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PubMed2006

Pilot study on the "quality of life" as reflected by psychosocial adjustment of children with thalassemia major undergoing iron-chelating treatment in western Taiwan.

Comprehensive care for thalassemia major (TM) patients has achieved great advances in the world, yet psychosocial developmental aspects of care in families with afflicted members has made only limited progress. Besides confronting the disease itself, a major task for children with TM is to develop into autonomous, healthy, and functioning adults. An emerging concept in considering the adjustment of children with chronic physical disorders is "quality of life"(QL). To study the QL with regard to reflection by psychosocial adjustment in TM children, we enrolled 55 TM patients undergoing intravenous (IV) and/or oral iron chelation, 39 of whom completed the content on issues related to QL according to Cramer and Devinsky. It was concluded that oral iron chelation can be better adjusted than IV iron chelation for a thalassemic child. This favors its use, but not necessarily in combination with IV iron chelation. Perception gaps that arise from age or generation merit concern. This approach to the study of QL, as reflected by psychosocial adjustment in children with TM, is an excellent method for learning about parental-child adjustment regarding a chronic physical condition such as TM.

Activities of Daily Living↗
PubMed2006

Pilot study on parental stress and behavioral adjustment to the thalassemia major disease process in children undergoing iron-chelation in western Taiwan.

Thalassemia was first described by Cooley and Lee in 1952 in several Italian children as a severe anemia with spleen and liver enlargement, skin discoloration, and bony changes. Great strides in management and intervention have not been matched by progress in psychosocial rehabilitation. Because parental stress and adaptation are of concern, this study focuses on parental stress and adjustment in response to the disease process of their afflicted children in western Taiwan. The parents of 18 thalassemia major patients (under 12 years of age) were interviewed (in two sessions) to determine their feelings, sources of stress, and support during their childrens' disease process. The study found that: 1) many parents suffer from stress as a result of the disease process, 2) all parents had similar concerns about iron chelation treatment, and 3) some resilience factors were present in the support system.

Adaptation, Psychological↗
PubMed1995

Effect of iron chelation on the in-vitro growth of Leishmania promastigotes.

The development of vaccines and drugs to control leishmaniasis is urgently needed. The presence of a leishmania transferrin receptor on the parasite suggests that an adequate supply of iron is needed for the life cycle of leishmania. We have investigated the effect of iron deprivation on the growth of leishmania promastigotes in vitro using an iron chelation approach. All chelators tested reduced the rate of promastigote multiplication in a dose-dependent fashion, whereas referrated ones did not. The hydroxypyridin-4-one chelators CP94 and L1 were found to be more efficient than desferrioxamine. We suggest that iron depletion may be an effective mechanism against leishmania infection.

Animals↗
PubMed1991

A high-performance liquid chromatographic method for the measurement of the iron chelator 1,2-dimethyl-3-hydroxypyridin-4-one in human plasma.

1,2-Dimethyl-3-hydroxypyridin-4-one (CP020 or L1) is a novel oral iron chelator that has proved to be effective in animals and humans. A rapid, accurate, and sensitive high-performance liquid chromatography method is described for measuring L1 in human plasma using a Hypercarb 7 microns column and monitoring the column eluent by ultraviolet absorption at 280 nm. CP020 and the internal standard (CP094) were extracted into dichloromethane (2 x 5 ml) from plasma at neutral pH [0.25 ml of plasma + 0.75 ml of 60 mM 3-(N-morpholino)propanesulfonic acid buffer, pH 7.4]. The method proved to be linear (r2 = 0.998) in the clinical range of 0.5-50 micrograms/ml when 0.25 ml of plasma was used, with the coefficient of variation less than 10% even at the lower concentration range.

Adolescent↗
PubMed1986

Orally active alpha-ketohydroxy pyridine iron chelators intended for clinical use: in vivo studies in rabbits.

Increased daily iron excretion from iron overloaded, 59Fe lactoferrin labelled rabbits was observed following the intragastric administration of 1,2-dimethyl-3-hydroxy pyrid-4-one (L1) or 1-ethyl-2-methyl-3-hydroxy pyrid-4-one (L1-NEt) at doses of 200 mg/kg. 59Fe excretion induced by these drugs was predominantly faecal and was comparable to that caused by similar doses of subcutaneous or intramuscular desferrioxamine. The effectiveness of the two alpha-ketohydroxy pyridine chelators was confirmed by repeated administration, intragastrically or by subcutaneous or intramuscular injection, to the same or other rabbits. Examination of the urine during the administration of the chelators revealed their high specificity for iron but not for copper, zinc, calcium or magnesium.

