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At least 451 records · Page 25Linked to original sources
PubMed1989

Prevention of postischemic cardiac injury by the orally active iron chelator 1,2-dimethyl-3-hydroxy-4-pyridone (L1) and the antioxidant (+)-cyanidanol-3.

In this study, we investigated the role of oxygen-derived free radicals and iron in mediating myocardial injury during ischemia and reperfusion. Iron is of special interest because it may enhance tissue injury during ischemia and reperfusion by catalyzing the formation of highly reactive hydroxyl radicals (by modified Haber-Weiss or Fenton reactions). Rat hearts, perfused by the Langendorff method, were subjected to global ischemia (15 minutes at 37 degrees C) and reperfusion. The effects of two iron chelators, 1,2-dimethyl-3-hydroxy-4-pyridone (L1) and 5-hydroxy-2-hydroxymethyl-4-pyrone (kojic acid), and one antioxidant, (+)-cyanidanol-3, on contractile function, coronary flow, lactate dehydrogenase release, and lactate production were studied. The combination of these iron chelators is of special importance because L1 is known to prevent lipid peroxidation, induced by ADP/Fe3+ and NADPH in microsomes, in contrast to kojic acid. We found significant protection of contractile function (apex displacement) during reperfusion with 50 microM L1 and 20 microM (+)-cyanidanol-3 (p less than 0.01, n = 6), whereas no protection was found with 50 microM kojic acid (n = 6). Measurements of lactate dehydrogenase release during reperfusion showed a protective pattern similar to that found for heart contractile function, although 50 microM kojic acid also showed a significantly lower lactate dehydrogenase release during the first 10 minutes of reperfusion. No differences in coronary resistance or lactate release were found between the various groups. Our findings indicate that iron and oxygen-derived free radicals are important in the pathogenesis of postischemic reperfusion injury probably because of the formation of hydroxyl radicals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Comparative aluminium mobilizing actions of several chelators in aluminium-loaded uraemic rats.

The relative effectiveness of deferoxamine (DFO), 1,2-dimethyl-1,3-hydroxypyrid-4-one (L1), and citric and succinic acids in mobilizing and promoting excretion of aluminium (Al) were compared in female uraemic rats which had previously received aluminium nitrate nonahydrate i.p. in a daily dose of 45 mg kg-1 for 3 weeks (5 days/week). Chelators were administered s.c. at doses equal to one-eighth of their respective LD50 for five days. L1 was also given p.o. in doses of 200 mg kg-1 day-1. Total urines were collected 24 h after each chelator administration. Total urinary Al excreted over the 5-day period, expressed as mg kg-1, were: controls, 3.4; DFO-treated, 4.5 (P < 0.05); citric acid-treated, 3.7; and succinic acid-treated, 2.7. Although the daily amounts of Al excreted into urine by L1-treated rats were significantly higher (P < 0.001) than those of the controls, most animals died during the period of treatment. Measurements of Al in selected tissues 24 h after the last administration of each chelator revealed that none of the compounds significantly altered the Al concentration in bone, kidney, and brain, whereas only DFO and succinic acid significantly reduced the levels of Al in spleen. Moreover, L1 (given s.c. or p.o.) and citric acid treatment led to a significant reduction in the liver Al burden. These results indicate the need for further investigations to determine the toxicity and the therapeutical safety margins of L1.

Aluminum↗
PubMed1994

Drugs recently associated with lupus syndromes.

A number of drugs have recently been implicated in a syndrome that resembles systemic lupus erythematosus. One of the difficulties in many of these patients is that the signs, symptoms and serological abnormalities reported in these patients may be a natural consequence of the primary diseases rather than the incriminated drug. A second problem with the studies is a lack of uniform reporting of the techniques used to detect autoantibodies. For example, a patient that has a highly positive ANA with a homogeneous pattern of staining or a positive LE cell test usually has antibodies directed against chromatin components (DNA, histones, high mobility group (HMG) proteins). The discrepancies in clinical criteria and the serological techniques in many of these reports, emphasize the importance of using guidelines for the diagnosis of drug-induced or drug-related lupus. In the future, it appears that the increased use of biological response modifiers such as interferon-alpha and other cytokines may prompt more reports of lupus syndromes associated with their use.

Deferiprone↗
PubMed2001

Desferrioxamine-chelatable iron, a component of serum non-transferrin-bound iron, used for assessing chelation therapy.

This study introduces a method for monitoring a component of serum non-transferrin-bound iron (NTBI), termed "desferrioxamine-chelatable iron" (DCI). It is measured with the probe fluorescein-desferrioxamine (Fl-DFO), whose fluorescence is stoichiometrically quenched by iron. DCI was found in the serum of most patients with thalassemia major (21 of 27 tested, range 1.5-8.6 microM), but only in a minority of patients with hereditary hemochromatosis (8 of 95 samples from 39 patients, range 0.4-1.1 microM) and in none of 48 controls. The method was applied to monitoring the appearance of iron in the serum of patients under chelation therapy. Short-term (2 hours) follow-up of patients immediately after oral administration of deferriprone (L1) showed substantial mobilization of DCI into the serum (up to 10 microM within 30-60 minutes). The transfer of DCI from L1 to Fl-DFO was observed in vitro with preformed L1-iron complexes, and occurred even at L1/iron ratios exceeding 3:1. Simultaneous administration of oral L1 and intravenous DFO to patients abrogated the L1-mediated rise in DCI, consistent with the shuttling of iron from L1 to DFO in vivo. A similar iron transfer from L1 to apo-transferrin was observed in vitro, lending experimental support to the notion that L1 can shuttle iron in vivo to other high-affinity ligands. These results provide a rationale for using chelator combinations, with the highly permeant L1 acting as an intracellular chelator-shuttle and the less permeant DFO serving as an extracellular iron sink. Potential applications of the DCI assay may be for studying chelator action and as an index of patient chelation status.

