L1 is the most widely studied oral
iron-chelating
drug and at present the only one shown to be effective at causing negative
iron balance in long-term clinical trials for
thalassemia major and other transfusion-dependent refractory anaemias. Because of side-effects, both in experimental animals and in humans, its development as a widely available
pharmaceutical agent has been delayed. However, for the large numbers of transfusion-dependent,
iron-overloaded patients who do not use DFX because of poor compliance, adverse effects or unavailability of the
drug, L1 may be a suitable alternative for
iron chelation. However, its use should be restricted to Ethical Committee approved clinical trials. Patients who are capable of using DFX effectively should be encouraged to continue doing so until an oral
iron chelator has been fully established for clinical use. It is hoped that 3-hydroxypyrid-4-one analogues of L1 as well as compounds related to
pyridoxal isonicotinyl
hydrazone,
HBED or
hydroxamic acid can be found both orally effective and safe for long-term administration. Current and future trials of L1 could address some of the following issues, beside extending present studies on the efficacy and adverse effects of L1: 1. The effect of administering a reduced dose of L1 (< 75 mg/kg per day) on the incidence of adverse effects and on long-term efficacy. 2. The efficacy and adverse effects of L1 at a low dose in patients with non-transfusional
iron overload such as thalassaemia intermedia, primary
haemochromatosis and congenital
haemolytic anaemias. 3. The effect of combining oral L1 with intravenous or subcutaneous DFX on the incidence of adverse effects and efficacy. 4. Elucidation of the mechanisms involved in
agranulocytosis and joint toxicity and finding methods to predict for individual susceptibility to these adverse effects and ways of preventing them.