Effective Iron Chelator Research Articles

Free radical and cytotoxic effects of chelators and their iron complexes in the hepatocyte.

In a comparative screening study of chelators intended for clinical use eleven iron chelators have been tested for their ability to mobilize (59Fe) iron from 59Fe-labelled ferritin and from hepatocytes of rats labelled with 59Fe-transferrin. The toxic effects of the chelators were also studied using microsomal lipid peroxidation induced by Fe3+/ADP and NADPH. From these tests it was shown that 1,2-dimethyl 3-hydroxypyrid-4-one (L1) and mimosine were the most effective iron chelators in iron mobilization and did not catalyse lipid peroxidation. In conclusion it can be stated that besides to investigate the iron binding capacity of new chelators also their ability to catalyse lipid peroxidation has to be ruled out.

Cytotoxic effects of the lipophilic iron chelator omadine

Cytotoxic effects were observed following 4 h incubation of human leukaemic cells with the iron chelator 1-hydroxypyridine-2-thione (omadine). Its Cytotoxic activity was comparable to that of the cytotoxic drug doxorubicin. At the same concentration two other effective iron chelators, desferrioxamine and 1,2-dimethyl-3-hydroxypyrid-4-one, were not cytotoxic. Addition of iron augmented the effect of omadine. It is suggested that the lipophilic properties of omadine and of its iron complex cause their intracellular accumulation and potent cytotoxic activity.

Iron chelation by pyridoxal isonicotinoyl hydrazone and analogues in hepatocytes in culture

Pyridoxal isonicotinoyl hydrazone (PIH) and several analogues were synthesized and assessed in the rat hepatocyte culture for their potential in iron chelation therapy. Pyridoxal isonicotinoyl hydrazone and pyridoxal benzoyl hydrazone were as effective as desferrioxamine (DFO) in reducing both net uptake of rat transferrin- 59Fe and incorporation into ferritin by hepatocytes. Dialysis studies showed that this was due to a cellular action and not to the extracellular chelation of transferrin-bound 59Fe. The analogues of PIH were more effective in mobilization studies than PIH and DFO, releasing more 59Fe from ferritin as well as from the stroma-mitochondrial membranes in hepatocytes prelabelled using transierrin- 59Fe. Chelator action was dependent on incubation time, concentration, temperature and lipophilicity. Pyridoxal benzoyl hydrazone, the most effective iron chelator, was also the most lipophilic, suggesting that access to cellular iron compartments as well as iron-binding affinity is important in effective iron chelation.

Susceptibilities of bacterial and fungal urinary tract isolates to desferrioxamine.

Desferrioxamine, a safe and effective iron chelator, was evaluated for its antibacterial and antifungal activity. The susceptibilities of 124 urinary tract isolates and 28 clinical isolates of Neisseria gonorrhoeae to desferrioxamine concentrations that are readily achievable in urine were determined. Of all isolates, 27% were inhibited by a concentration of less than or equal to 12.5 mM. Proteus mirabilis and N. gonorrhoeae isolates were particularly susceptible to the chelator. Desferrioxamine appears to have limited potential as an antibacterial agent.

Effect of a specific iron chelating agent on animal models of inflammation.

Iron is an important catalyst of oxidative radical reactions and promotes the formation of the hydroxyl radical from the superoxide anion radical and hydrogen peroxide. The stimulatory effect of the hydroxyl radical on lipid peroxidation prompted the speculation that free iron may directly promote inflammation and that iron chelating agents may have useful anti-inflammatory properties. This hypothesis is tested in animal models of inflammation with a specific iron chelating agent, desferrioxamine. At low doses (6 . 6 mg/kg) intraperitoneal desferrioxamine stimulated the induction of acute foot pad swelling in rats by monosodium urate but at higher doses (above 200 mg/kg) it suppressed this inflammatory reaction. A similar anti-inflammatory effect was observed in carrageenan-induced foot pad swelling. In guinea-pigs in which a Glynn-Dumonde synovitis was induced with bovine gammaglobulin, desferrioxamine (100 mg/kg) stimulated the acute inflammatory induction phase of this chronic allergic monoarthritis model. Repeated administration of desferrioxamine (100 mg/kg) from the seventh to the twelfth day after intra-articular challenge with bovine gammaglobulin markedly depressed the chronic inflammatory phase. In-vitro experiments suggest that desferrioxamine inhibits iron-catalysed lipid peroxidation when it is poorly saturated with iron, but loses this effect when it is iron saturated. Such an effect may explain our results with desferrioxamine in the animal studies and suggests that effective iron chelation and its removal may modify the inflammatory process in man.

Effective iron chelation following oral administration of an isoniazid-pyridoxal hydrazone.

When isoniazid and pyridoxal are mixed in equimolar quantities a hydrazone is formed which is able to complex with iron. The oral administration of this compound to rats in single doses of 25--100 mg/kg leads to an increase in faecal iron excretion up to 8 times the normal level. In tissue culture the compound is able to remove iron from Chang cells. The results suggest that this compound may be of potential value for the oral therapy of iron overload.

Magnesium Toxicity.

s1 April 1963Magnesium Toxicity.R. E. Randall Jr., M.D.R. E. Randall Jr., M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-58-4-744_3 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptThe toxic effects of an elevated serum magnesium have been known for years but not widely recognized nor systematically studied in man. Six patients have been studied who developed significant hypermagnesemia while receiving magnesium compounds either parenterally or orally as antacids or laxatives (milk of magnesia, magnesium sulfate, and Maalox®). Hypotension, respiratory failure, and hyporeflexia developed in 3 instances, coma in 4, pronounced electrocardiographic changes in at least one, and sudden death from cardiac arrest in 1 instance. Renal failure, present in all patients, was believed principally responsible for the retention of magnesium while obstipation may have been a contributing... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Boston, Mass. (CI) PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited ByMetabolically programmed iron chelatorsDesferrithiocin: A Search for Clinically Effective Iron Chelators 1 April 1963Volume 58, Issue 4Page: 744-744KeywordsHeartHypermagnesemiaHypotensionMagnesiumMilkRenal failureRespiratory failureSudden cardiac deathSulfatesToxicity Issue Published: 1 April 1963 PDF DownloadLoading ...