Adolescent↗
PubMed2004

Iron: a target for the management of Kaposi's sarcoma?

BACKGROUND: Kaposi's sarcoma (KS) is a mesenchymal tumour associated with human herpesvirus-8 infection. However, the incidence of human herpesvirus-8 infection is far higher than the prevalence of KS, suggesting that viral infection per se is not sufficient for the development of malignancy and that one or more additional cofactors are required. DISCUSSION: Epidemiological data suggest that iron may be one of the cofactors involved in the pathogenesis of KS. Iron is a well-known carcinogen and may favour KS growth through several pathways. Based on the apoptotic and antiproliferative effect of iron chelation on KS cells, it is suggested that iron withdrawal strategies could be developed for the management of KS. Studies using potent iron chelators in suitable KS animal models are critical to evaluate whether iron deprivation may be a useful anti-KS strategy. SUMMARY: It is suggested that iron may be one of non-viral co-factors involved of KS pathogenesis and that iron withdrawal strategies might interfere with tumour growth in patients with KS.

Africa↗
PubMedDate not supplied

Microencapsulation of an iron chelator for sustained release and crystal habit modification.

DMHP (1,2-dimethyl-3-hydroxy-pyrid-4-one) is an orally-active iron chelator that has a short biological half-life and hence a sustained-release formulation is currently being developed. DMHP exists as needle-like crystals that cannot be size-characterized accurately for pharmaceutical manufacturing. The current study was undertaken to simultaneously achieve crystal-habit modification and provide sustained-release properties using a microencapsulation technique. Eudragit-RS, -RL, -L90 and Cellulose Acetate Phthalate were used in a phase-separation method to produce discrete, spheroidal, free flowing microcapsules of DMHP that could be sized readily. The obtained microcapsules were evaluated for drug content, size distribution, micromeritic properties, and in-vitro dissolution in gastric followed by intestinal pH environments at 37 degrees C. In-vitro dissolution studies revealed that DMHP release from the microcapsules can be retarded for up to 10 h. Changes in polymer type, polymer content, and processing parameters resulted in drastic changes in the microencapsulation process, and release characteristics of the microcapsules.

Acrylic Resins↗
PubMedDate not supplied

Blood disorders: future trends in iron chelation.

The treatment of iron overload in thalassaemic patients has for some time involved long periods of subcutaneous drug therapy. The inconvenience of sporting a portable syringe driver for up to ten hours at a time has led to reduced patient compliance rates, particularly among adolescent and teenage groups. Dorothy Jordan and George Kontoghiorghes describe a recent breakthrough which could result in many patients being able to resort to oral iron chelation therapy.

Adolescent↗
PubMed2002

I beg to differ.

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Academic Medical Centers↗
PubMed2003

The Olivieri case.

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Conflict of Interest↗
PubMed2003

Clinical research: a tale of two studies.

Threats to the status of clinical research have been well documented in the past three decades, and the National Institutes of Health and the Congress have done much to alleviate them. But the relationships of academic investigators and pharmaceutical companies remain a treacherous area. This vital nexus, on which so much progress depends, must be carefully maintained. In this paper I present two examples of academic/pharmaceutical company collaborations, both in search of a similar drug. The cases illustrate both some important hazards and accomplishments of clinical research.

Benzoates↗
PubMedDate not supplied

Urinary metabolic profiles in human and rat of 1,2-dimethyl- and 1,2-diethyl-substituted 3-hydroxypyridin-4-ones.

The urinary metabolic profiles of two novel orally active iron chelators, 1,2-dimethyl-3-hydroxypyridin-4-one (CP20 or L1) and 1,2-diethyl-3-hydroxypyridin-4-one (CP94), have been studied in rats. The metabolism of CP20 was also studied in humans. Four novel metabolites of CP20, and a further three metabolites of CP94 were characterized. CP20 was found to undergo extensive phase II metabolism at the 3-hydroxy position, forming predominantly the O-glucuronide, which accounted for 44% of the dose administered in rat and greater than 85% of the dose administered in man. The 3-O-methylated CP20 metabolite (metabolite I) accounted for 1% of the administered dose in both species, whereas the unmetabolized CP20 amounted to 10.5% and 4% of the dose administered in the rats and man, respectively. In contrast, CP94 was extensively hydroxylated at the 2-ethyl position to give its 2-(1-hydroxyethyl) metabolite in the rat, which accounted for 40% of the administered dose. The O-glucuronide metabolite of CP94 accounted for 13.8% of the administered dose, whereas the unmetabolized CP94 amounted to 6.9% of the administered dose. At 72 hr, urinary levels of CP20 and CP94 and their metabolites in the rat accounted for about 55-60% of the administered dose. A large portion of the dose is therefore probably eliminated via the bile. The identity of the above metabolites was established using a combination of two or more of the following techniques: fast atom bombardment-mass spectroscopy, LC-MS, UV-VIS spectroscopy, NMR spectroscopy, specific enzyme hydrolysis assays, and chemical synthesis of compounds.

Animals↗