Biological fate of a representative lipophilic metal compound (ferrocene) deposited by inhalation in the respiratory tract of rats.
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Animals↗
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Electrochemical enzyme immunoassay for detection of toxic substances.
Sensors that provide reliable, rapid measurement of toxic substances are needed to solve significant human health and safety problems. We developed a new biosensor design that combines the advantages of immunoassay with electrochemical response. We established that this enzyme-linked immunosensor measures toxic substances in biological samples. The biosensor consists of two major elements: (1) an electrical conducting layer having immobilized enzyme, polyclonal or monoclonal antibodies, and other necessary reagents, and (2) the electronic components used in the signal readout. The result is an amperometric immunoassay based on coupling the immunochemical reaction to the enzyme electrode response by using a soluble, electrochemically active mediator. The specific question addressed was: Does the system's immunochemical detection reliably respond at sufficiently low analyte concentrations? We present our results in these areas: (1) enzyme immobilization on colloidal gold; (2) colloidal gold-enzyme deposition on the electrode surface; (3) mediator-antigen conjugate synthesis; (4) antibody incorporation at the electrode surface; (5) bioelectrode characterization and optimization; and (6) immunosensor demonstration to detect antigen. Sensors that employ immunochemical detection will have broad applicability to detect/diagnose toxic substances in biological samples such as blood and urine and in environmental samples such as wastewater and drinking water.
Biosensing Techniques↗
Potentially-implantable, ferrocene-mediated glucose sensor.
We describe the construction and in vitro testing of a new potentially-implantable amperometric glucose sensor which is based on mediated electron transfer between immobilized glucose oxidase and a graphite base electrode. Under potentiostatic control, entrapped 1,1'-dimethylferrocene acts as an alternative electron acceptor to oxygen and provides a sensing strategy which is relatively unaffected by possible fluctuations in in vivo oxygen tension. Simple 1 mm wide electrodes with a polyurethane membrane gave linear current responses to at least 20 mmol/l glucose with a mean response time of 68 s. An acceptable proportion (17%) of electrodes had low or zero drift over 17 h at 37 degrees C. With plasma samples from diabetic and non-diabetic subjects, glucose concentrations measured by the sensor were significantly correlated with values obtained by a reference laboratory glucose analyser but were proportionally lower. Extension of this study to in vivo testing and further miniaturization of electrodes is justified.
Blood Glucose↗
Amperometric enzyme-immunosensor based on ferrocene-mediated amplification.
Coimmobilized glucose oxidase and anti-T4 antiserum are employed in the construction of a biosensor for thyroxine measurements. The resulting enzyme-immunosensor yields an amplified response to T4 with a detection limit of 15 nM.
Biosensing Techniques↗
Ferrocene-carbamate as prophylaxis against soman poisoning.
The effect of a carbamate derivative of ferrocene as a prophylactic agent toward soman poisoning was studied in mice. A sixfold decrease of the acute toxicity (24-hr LD50) of soman was obtained when the carbamate (5.5 mg/kg = 1/30 X LD50) was given intraperitoneally 30 min before soman. In this experiment atropine (20 mg/kg ip) was given 10 min before soman as support. The protection was lower when atropine or atropine plus toxogonin were given as therapy (1 min after soman). At these protective doses of the ferrocene -carbamate, a 30% inhibition of blood acetylcholinesterase activity was seen. Like physostigmine, the ferrocene -carbamate inhibited the brain acetylcholinesterase, suggesting that the compound entered the brain tissue.
Animals↗
Toxicological evaluation of substituted dicyclopentadienyliron (ferrocene) compounds.
The acute toxicity of 3 substituted ferrocenes: acetylferrocene, ethylferrocene, and 2,2-bis(ethylferrocenyl)propane (Catocene) were studied in rats, rabbits and monkeys. Acetylferrocene was found to be the most toxic. The oral lethal dose was less than 5 mg/kg for female rats, between 5 and 50 mg/kg for male rats, and between 10 and 100 mg/kg for monkeys. The toxicity of acetylferrocene appeared to be delayed, with most mortality occurring on the third day after dosing. Acetylferrocene was also highly toxic by skin or eye exposure. Gross pathological examination revealed signs of pneumonopathy in both the rats and monkeys. The mechanism by which monkeys are less susceptible than rats to the toxicity of acetylferrocene is not clear.
Administration, Oral↗
Sensitive ferrocene reagents for derivatization of thiol compounds in high-performance liquid chromatography with dual-electrode coulometric detection.