Animals↗
PubMed1990

Studies of an oral iron chelator: 1,2-dimethyl-3-hydroxy-pyrid-4-one. I. Iron excretion in rats: development of a new rapid microwave method for iron analysis in faeces.

We have developed a simple, rapid method for analysing faecal iron using a microwave oven for digestion followed by atomic absorption spectrometry. The chelating effect of 1,2-dimethyl-3-hydroxy-pyrid-4-one (DMHP) has been tested in rats with experimental iron overloading and three routes of DHMP administration, oral, subcutaneous, and intraperitoneal, have been compared. Regardless of the route of administration, we have found that DMHP promotes iron excretion via the urine. We have not observed a difference in the amount of iron excreted in the faeces before and after DMHP administration by any route. The subcutaneous route of administration is the most effective in promoting iron excretion, followed by the intraperitoneal route. Although most convenient for clinical use, oral administration promotes the excretion of only a small fraction of that by the subcutaneous route.

Animals↗
PubMed1990

Long-term trial with the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1). I. Iron chelation and metabolic studies.

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.

Anemia↗
PubMed1990

Long-term trial with the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1). II. Clinical observations.

1,2-Dimethyl-3-hydroxypyrid-4-one (L1) has been given daily for 1-15 months to 13 transfusion dependent iron loaded patients. No significant change occurred in liver, renal or cardiac function, ECG and radionucleotide angiocardiogram, in audiometry tests and in visual function and electrical retinography. No skin rashes, gastrointestinal symptoms and no neurological changes that could be detected clinically were observed. Two of the patients died of their underlying diseases. One patient had severe cardiac abnormalities before receiving L1 and died of congestive heart failure with infections 5 weeks after stopping a 2-month course of L1. The other, a patient with myelodysplasia suffered recurring infections due to progression of the disease. Joint and muscle pains occurred in five patients. In two these disappeared despite continuing the drug; another patient developed swollen ankle joints which gradually resolved on stopping L1 therapy; a patient with underlying osteoarthritis complained of mild pain and stiffness in her knees which remained intermittent both on and off the drug while in the fifth patient peripheral small joint swelling and pain present before starting L1 improved with L1 therapy. One patient, with Blackfan Diamond anaemia, developed a Lw red cell antibody 6 months after commencing L1. This disappeared on stopping the drug and did not reappear. She then developed severe agranulocytosis and thrombocytopenia 6 weeks after recommencing L1 after 3 months discontinuation of the drug. No other patient showed a change in granulocyte or platelet count.

Adolescent↗
PubMed1990

L1 (1,2-dimethyl-3-hydroxypyrid-4-one) for oral iron chelation in patients with beta-thalassaemia major.

L1 was given to eight patients with beta-thalassaemia major who had previously been treated with deferoxamine (DF) for 4-10 years. The patients' ages ranged from 11 to 27 years. Serum ferritin values ranged from 1.3 to 11.5 x 10(3) micrograms/l. L1 was given twice daily at a daily dose of 55-80 mg/kg body weight and was continued for 10 months in two patients, 9 months in three, 7 months in two patients and 4 months in one patient. As previously observed with DF, each patient's urinary iron excretion (UIE) varied greatly from day to day. The mean UIE of the eight patients ranged from 11 to 49 mg/d (0.2-0.87 mmol/d) on subcutaneous DF and from 16 to 53 mg/d (0.28-0.95 mmol/d) on L1. Two patients excreted significantly more and one patient significantly less iron while on L1. If the UIE was calculated as mmol Fe/mmol creatinine there was no statistically significant difference. Serum ferritin values fluctuated widely in all, with a consistent downward trend in three, no change in four and an increase in one of two non-splenectomized patients. This patient's splenomegaly and need for transfusions continued to increase while on L1. No toxicities attributable to the drug were detected during the period of study and tolerance of the drug was excellent.

Adolescent↗
PubMed1992

Serum non-transferrin-bound iron in beta-thalassaemia major patients treated with desferrioxamine and L1.

