorylation regulates most aspects of cell life, whereas abnormal phosphorylation is a cause or consequence of disease. A growing interest in developing orally active protein-kinase inhibitors has recently culminated in the approval of the first of these drugs for clinical use. Protein kinases have now become the second most important group of drug targets, after G-protein-coupled receptors. Here, I give a personal view of some of the most important advances that have shaped this field.

Animals↗

PubMed1986

Iron mobilization from ferritin using alpha-oxohydroxy heteroaromatic chelators.

Several alpha-oxohydroxy heteroaromatic chelators have been shown to mobilize iron from horse spleen ferritin. Although the reactions were slow, taking up to 3 days to reach completion, the amounts of iron mobilized were higher than those reported for other chelators. These results increase the prospects for the clinical use of alpha-oxohydroxy chelators in the treatment of iron overload.

Chelating Agents↗

PubMed1987

Comparative study of iron mobilization from haemosiderin, ferritin and iron(III) precipitates by chelators.

The heteroaromatic chelators 1,2-dimethyl-3-hydroxypyrid-4-one, maltol, mimosine and 2,4-dihydroxypyridine-N-oxide, have been shown to mobilize iron from human spleen haemosiderin, ferritin and also from iron(III) precipitates, all containing equal amounts of iron, at physiological pH. In the case of almost every chelator, the least-solubilized polynuclear iron form was ferritin, whereas haemosiderin was more soluble and the iron(III) precipitate the most soluble of all. Most of the chelators were more efficient than desferrioxamine at releasing iron from ferritin, but less efficient in the removal of iron from the other two polynuclear iron forms. It is suggested that the chelator differences in iron mobilization may be related to variations in the chelator molecular structure, the protein structure, iron forms and in the mechanism of iron release.

Deferiprone↗

PubMed1988

The iron chelators desferrioxamine and 1-alkyl-2-methyl-3-hydroxypyrid-4-ones inhibit vascular prostacyclin synthesis in vitro.

The iron chelators desferrioxamine (DFO), 1,2-dimethyl(L1)-, 1-ethyl-2-methyl(L1NEt)- and 1-propyl-2-methyl(L1NPr)-3-hydroxypyrid-4-ones inhibited rat aortic prostacyclin (PGI2) synthesis in vitro (rank order of potency: DFO greater than L1 greater than L1NEt greater than L1NPr) when stimulated with adrenaline, arachidonate and the Ca2+ ionophore A23187. The inhibitory action of the chelators was blocked by Fe3+ and Al3+ and reversed by washing and H2O2, but not by ascorbate. These data suggest that iron chelators inhibit prostanoid synthesis in intact tissue through the removal or binding of Fe3+ linked to cyclo-oxygenase. These iron chelators may be of therapeutic value in the treatment of inflammatory and other diseases via two mechanisms: (1) the inhibition of pro-inflammatory prostanoid synthesis and (2) the inhibition of toxic-free-radical generation by cyclo-oxygenase.

Aluminum↗

PubMed1993