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Biomedical subjects

A M Fredenburg

Publications and source records attributed to A M Fredenburg.

9 recordsLinked to original sources
PubMed2000

The hexadentate hydroxypyridinonate TREN-(Me-3,2-HOPO) is a more orally active iron chelator than its bidentate analogue.

Bidentate hydroxypyridinone chelators effectively complex and facilitate excretion of trivalent iron. To test the hypothesis that hexadentate chelators are more effective than bidentate chelators at low concentrations, urinary and biliary Fe excretions were determined in Fe-loaded rats before and after administration of a bidentate chelator, Pr-(Me-3,2-HOPO), or its hexadentate analogue, TREN-(Me-3,2-HOPO). The bidentate chelator slightly increased biliary Fe excretion in Fe-loaded rats after IV (90 micromol/kg) and PO (90 or 270 micromol/kg) administration, but chelation efficiency did not exceed 1%. The hexadentate chelator markedly increased biliary Fe excretion, achieving overall chelation efficiencies of 14% after IV administration of 30 micromol/kg and 8 or 3% after PO (30 or 90 micromol/kg) administration. The hexadentate chelator was significantly more effective than the bidentate chelator after IV injection and oral dosing. In chelator-treated Fe-loaded or saline-injected rats, >90% of the excreted Fe was in the bile. Oral TREN-(Me-3,2-HOPO), given to non-Fe-loaded rats, did not appreciably change Fe output, indicating that there was little Fe depletion in the absence of Fe overload. These results support the hypothesis that greater Fe chelation efficiency can be achieved with hexadentate than with bidentate chelators at lower, and presumably safer, concentrations. The results also demonstrate that TREN-(Me-3, 2-HOPO) is a promising, orally effective, Fe chelator.

Animals↗
PubMed2000

Glomerular lesions in male rabbits treated with aluminium lactate: with special reference to microaneurysm formation.

Novel glomerular lesions were seen in male rabbits after intravenous administration of aluminum lactate. Eight rabbits in the treated group were given 0.1 mmol/kg of aluminum lactate 5 days a week for 4 weeks. The control group of 8 rabbits was given 0.3 mmol/kg of sodium lactate by the same injection protocol. In the treated group, the mesangial cells in the glomerular tufts in 6 of 8 rabbits were distended with grayish blue granular material, which was identified by laser microprobe mass spectrometry and acid solochrome azurine stain as an aluminum compound. Other consistent findings in the glomeruli included microaneurysm in 6 of 8 rabbits and segmental sclerosis in 6 of 8 rabbits. Less frequently observed glomerular changes included crescent formation, necrosis with calcification, fibrosis of the Bowman's capsule, cystic dilation of the Bowman's space, and exudation of erythrocytes into the Bowman's space. The mechanism by which aluminum lactate induces the glomerular changes is not certain. However, the pathogenesis may involve the deposition of aluminum in the mesangial cells, resulting in mesangiolysis which in turn causes microaneurysm. The sclerotic change is interpreted as a sequela of microaneurysm. The findings suggest that aluminum induces glomerular lesions in rabbits. This may serve as a good animal model to study mesangiolysis and microaneurysm formation.

Aluminum↗
PubMed1997

Short-term oral 3-hydroxypyridin-4-one dosing increases aluminum excretion and partially reverses aluminum-induced toxicity in the rabbit independent of chelator lipophilicity.

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.

Administration, Oral↗
PubMed1996

The pharmacokinetics and blood-brain barrier permeation of the chelators 1,2 dimethly-, 1,2 diethyl-, and 1-[ethan-1'ol]-2-methyl-3-hydroxypyridin-4-one in the rat.

The 3-hydroxypyridin-4-ones (HPs) are iron and aluminum chelators. Their ability to enter the brain had not previously been directly determined. To determine whether they cross the blood-brain barrier (BBB), three HPs possessing a wide range of lipophilicity were examined: 1-[ethan-1'ol]-2-methyl-HP (CP40), 1,2-dimethyl-HP (CP20, L1, deferiprone), and 1,2-dimethyl-HP (CP94, EL1NEt). Their pharmacokinetics were determined in rats to establish dosing parameters for microdialysis studies of BBB permeation. Studies were then conducted with microdialysis probes in the blood, frontal cortex, and lateral ventricle to determine the rate and extent of HP BBB permeability. All three HPs were detectable in brain dialysate samples collected 0-7 min after HP injection, demonstrating rapid entry into the brain. The extent of unbound distribution (an indicator of the mechanism of BBB permeation) was 0.9 and 1.2 for the frontal cortex and lateral ventricle for CP20, and was 1.1 and 1.6 for CP94, suggesting diffusion across the BBB. The extent of unbound distribution of CP40 was 0.2 for both the frontal cortex and lateral ventricle, suggesting the presence of a transporter moving it out of brain extracellular fluid. Introduction of cyanide into the brain did not affect the brain to blood CP40 ratio, suggesting that the transporter is not energy-dependent. Both CP94 and CP40 caused death due to respiratory failure, whereas CP20 did not. The ability of less toxic bidentate HP chelators, such as CP20, to enter the brain may enable their use in the treatment of metal-induced diseases and iron-facilitated oxidative injury involving the central nervous system.

