Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of 3-hydroxypyridin-4-one (HPO) iron chelators and desferrioxamine (DFO) on murine hemopoiesis in vivo and in vitro have been compared in order to investigate the mechanism by which leucopenia in mice and granulocytopenia in man occurs with 1,2-,dimethyl-HPO (CP20). Administration of 60 doses of 200 mg/kg CP20 to Balb/c mice resulted in significant anemia, lymphopenia and granulocytopenia accompanied by bone marrow hypocellularity. DFO and CP94 (1,2,diethyl-HPO) at the same dose also caused lymphopenia but marrow cellularity was unaffected. When marrow from untreated mice was incubated with HPOs and DFO, erythroid burst-forming cells (BFU-E) and granulocyte/macrophage colony forming units (CFU-G+Mac), colony growth was inhibited in a dose-dependent manner at micromolar concentrations. The addition of iron to saturate the chelators abrogated the effects of DFO, but not those of the HPOs. With the HPO-iron complexes, addition of sufficient iron to saturate the transferrin in the medium reversed the inhibitory effects of the relatively hydrophilic CP20-iron complex but not those of the more lipophilic CP94-iron complex. Addition of further iron-saturated transferrin also corrected inhibition by the CP94-iron complex. These results show that HPO-iron complexes potentially have antiproliferative effects unlike DFO-iron complex (FO). The difference in the relative effects of CP20 to CP94 on hemopoiesis in vivo and in vitro suggests that additional factors to those inhibiting hemopoiesis in marrow cultures may operate with the long-term administration of iron chelators in vivo.
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PMID:In vivo and in vitro effects of 3-hydroxypyridin-4-one chelators on murine hemopoiesis. 841 63

The objectives of the present study were to determine the efficacy and toxicity of repeated oral administration of 3-hydroxypyridin-4-one (HP) chelators in a rabbit model of aluminum (Al) accumulation and toxicity, and the influence of chelator lipophilicity on these effects. Efficacy was assessed as chelator-induced Al mobilization and excretion and reversal of Al accumulation and Al-induced toxicity. Chelator-induced toxicity was assessed by multiple measures. Six HPs were given orally 12 times over 1 month to Al-loaded rabbits, which had significant elevation of Al in most tissues and evidence of Al-induced nephrotoxicity, osteomalacia, and anemia. Intravenous desferrioxamine (DFO), the current chelator of choice for the treatment of Al-overload and toxicity, was included as a positive control. All six HPs and DFO demonstrated efficacy evidenced by significantly greater urinary and biliary Al elimination after the twelfth dose than seen in saline-treated controls. All of the HPs were more effective than DFO. Chelator-induced urinary Al excretion accounted for 58-98% of total (urinary plus biliary) Al excretion. Chelator-facilitated Al excretion was nearly complete within 12 hr, demonstrating a fairly short duration of action in rabbits with intact renal function. HP treatments did not consistently affect tissue concentrations of Al or other metals. However, there was a trend toward chelator-induced reduction of Al-induced nephrotoxicity. The influence of HP lipophilicity was limited to a positive correlation between HP x Al lipophilicity and biliary Al output and a negative correlation between HP and HP x Al lipophilicity and reduction of Kupffer cell Al. Little toxicity was evident after repeated oral HP dosing. Adrenal weight increased after treatment with several HPs. There was a decrease in testes weight after several HPs, which is consistent with an antiproliferative effect. More frequent dosing and/or a longer duration of HP treatment might produce greater reversal of the Al-induced toxicity and perhaps reveal more adverse effects than seen in this study. There was a lack of profound toxicity during this short-term study. The 1,2-dimethyl (CP20) and 1,2-diethyl (CP94) HPs, which have been the most extensively studied HPs, were the least effective of the HPs examined. These results encourage the further investigation of other HPs as oral alternatives to DFO for the treatment of Al accumulation and toxicity.
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PMID:Short-term oral 3-hydroxypyridin-4-one dosing increases aluminum excretion and partially reverses aluminum-induced toxicity in the rabbit independent of chelator lipophilicity. 902 49