Non-transferrin-bound iron (NTBI) in plasma is toxic due to its ability to participate in free radical formation with resultant peroxidation and damage to cell membranes and other biomolecules. NTBI concentration was determined in serum in 12 normal volunteers and in 52 patients with beta-thalassaemia major by a modification of the method described by Singh et al (1990). There was no detectable NTBI in normal individuals. In the patients NTBI values ranged from -1.5 to 9.0 mumol/l (mean +/- SD: 3.6 +/- 2.3). The patients' serum ferritin concentrations ranged from 207 to 11,400 micrograms/l (2674 +/- 2538), total serum iron from 20 to 61 mumol/l (39.5 +/- 9.6) and transferrin saturation from 44 to 110% (84.5 +/- 13.8). The NTBI correlated significantly with serum ferritin (r = 0.467, P < 0.001), total serum iron (r = 0.608, P < 0.001) and transferrin saturation (r = 0.481, P < 0.005). When patients were grouped according to their compliance with desferrioxamine (DFX) therapy, the good compliers had significantly lower NTBI concentrations compared to the poor compliers (poor: 5.4 +/- 1.8 mumol/l v good: 2.7 +/- 1.7 mumol/l, P < 0.001). There was also a significant difference between the level of NTBI and whether or not the patients had complications of iron overload (5.2 +/- 1.7 mumol/l v 2.9 +/- 1.6 mumol/l, P < 0.001). During this study 10 patients were entered into a trial of the oral iron chelator 1,2- dimethyl-3-hydroxypyrid-4-one (L1). Their NTBI values were observed during the first 6 months of the trial and showed a significant fall (paired t-test: P = 0.007). These results suggest that the level of NTBI may prove helpful in assessing the efficiency of chelation in patients with transfusion dependent anaemia and help to predict organ damage.

Adolescent↗
PubMed1992

Long-term assessment of efficacy and safety of L1, an oral iron chelator, in transfusion dependent thalassaemia: Indian trial.

From August 1989 to May 1991, 52 patients with transfusion dependent thalassaemia major received L1 (1,2-dimethyl-3- hydroxypyrid-4-one), the oral iron chelator, for a period of 3-21 months (mean +/- SD: 14.2 +/- 6.8). Mean (+/- SD) urinary iron excretion varied from 6.2 +/- 4.6 mg/d on 25 mg/kg/d of L1 to 42.3 +/- 37.1 mg/d on 100 mg/kg/d of L1. Mean (+/- SD) drop in S ferritin was 1465 +/- 990 micrograms/l after 5.0 +/- 0.8 months to 3641.2 +/- 2299.3 micrograms/l after 20.1 +/- 0.9 months of therapy. There was no evidence of neutropenia, thrombocytopenia, ear or eye toxicity. L1-related arthralgia, which was reversible on dose reduction or stoppage, was seen in 20 patients (38.5%), while minor gastrointestinal (GI) tract symptoms occurred in seven (3.5%) cases. We conclude that although L1 is an effective iron chelator, further studies are required to understand the mechanism of L1 related arthralgia and also to find a safer but effective dose on which incidence of L1 related arthralgia is minimal.

Adolescent↗
PubMed1994

The transport of two iron chelators, desferrioxamine B and L1, across Caco-2 monolayers.

The transport of two iron chelators, desferrioxamine B (DFO) and L1 (1,2-dimethyl-3 hydroxypyridin-4-one) has been studied in vitro using the human adenocarcinoma cell line, Caco-2. The transport of DFO and L1 has also been compared with that of their iron-bound complexes, ferrioxamine (FO) and L1(3)-Fe, respectively. We report an apparent permeability coefficient (Papp) value for DFO of 0.170 x 10(-7) +/- 0.080 cm s-1. The Papp value of L1 was 1.297 x 10(-5) +/- 0.133 cm s-1. The Papp values of their iron bound complexes FO and L1(3)-Fe are 0.230 x 10(-7) +/- 0.065 cm s-1 and 2.356 x 10(-6) +/- 0.365 cm s-1, respectively. We have shown that the transport of DFO and FO is similar in the Caco-2 cell system. The transport of L1, however, is greatly reduced when complexed to iron. The value for total uptake after 60 min for DFO into the Caco-2 cells was 1.49 +/- 0.09 x 10(-3) nmol per filter. The values for total uptake after 60 min for L1 and L1(3)-Fe were 0.37 +/- 0.03 nmol per filter and 0.04 +/- 0.01 nmol per filter, respectively. Our results indicate that the poor oral bioavailability of DFO can be attributed to the low epithelial permeability of the molecule coupled with its size (mol wt 656). In contrast, the oral bioavailability observed with L1 is due to the high lipophilicity and low molecular weight (mol wt 139) of the molecule. We believe that these differences between the two molecules account for L1 being better orally absorbed than DFO.

Biological Transport↗
PubMed1995

Iron chelators induce apoptosis in proliferating cells.

