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PubMed2001

[Therapeuetic management of patients with thalassemia major].

In industrialised countries, the use of regular blood transfusions and of chelation therapy with Deferoxamine (DFO) has led to the transformation of thalassemia major from a fatal disease in early childhood to a chronic illness associated with prolonged survival. Transfusion regimens maintaining pretransfusion hemoglobin > 9-10 g/dl are effective in suppressing erythroid marrow expansion. Long term DFO therapy using subcutaneous infusions at least 4-6 d a week have clearly demonstrated major effects on iron overload complications. DFO treatment reduces excessive iron and prevents cardiac, hepatic and endocrine diseases. Nonetheless, compliance is difficult for many patients and the cost of DFO limits its use in developing countries. The only oral iron chelating agent that has been investigated extensively is Deferiprone (L1). In France, this oral agent can be administered in patients experiencing toxic side effects under DFO treatment. Since 1981 more than 1500 bone-marrow transplants have been performed word-wide, mostly in Italy. Allogenic BMT is currently able to cure 85% of thalassemic children with an available HLA matched sibling donor.

Blood Transfusion↗
PubMed2001

Royal Society of Chemistry--sixth international symposium on applied bioinorganic chemistry.

This was the sixth in a series of symposia that began in Beijing, China in 1986. Approximately 100 chemists, environmental and biomedical scientists from 25 countries attended the meeting and presented some 80 papers on topics ranging from cancer chemotherapy to the production of paper. About half the papers presented could be broadly described as having medical implications, and of these, approximately half related directly to the use of platinum and the potential uses of other metals, such as palladium and the lanthanides, as anticancer agents. Many of these papers provided valuable insights into mechanisms of action and offered pointers for future research, but only rarely did they point to potential new drugs that might find early exploitation in clinical medicine. Two of the more exciting clinical developments were the introduction of the insulin-mimetic bis(maltolato)oxovanadium(IV) (KP-102; Kinetek Pharmaceuticals Inc/University of British Columbia) into clinical trials in the UK for the treatment of Type II diabetes, and the increasing importance of the orally active agent 3-hydroxy-pyridin-4-one-deferiprone (Apotex Inc/Cipla Ltd), in the treatment of iron overload in thalassemia.

Journal Article↗
PubMed1994

[Current possibilities in the therapy of iron overload].

Tissue damage, cardiac and hepatic failure are the most frequent consequences of chronic iron accumulation within the body. A long term administration of chelating agents may prevent organ damage by surplus of iron as well as improve cardiac and liver function in iron overloaded patients. Desferrioxamine (Desferal) is the only one chelating agent for routine clinical use. To produce a therapeutic effect parenteral administration of the drug in prolonged infusions is needed and therefore many investigators try to search for orally active chelator with effect comparable to desferrioxamine. Hydroxypyridones, especially 1,2-dimethyl-3-hydroxypyrid-4-one (L 1-Deferiprone), are the most intensively studied oral iron chelators. In animal and clinical studies L 1 administration caused iron excretion comparable to that obtained by desferrioxamine, however, some serious adverse effects (including agranulocytosis) related to L 1 treatment were observed. This problem still precludes wide large-scale clinical application of L 1. Other compounds possessing chelating activity after oral administration, eg. 1,2-diethyl-3-hydroxypyridone, PIH or HBED are also currently under investigation. Development of a safe inexpensive and orally effective iron chelator is the main objective of ongoing animal and clinical studies.

Deferoxamine↗
PubMed1990

Effect of novel 1-alkyl-3-hydroxy-2-methylpyrid-4-one chelators on uptake and release of iron from macrophages.

The effect of several iron chelators on iron uptake and release by mouse peritoneal macrophages has been investigated. The 1,2-dimethyl (L1) and 1-ethyl-2-methyl (L1NEt) derivatives of 3-hydroxypyrid-4-one markedly enhanced iron mobilisation from macrophages pulsed with 59Fe-transferrin-antitransferrin immune complexes and were more effective than desferrioxamine, maltol, or mimosine. Release increased with increasing chelator concentration. None of the chelators donated significant amounts of iron to macrophages, and none showed any cytotoxic effect. The synthetic alpha-ketohydroxypyridine chelators may therefore be active in removing iron from the reticuloendothelial system as well as from hepatocytes, and indeed may be superior to desferrioxamine.