Animals↗
PubMed1996

The 3-hydroxypyridin-4-ones more effectively chelate aluminum in a rabbit model of aluminum intoxication than does desferrioxamine.

This study was conducted to assess the influence of lipophilicity on the in vivo aluminum (Al) chelation activity of 3-hydroxypyridin-4-ones (HPs). Chelation activity was evidenced as increased Al elimination in an animal model of Al accumulation and toxicity. The subjects were Al-loaded rabbits. A non-Al-loaded group was included to characterize the rabbit model of Al intoxication. Eight HPs and desferrioxamine (DFO), the drug currently used to treat Al intoxication, were studied. Chelation activity was determined from quantitative biliary and urinary Al excretion and serum Al determinations conducted for 24 hr after DFO or HP intravenous administration, compared with saline. Toxicity was evaluated by observation, blood biochemistry assays, hematological evaluation, gross necropsy, and histopathological assessment of the liver. Al loading produced nephrotoxicity, hepatotoxicity, and anemia. Each of the chelators mobilized Al into serum. The efficiency of Al chelation, calculated from 24-hr biliary plus urinary Al output, ranged from 2.8 to 11.7% for the HPs, compared with 2.1% for DFO. Urinary Al excretion accounted for 78-98% of total Al excretion. Nearly all of the chelator-facilitated Al excretion occurred within 8 hr of dosing. Al chelation efficacy did not correlate with HP or HP Al lipophilicity; however, increasing HP lipophilicity increased the biliary fraction of the excreted Al. There was no evidence for toxicity after HP dosing, other than the previously shown ability of one of the HPs to produce seizures. The greater chelation efficacy of the HPs than DFO provides advantages over DFO. The lack of toxicity after a single dose of all but the most lipophilic HP encourages their further evaluation as orally effective chelators.

Aluminum↗
PubMed1988

Quality assurance: establishing a program for libraries.

"Quality Assurance" (QA) is a practical tool for library management, a link in the library's relationship with administrative decision makers. Instituting or refining a QA program takes into account formal and informal methods. Described are one library's program and problem-solving model, the role of others in the library's program, types of recordkeeping, and integration of the library program with organizational QA. Positive results include participation in management-level activities and improvement in quality and delivery of services and products. Ten suggestions are made to begin a QA program.

Hospital Bed Capacity, 300 to 499↗
PubMedDate not supplied

Pharmacokinetics of representative 3-hydroxypyridin-4-ones in rabbits: CP20 and CP94.

Selected 3-hydroxypyridin-4-ones (HPs) are under clinical investigation as iron chelators. Representative HPs have been shown to be potential aluminum chelators by use of in vitro test systems. This study was conducted to determine systemic availability of representative HPs in rabbits prior to studies of their oral efficacy as aluminum chelators. Each of 12 rabbits was administered 0.45 mmol/kg 1,2-dimethyl- (CP20; L1) and of 1,2-diethyl-3-hydroxypyridin-4-one (CP94; EL1NEt) by gastric lavage and by injection into a lateral ear vein. Each rabbit received both compounds via both routes with at least 7 days between doses. Blood samples (1.5 ml) were collected up to 24 hr after dosing. The HPs were extracted, then analyzed by HPLC with a column packed with graphitized carbon. The mean (+/- SD) systemic clearance, steady-state volume of distribution, mean residence time, mean oral absorption time, and systemic availability for CP20 and CP94 were 0.8 +/- 0.3 and 2.1 +/- 1.4 liter/hr/kg; 1.2 +/- 0.5 and 1.2 +/- 0.5 liter/kg; 1.7 +/- 0.7 and 0.7 +/- 0.3 hr; 0.9 +/- 1.6 and 0.6 +/- 0.5 hr; and 72 +/- 20 and 57 +/- 27%, respectively. Rabbits demonstrated fairly good absorption and rapid elimination of 1,2-dimethyl- and 1,2-diethyl-3-hydroxypyridin-4-one.

Animals↗