The iron chelators 1,2-dimethyl-3-hydroxypyrid-4-one (L1) and desferrioxamine (DFO) were found to induce apoptosis of proliferating activated T-lymphocytes and of the promyelocytic cell line HL60, but not of resting peripheral blood lymphocytes or granulocytes. The induction of apoptosis was quantified by propidium iodide staining of apoptotic/dead cells and flow cytometry. In activated T-lymphocytes incubated with the chelators at equivalent iron-binding concentrations (300 microM L1 or 100 microM DFO) for 24 h, L1 caused a 54% increase in cell death and DFO a 57% increase. In HL60 cells L1 caused a 50% increase in cell death and DFO a 40% increase. DNA cytofluorometry of HL60 cells treated with either chelator showed an increase in the percentage of cells with hypodiploid DNA content. Presaturation of the chelators with ferric chloride abrogated these effects. L1 and DFO did not induce apoptosis in resting peripheral blood lymphocytes or granulocytes, even after 48 h of incubation.

Apoptosis↗
PubMed1986

Dose response studies using desferrioxamine and orally active chelators in a mouse model.

59Fe excretion studies in response to different doses (4-9 mg) of three N-substituted 3-hydroxypyrid-4-one chelators, (1,2-dimethyl-3-hydroxypyrid-4-one, 1-ethyl-2-methyl-3-hydroxypyrid-4-one, 1-propyl-2-methyl-3-hydroxypyrid-4-one), and desferrioxamine in iron overloaded 59Fe lactoferrin labelled mice (40 +/- 4 g) have shown that the former chelators, when administered intraperitoneally and intragastrically, caused comparable 59Fe excretions to intraperitoneal desferrioxamine of equivalent doses. No apparent ill effects were observed when doses of 300 mg/kg were administered for 24 d.

Administration, Oral↗
PubMed1994

Differential toxicity of alpha-keto hydroxypyridine iron chelators and desferrioxamine to human haemopoietic precursors in vitro.

Compliance with iron chelation therapy improves life expectancy in transfusion-dependent haematological disorders. However, failure of compliance with parenteral desferrioxamine (DF) therapy and the expense incurred makes this drug unavailable for most patients in the developing world. We have been evaluating the orally active iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) in both preclinical and clinical trials. Five patients have developed reversible agranulocytosis during treatment with this agent. We have now studied the effects of L1, other alpha-ketohydroxypyridines and DF on bone marrow myeloid progenitors using the CFU-GM system. The results show that L1 is less toxic than DF to normal bone marrow myeloid progenitors (ID50:130 mumol/l versus 7.9 mumol/l). The L1 ID50 is within the previously reported range of peak plasma values (80-450 mumol/l). When saturating concentrations of iron were added to the cultures, the mean toxicity of all the chelators was significantly decreased over the range of doses tested, e.g. L1 ID50, 567 mumol/l; DF ID50, > 1000 mumol/l. The toxicity of L1 in vitro was similar for marrows from 3 normal donors and for the recovery marrow from a patient with thalassaemia major who had experienced agranulocytosis. Further studies are required to elucidate the mechanisms of L1-induced agranulocytosis.

Bone Marrow Cells↗
PubMed1995

Action of reactive oxygen species and their antagonists on twitch tension of the rat phrenic nerve-diaphragm.

Reactive oxygen species have been implicated in normal and pathological processes of many tissues, including skeletal muscle. I extended previous studies by examining the effect of these intermediates and eight of their antagonists (superoxide dismutase, catalase, deferoxamine, [Cu(II)]2(3,5-diisopropylsalicylate)4, 1,2-dimethyl-3-hydroxy-pyridone, 1,3-dimethyl-2-thiourea, N-(2-mercaptopropionyl)-glycine, vitamin E) on indirectly stimulated twitch tension of an in vitro neuroskeletomuscular preparation, the phrenic nerve-diaphragm of the rat. In the absence of exogenous reactive oxygen species, none of the antagonists potentiated twitch tension, and all but one (N-[2-mercaptopropionyl]-glycine) of the membrane-permeant antagonists attenuated twitch tension. The reactive oxygen intermediate-generating system of purine plus xanthine oxidase reduced indirectly stimulated twitch tension by 36% while having no effect on directly stimulated twitch tension. Catalase (but not superoxide dismutase or deferoxamine) eliminated the reduction in twitch tension, indicating that hydrogen peroxide played a role in the reduction. The membrane-permeant antagonists [Cu(II)]2(3,5-diisopropylsalicylate)4 and 1,2-dimethyl-3-hydroxy-pyridone also eliminated the reduction in twitch tension caused by reactive oxygen species, suggesting that hydrogen peroxide could have acted intracellularly through an iron-catalyzed Haber-Weiss reaction to produce hydroxyl radical, which in turn reacted with intracellular components, thereby reducing twitch tension.

Analysis of Variance↗