Animals↗
PubMed2001

Genotoxicity of iron chelators in L5178Y mouse lymphoma cells.

To further study the mechanism of observed iron mutagenicity and cellular toxicity, a number of different iron chelators were evaluated to select a compound that was not mutagenic and had limited toxicity to mouse lymphoma cells. A series of iron chelators including those used clinically, those under development for clinical applications, and those used in nonclinical applications were evaluated. The mutagenic activity of the iron chelators was assessed in L5178Y mouse lymphoma cells. Eight of the 12 iron chelators that were tested induced mutagenic responses both with and without the addition of S9. Among those chelators used clinically or developed for clinical use, the only compound that did not induce a mutagenic response was the starch deferoxamine conjugate. In contrast, deferoxamine mesylate showed the highest toxicity in this group of chemicals and the concentrations leading to toxicity and mutagenicity between the activated and nonactivated assays were not significantly different. The other three chelators that were not mutagenic were Na2EDTA, phytic acid, and ferrozine.

Animals↗
PubMed1994

Critical comparison of novel and existing methods of compliance assessment during a clinical trial of an oral iron chelator.

The assessment of compliance is critical in the evaluation of the effectiveness of a new therapeutic agent. Fifteen patients with transfusion-dependent beta-thalassemia, many of whom had previously demonstrated erratic compliance with deferoxamine, were enrolled in a clinical trial of a new oral iron chelator, 1,2-dimethyl-3-hydroxypyrid-4-one (L1). Their compliance with this medication was estimated by several existing methods and the novel Medication Event Monitoring System (MEMS). Overall compliance as assessed by the MEMS was 78.5 +/- 13.0% of prescribed doses taken, significantly lower than the corresponding rates calculated by pill counts and diaries (91.5 +/- 9.2% and 94.1 +/- 4.3%, respectively). However, several serious problems were encountered with the MEMS, mostly in the form of incorrect use of the device by the patients. Disclosure of the nature of the MEMS and the compliance monitoring process did not alter the rate of adherence with L1 therapy. Compliance as determined by pill counts did not differ between the 1st and 2nd 6-month periods. Although not reaching statistical significance, a trend towards better L1 compliance occurred in those patients in whom serum ferritin levels decreased. Patients who filled at least 50% of their diaries had significantly better compliance by pill counts than those who completed less than 50% of their diaries (95.9 +/- 4.1% and 86.5 +/- 11.1%, respectively). Steady-state L1 trough concentrations and 24-hour urinary iron excretion did not correlate with L1 compliance.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1991

Solid state properties of an oral iron chelator, 1,2-dimethyl-3-hydroxy-4-pyridone, and its acetic acid solvate. I: Physicochemical characterization, intrinsic dissolution rate, and solution thermodynamics.

1,2-Dimethyl-3-hydroxy-4-pyridone (1), a crystalline oral iron chelator, forms an acetic acid solvate (2) on recrystallization from acetic acid and carbon tetrachloride. Compound 2 forms compact prisms, and 1 forms needles from water (mp 274 degrees C). The X-ray powder diffraction patterns of 1 and 2 differ, indicating distinct solid phases. Compound 2 has an extra DSC endotherm at 82 degrees C that is accompanied by a weight loss of 29% in TGA, corresponding to the desolvation of a 1:1 acetic acid solvate. Comparison of the solid-state 13C NMR of 1 and 2 revealed two additional peaks for 2 at 20.3 and 175.6 ppm, characteristic of -CH3 and -COOH, respectively, of acetic acid. The integrated intensities confirmed the 1:1 stoichiometry between 1 and acetic acid. However, 2 underwent desolvation in air at 25 degrees C as suggested by a change in its appearance to opaque crystals and as confirmed by X-ray powder diffraction, DSC, and TGA. Desolvation of 2 at 25 degrees C was a zero-order process with a rate constant of 6.9 mumol.h-1. X-ray powder diffraction showed that crystals or compacted discs of 1 are converted to 2 in contact with glacial acetic acid (A), whereas crystals or discs of 2 are converted to 1 in contact with water. The intrinsic dissolution rate (J) and the apparent solubility (Cs) of compacted discs of 1 and 2 were measured in water at 25 degrees C, and the following relations were determined: J(2)/J(1) = 1.39 and Cs(2)/Cs(1) = 1.70.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetates↗
PubMed1992

Crystal structures of a new oral iron chelator, 1,2-dimethyl-3-hydroxy-4-pyridone, and its solvates with acetic acid and formic acid.

