Long‐term trial with the oral iron chelator 1,2‐dimethyl‐3‐hydroxypyrid‐4‐one (L₁) I. IRON CHELATION AND METABOLIC STUDIES

Abstract

A long-term clinical trial of 1-15 months has been carried out with the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) in 13 transfusion-dependent iron-loaded patients. Urinary iron excretion was greatest in patients with thalassaemia major and was related to the number of previous transfusions but not to the serum ferritin level. Substantial increases of urinary iron were observed in all the patients when the frequency of the daily dose was doubled and in response to 2 x 3 g L1 daily 11 of 12 patients tested excreted greater than 25 mg iron daily, the mean daily intake of iron from transfusion. Serum ferritin levels have fluctuated but overall have remained unchanged. Pharmacological studies in five patients have indicated rapid absorption probably from the stomach and variable plasma half life of 77 +/- 35 min (X +/- SD). Glucuronation was identified as a major route of L1 metabolism. Short-term intensive chelation studies using repeated administration of L1 resulted in further increases of urinary iron excretion by comparison to a single dose. In one case 325 mg of iron were excreted in the urine following the administration of 16 g (5 x 2 g + 2 x 3 g) within 24 h. Iron excretion studies were carried out in six transfusional iron-loaded patients who were maintained on a low iron diet before and during chelation. No significant increases of faecal iron excretion were observed with L1 using daily doses of up to 3 x 3 g and 4 x 2 g. The high level of compliance during treatment with L1 and the levels of urine iron excretion that can be achieved increase the prospects for oral chelation in transfusional iron-loaded patients.

Role of deferiprone in chelation therapy for transfusional iron overload

“…14,34 Although one study reported fecal iron excretion with deferiprone ingestion to be 15% to 23% of total excretion, 34 other studies, either published or in abstract form, showed no increase or only negligible increase in fecal iron excretion and no detectable deferiprone in feces. 12,35,36 Metabolic balance studies in 13 patients showed that the level of total iron excretion in response to deferiprone (75 mg/kg) was 62% (range, 24%-129%) of that achieved with deferoxamine (60 mg/kg over 8 hours subcutaneously). 35 Although all patients were in net negative balance when treated with deferoxamine, only 6 of 13 were in net negative balance as a result of taking deferiprone.…”

“…Several groups subsequently confirmed in longer term studies that deferiprone was an orally active iron chelator, [11][12][13][14][15] and substantial data concerning the efficacy and toxicity of deferiprone have accumulated over 15 years. The results of these trials and of animal and cell culture studies have been extensively reviewed.…”

Transition of Thalassaemia and Friedreich ataxia from fatal to chronic diseases

“…The above study suggests that the iron mobilised by L1 in individuals with normal body iron store levels including focal iron deposits in FA patients could be redistributed in the body via transferrin instead of being excreted. Measurement of urinary iron excretions have shown that usually only about 1-3 mg iron can be excreted by normal individuals of about 75 kg body weight, per a 3 g dose of L1 [67,[124][125][126] . In comparison, in iron loaded TM patients of approximately the same body weight, substantial increases in iron excretion of up to 71.5 mg can be observed by using the same dose of L1 [67,[123][124][125][126] .…”

“…Measurement of urinary iron excretions have shown that usually only about 1-3 mg iron can be excreted by normal individuals of about 75 kg body weight, per a 3 g dose of L1 [67,[124][125][126] . In comparison, in iron loaded TM patients of approximately the same body weight, substantial increases in iron excretion of up to 71.5 mg can be observed by using the same dose of L1 [67,[123][124][125][126] . Despite that the net amount of iron excreted by L1 in normal individuals is small, continuous administration over prolonged periods of many months and years may cause iron deficiency, unless iron can be replaced from dietary sources or from iron supplements [64,123] .…”

The Effects of Iron Chelation and Hypoxic or Hyperoxic Oxygen Manipulation on the Accumulation/Photobleaching of Protoporphryin IX and Cytotoxcity in Human Glioma Cells

“…Topical CP94 administration has been investigated in humans as way of improving PpIX-induced PDT for the treatment of certain non-melanoma skin cancers and precancers. Dose escalating pilot studies in nodular basal cell carcinoma (one treatment cycle without lesion debulking) with simultaneous topical ALA [26] or MAL administration [27] have already been conducted and determined that CP94 administration was a safe, effective and feasible treatment modification which did not produce any additional adverse reactions.…”