Three N-substituted maleimides possessing ferrocene as an electrophore were prepared and evaluated for pre-column derivatization of thiol compounds in high-performance liquid chromatography with dual-electrode coulometric detection. The utility of these reagents was investigated by employing N-acetyl-L-cysteine as a model compound. Among the three, N-(ferrocenyl) maleimide was the most favourable reagent with respect to reactivity, stability and electrochemical properties. The dual-electrode coulometric detection of the adduct showed high selectivity and sensitivity with a detection limit of 0.06 pmol. The proposed method is applicable to the determination of glutathione in biological specimens.
Adult↗
Liver iron quantification: studies in aqueous iron solutions, iron overloaded rats, and patients with hereditary hemochromatosis.
For the noninvasive liver iron quantification by MRI in human iron overload diseases, fundamental proton relaxation mechanisms were studied in aqueous solutions with ferritin and other iron compounds, in experimentally iron overloaded rats, and in patients with iron overload diseases. MR-relaxation rates as a function of iron concentrations in the range of 0-7.5 mg Fe/g aqueous iron solutions, 0-5.4 mg Fe/g rat liver in vivo, and 0.16-4.9 mg Fe/g human liver in vivo were determined from multi- and sets of single-spin echo sequences (1.5 T imager). As predicted by theory, transverse relaxation rates (1/T2) in aqueous iron solutions, in liver tissue of rats, and in human liver tissue increased linearly with the iron concentration. A preliminary calibration for the liver iron quantification by MRI was performed from in vivo measurements of liver 1/T2-relaxation rates and liver iron quantification by atomic absorption spectroscopy in biopsies from 13 patients. With the single spin-echo method, precise in vivo liver iron quantification in humans also above 2.0 mg Fe/g liver tissue (T2 < 15 ms) should be accomplished on any imager with shortest spin-echo time available, at least TE < 20 ms.
Adult↗
Chronic feeding of carbonyl-iron and TMH-ferrocene in rats. Comparison of two iron-overload models with different iron absorption.
1. The use of carbonyl-iron and (3,5,5-trimethylhexanoyl)-ferrocene (TMH-ferrocene) as a dietary iron-overload model was studied in rats using 59Fe-labelled compounds. 2. The intestinal absorption of carbonyl-iron but not from the TMH-ferrocene-iron was dependent upon the dosage and downregulated in iron-loaded rats. 3. In both models, and similar to hereditary haemochromatosis in humans, the storage of excess iron in the liver started in hepatocytes, whereas the range of iron-loading was strikingly different. 4. Because of the fast and progressive iron-loading, the TMH-ferrocene-model is the most encouraging animal model for experimental haemochromatosis.
Administration, Oral↗
[Ferrocene, ruthenocene and rhodocene analogs in haloperidol synthesis and organ distribution after labeling with 103Ru and 103mRh].
Ferrocene-Haloperidol was synthesized by N-alkylation of 4-(4'-chlorophenyl)- 4-hydroxypiperidine with 1-ferrocenyl-4-chlor-butan-1-on. By heating the ferrocene-haloperidol with 103RuCl3 the 103Ru-labelled ruthenocene-haloperidol was obtained. This compound showed a high affinity for lung but not for brain in rats and mice. The decay of the 103Ru labelled compound results in the formation of the 103mRh labelled rhodocene-haloperidol, which is rapidly oxidized by air to the corresponding rhodocinium-haloperidol. This compound can be separated by extraction and TLC.
Animals↗
[Improved diagnosis using deuterated radiopharmaceuticals?--A comparison of the brain affinity of amphetamine analogs].
Ruthenocene amphetamine analogues have the same brain uptake as iodo-labelled amphetamines. This paper compares the organ-distribution of 103Ru labelled ruthenocene- or ferrocene-amphetamine analogues in mice and rats with the same amphetamine in which H-atoms were partly substituted by D-atoms. The uptake in the brain is increased up to 180-200% for deuterium substituted compounds. The pattern of excreted metabolites leads to the conclusion that the deuterated amphetamines are more slowly metabolised than normal (H) compounds.
Amphetamine↗
An approach to the use of stable isotopes for DNA sequencing.
The sequencing of DNA by current procedures involves the use of radioisotopic or fluorescent labels. We propose that stable isotopes can be used as such labels and that the large number of stable isotopes available would allow multiplexing so that many DNA segments could be sequenced simultaneously. We have developed methods to use 57Fe2O3 to synthesize ferrocene and to attach the ferrocene to the 5' end of oligonucleotides. The 57Fe-labeled M13 universal primer functioned normally in a Sanger sequencing procedure. When a 57Fe-labeled oligonucleotide had migrated on a polyacrylamide gel it was readily located on the dried gel by scanning with resonance ionization spectroscopy (RIS) coupled with mass spectrometry. Using a 57Fe-labeled primer in a PCR reaction a 2000-bp DNA was produced that was detected by RIS on nylon membrane after agarose electrophoresis. The rapid analysis features of RIS coupled with the multispectral multiplexing possibilities of stable isotopes should significantly increase the rate of determination of DNA sequences.
