Al-Refaie, Faris N.; (1998) Oral iron chelation therapy with deferiprone (L1). Doctoral thesis (M.D), UCL (University College London).

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Abstract

Aims: To evaluate the oral iron chelator deferiprone (L₁) by conducting 2 long-term clinical trials in patients with iron overload and to assess its effectiveness and study its adverse effects both in vivo and in vitro. Results: L₁ was used long term(>6 months) in 53 patients with iron overload at a dose of approximately 50-100mg/kg/day. Urinary iron excretion (UIE) ranged between 5.3 and 66.8mg/24h. In a significant number of patients a dose in excess of 60mg/kg/day was required to induce a UIE in excess of 0.5mg/kg/day to result in a negative iron balance. No significant change in the mean UTE was observed when L₁ was given with or without food or vitamin C or in 2 or 4 divided daily doses. Serum ferritin fell in 36 of the 53 patients (68%) treated long term. The fall in serum ferritin was more marked in those patients with the highest body iron load as assessed by serum ferritin levels. Two patients developed agranulocytosis and 3 less severe neutropenia whilst receiving L₁. Studies using liquid culture systems have failed to show an increased susceptibility of the patients' myeloid precursors (CFU-GM) to L₁, alone or bound to iron, compared to normal myeloid precursors. Furthermore, the toxicity of free or iron bound L₁ to normal or the patients' myeloid precursors was less than that of desferrioxamine (DFX). Joint or musculoskeletal problems was observed in 14 of 53 (26%) patients treated long term. The results here show for the first time that L₁ can cause mild zinc deficiency in some patients. This was more marked in patients with diabetes mellitus. Nine of 63 patients (14%) treated with L₁ developed nausea and 17 of 54 (32%) developed a transient fluctuation in the serum level of aspartate transaminase (AST). L₁ was rapidly absorbed (abt1/2: 22.2±17.7min) and eliminated (elt1/2: 9l.1±33.1min) mainly as L₁-glucuronide (L₁G) but also as free L₁ and L₁-iron complex in urine. L₁ efficiency was 3.8±1.9%. It was found that L₁G can accumulate in patients with impaired renal function. Using urea-polyacrylamide gel electrophoresis L₁ was found to be capable of removing significant proportion of transferrin iron. Assuming that all the iron removed from transferrin by L₁ was excreted in urine in 24 hours, it was found that this comprised 21.3±20.2% (5.8-67.1%) of total UIE. Using an HPLC (high-pressure liquid chromatography)-based method L₁ was found to be capable of causing a significant fall in the serum concentrations of non-transferrin-bound iron in patients with iron overload. Conclusions: L₁ was shown to be an effective iron chelator in inducing a significant urinary iron excretion in a considerable number of patients leading to a reduction in body iron stores as evident by a fall in serum ferritin. But long-term use was associated with adverse effects the most important of which were agranulocytosis and joint toxicity.

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