The crystal structures of a new oral iron chelator, 1,2-dimethyl-3-hydroxy-4-pyridone (DMHP), and of its 1:1 solvates with formic acid (DMHP,F) and acetic acid (DMHP,A) were determined by single-crystal X-ray diffraction. The data were collected at temperatures of 23 +/- 1 degrees C for DMHP, -64 +/- 1 degrees C for DMHP,F, and -120 +/- 1 degrees C for DMHP,A. The iron chelator DMHP is orthorhombic [Pbca, a = 7.290(5) A, b = 13.046(4) A, c = 13.748(6) A, Z = 8]. The DMHP molecules form centric dimers, each in a 10-membered ring in which the OH group of one molecule is hydrogen-bonded to the CO oxygen of the other [O-H...O; 0.91(4) A, 153(3)degrees, 1.85(4) A]. In each DMHP molecule, the OH group and CO oxygen are insignificantly intramolecularly hydrogen-bonded [O-H...O; 0.91(4) A, 107(3)degrees, 2.33(4) A]. DMHP,F is monoclinic [C2/c, a = 21.825(9) A, b = 3.811(5) A, c = 20.491(6) A, beta = 92.80(3)degrees, Z = 8]. The fundamental intermolecular and insignificant intramolecular hydrogen-bonded dimer structure of DMHP is maintained but is distorted and is supplemented by hydrogen bonds between the CO oxygen of each DMHP molecule and the OH group of one formic acid molecule [O-H...O; 0.99(5) A, 176(3)degrees, 1.53(4) A]. However, the two DMHP and the two formic acid molecules are twisted out of plane like the blades of a four-bladed propeller. DMHP,A is triclinic [P1, a = 8.458(2) A, b = 8.471(2) A, c = 6.986(3) A, alpha = 104.33(2)degrees, beta = 92.57(2)degrees, gamma = 88.78(2)degrees, Z = 2].(ABSTRACT TRUNCATED AT 250 WORDS)

Acetates↗
PubMed1995

Relationships between crystal structures, thermal properties, and solvate stability of dialkylhydroxypyridones and their formic acid solvates.

Four 1,2-dialkyl-3-hydroxy-4-pyridones (DAHPs), which are iron chelators potentially suitable for oral administration, and their formic acid solvates (DAHP-Fs) were examined in powder form by powder X-ray diffraction (PXD), differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), and hot-stage microscopy (HSM). The experimental PXD pattern of each DAHP-F is different from that of the corresponding DAHP, indicating different crystalline phases. The PXD patterns calculated from the published crystal structures closely resemble the corresponding PXD patterns determined experimentally, indicating that the powdered materials studied are structurally identical with the single crystals previously examined. The DAHPs have similar DSC profiles consisting of melting followed by vaporization. The DSC profiles of the DAHP-Fs share five common features: melting and desolvation of the solvate, crystallization of the nonsolvate, vaporization of the released formic acid, melting of the nonsolvate, and vaporization of the nonsolvate. The weight loss steps in TGA indicate that each DAHP-F contains 1 mol of formic acid/mol of DAHP. The threshold temperature for desolvation of each DAHP increases with decreasing length of the hydrogen bond between the pyridone carbonyl oxygen and the formic acid carboxyl proton, corresponding to an increase in solvate stability. Thus, the relative stabilities of the solvates are delineated and are related to the length of the hydrogen bond between the DAHP and the formic acid molecules.

Calorimetry, Differential Scanning↗
PubMed1994

Effects of chelators on iron uptake and release by the brain in the rat.