Base Sequence↗
Local monitoring of proton spin diffusion in static and rotating samples via spy detection.
A method is described for investigating local proton "spin diffusion" by means of a 13C spin probe. The procedure does not require spectral resolution of proton resonance lines and can be applied in the laboratory frame of reference as well as in the rotating frame. Experimental results are presented for a static single crystal of ferrocene and for a powder sample under magic-angle spinning. The spin-diffusion rate constant is found to be proportional to the spinning speed in the range from 1 to 8 kHz.
Carbon↗
Cross-polarization dynamics and spin diffusion in some aromatic compounds.
The inversion-recovery cross-polarization (IRCP) magic-angle spinning experiment has been applied to study the 13C-1H cross-polarization dynamics of protonated aromatic carbons in ferrocene, 5,6-dimethoxyindole (DMI) and some indole derivatives. Using the 13C-detected proton spin diffusion (SD) experiment recently developed by Zhang et al. [Solid State Nucl. Magn. Reson., 1 (1992) 313], the slow decaying or incoherent stage of the IRCP experiment is shown to be controlled by the spin diffusion process at the directly bound proton. Moreover, a simple phenomenological model treating spin diffusion as a relaxation process provides an excellent agreement with both the IRCP and SD experimental data for all the different C-H pairs of DMI and its derivatives. The resulting time constants of the non-exponential spin diffusion decays are related to the local intra- and intermolecular network of dipolar interactions. This model is nevertheless found to be inadequate for ferrocene because intramolecular spin diffusion then has an inhomogeneous character.
Diffusion↗
Mediated amperometric determination of xylose and glucose with an immobilized aldose dehydrogenase electrode.
An enzyme electrode was constructed for amperometric determination of xylose and glucose. The electrode is based on the PQQ-dependent membrane-bound aldose dehydrogenase (ALDH) from Gluconobacter oxydans. ALDH was covalently immobilized on a graphite electrode. Immobilized dimethylferrocene, soluble ferrocene carboxylic acid and phenazine methosulphate were used as electron transfer mediators. When xylose was measured electrochemically using an electrode modified with ALDH and dimethylferrocene, the linear measurement range extended to 100 mM. For glucose measurement the linear measurement range was about one-tenth of that for xylose. The electrode showed fairly good stability; 50% of the original electrode response was still obtained after 5 days of intermittent use. The effect of possible leakage of adsorbed mediator was determined by measuring the response of an electrode with soluble mediator as a function of time. The reproducibility of the electrode was good, the standard deviation of the electrode response in ten measurements with the same electrode being only 2.7%.
Biosensing Techniques↗
Amperometric enzyme electrode for determination of theophylline in serum.
This paper describes an amperometric enzyme electrode for the rapid determination of theophylline in serum. The method is based on the catalysed oxidation of theophylline by the haem-containing enzyme theophylline oxidase. Results are presented for two approaches. First, ferrocene monocarboxylic acid was used as a mediator. The second-order rate constant was 1.1 x 10(3) 1 mol-1 s-1. Secondly, the organic conducting salt NMP.TCNQ was used to construct enzyme electrodes. These electrodes were employed for the rapid (60 s) measurement of theophylline in serum at a working potential of +100 mV versus Ag/AgCl. Linear calibration curves were obtained over the clinically relevant range (y = 0.13x + 0.22, n = 8). Caffeine, theobromine and 3-methylxanthine at levels up to 100 mg l-1 do not interfere and 1-methylxanthine shows cross-reactivity at concentrations greater than 50 mg l-1.
Biosensing Techniques↗
Non-leaking amperometric biosensors based on high-molecular ferrocene derivatives.
Poly(ethylene glycol)-bound ferrocene derivatives, synthesized after activation of ferrocene carboxylic acid with 1,1'-bis carbonyl diimidazol, are able to transfer electrons from the active site of reduced glucose oxidase to electrode surfaces. This opens a route to non-leaking mediated enzyme electrodes for the determination of glucose.
Biosensing Techniques↗
A glucose sensor fabricated by the screen printing technique.
A novel glucose sensor employing ferrocene-modified glucose oxidase is fabricated using the screen printing technique. Glucose oxidase is covalently bound to the electron mediator ferrocenecarboxylic acid in order to obtain higher enzyme activity. The ferrocene-glucose oxidase shows an increased catalytic current because the ferrocene acts as an electron transfer relay between the active centre of the enzyme and the gold electrode. Glucose sensors employing enzymes modified with ferrocene in various ways are successfully fabricated using the screen printing technique. The ink component containing the ferrocene-glucose oxidase is specially developed to be applicable to the printing machine. The printed glucose sensor chip offers a stable calibration profile and stable electrochemical properties.
Biosensing Techniques↗