The iron chelators desferrioxamine (DFO), pyridoxal isonicotinoyl hydrazone (PIH), 2,2'-bipyridine, diethylenetriamine penta-acetic acid (DTPA) and 1,2 dimethyl-3-hydroxy pyrid-4-one (CP20) were analysed for their ability to change 59Fe uptake and release from the brain of 15- and 63-day rats either during or after intravenous injection of 59Fe-125I-transferrin. DTPA was the only chelator unable to significantly reduce iron uptake into the brain of 15-day rats. This indicates that iron is not released from transferrin at the luminal surface of brain capillary endothelial cells. CP20 was able to reduce iron uptake in the brain by 85% compared to 28% with DFO. Only CP20 was able to significantly reduce brain iron uptake in 63 day rats. Once 59Fe had entered the brain no chelator used was able to mediate its release. All of the chelators except CP20 had similar effects on femur iron uptake as they did on brain uptake, suggesting similar iron uptake mechanisms. It is concluded that during the passage of transferrin-bound iron into the brain the iron is released from transferrin within endothelial cells after endocytosis of transferrin.

2,2'-Dipyridyl↗
PubMed1996

Human gelatinase B, a marker enzyme in rheumatoid arthritis, is inhibited by D-penicillamine: anti-rheumatic activity by protease inhibition.

The direct and indirect inhibitory potential of D-penicillamine toward human neutrophil and synovial fluid gelatinase B, a marker enzyme for disease severity in RA, was investigated. Gelatinase and plasminogen activator activities were assessed by SDS-polyacrylamide gel electrophoresis zymography. D-penicillamine significantly inhibits purified and synovial fluid gelatinase B in vitro at concentrations attainable in vivo and also blocks in vitro plasminogen activation. Protease inhibition may be a mechanism of action for D-penicillamine as DMARD.

Anti-Bacterial Agents↗
PubMed2005

The Olivieri case: lessons for Australasia.

The case of Dr. Nancy Olivieri, the Hospital for Sick Children, the University of Toronto, and Apotex Inc. vividly illustrates many of the issues central to contemporary health research and the safety of research participants. First, it exemplifies the financial and health stakes in such research. Second, it shows deficits in the ways in which research is governed. Finally, it was and remains relevant not only in Toronto but in communities across Canada and well beyond its borders because, absent appropriate policies, what happened in Toronto could have happened (and could well still happen) elsewhere. In Part One of this paper, we review the facts of the Olivieri case relevant to the issues we wish to highlight: first, the right of participants in a clinical trial to be informed of a risk that an investigator had identified during the course of the trial and the obligation of the investigator to inform participants (both her own and those of other investigators); and second, the obligation of institutions to protect and promote the well-being of research participants as well as academic freedom and research integrity, the obligations of research sponsors to inform participants, research regulators, and others about unforeseen risks, and the obligations of research regulators to ensure that participants are informed of unforeseen risks and to otherwise protect and promote research integrity. In Part Two, we relate these facts and issues to New Zealand and Australia. We also make detailed recommendations for changes to the various instruments used for the governance of research involving humans in Australasia.

Australia↗
PubMed1992

Studies of in vivo iron mobilization by chelators in the ferrocene-loaded rat.

The oral efficacy of the oral iron chelators 1,2-dimethyl-3-hydroxypyrid-4-one (CP20), 1,2-diethyl-3-hydroxypyrid-4-one (CP94) and desferrioxamine B (DFO) has been compared with intraperitoneal DFO in an experimental model of iron overload with similar biochemical and biophysical characteristics to those observed for human genetic haemochromatosis. The hepatic iron stores in the ferrocene-loaded rat were relatively stable and did not decrease at the end of the loading period. In contrast, the iron dextran rat model showed a rapid depletion of its iron stores 2 weeks after cessation of intraperitoneal injection. When CP20 and CP94 were administered to the ferrocene-loaded rat model in combination with an iron-free diet there were significant decreases in (i) total homogenate iron and (ii) hepatic ferritin iron when compared to the iron-loaded rat receiving the iron-free diet alone. Desferrioxamine, when administered by gavage, only showed chelation of ferritin iron, while intraperitoneal injection of desferrioxamine showed significant depletion of iron both in the total homogenate and ferritin. Subcellular fractionation of the hepatic organelle clearly showed that where there was depletion of homogenate iron there was a net decrease in the lysosomal fraction, while changes in ferritin iron were reflected by decreases in the cytosolic iron content. Although no assessment of net iron excretion was made, we suggest that the use of this animal model should ascertain the site of chelation by iron chelators.

Animals↗