[Inductively coupled plasma mass spectrometry. Perspectives in analysis and in biology]. / Spectrométrie de Masse à Plasma couplé par induction (ICP-MS). Potentialités en analyse et en biologie.

ICP-MS is an instrumental method of multi-elementary qualitative and quantitative analysis. It associates with a mass spectrometer (MS) an ion source composed of a plasma torch fed with inductive coupling with a high frequency electromagnetic generator (ICP), similar to that used as a light source in highly-successful Atomics Emission Spectrometry (AES). ICP-MS can be applied to simultaneous analysis of numerous metallic and metalloid elements (80 or so). Its sensitiveness is all in all far better than that available with previous spectrometric techniques, which nevertheless remain more advantageous for processing certain low atomic mass elements. Thanks to its broad dynamic range, ICP-MS allows quantification of an array of elementary concentrations within a single sample. ICP-MS offers particularly interesting perspectives in geochemistry and metal processing, as well as in biochemistry and food or toxicology and environmental analysis. Implementation is rapid and the technique is suitable for series or continuous analyses, or for analysis of any evolving medium such as effluents from gas or liquid chromatography or from capillary electrophoresis, making it a valuable tool for speciation analyses. Finally it enables non-radioactive isotopic labeling, essential for nutritional studies of trace elements, and sufficiently accurate isotopic dilutions, even with more accessible machines.

Cholinesterase inhibition by derivatives of 2-amino-4,6-dimethylpyridine.

Derivatives of 2-amino-4,6-dimethylpyridine, aryl(alkyl)carboxamides, thiocarbamides and amidrazones, already known for their anti-inflammatory properties, were found to be moderately active inhibitors of acetyl and butyrylcholinesterase. Quantitative structure-activity relationships showed that the binding affinity was enhanced by the following structural modifications: (1) increase in molecular volume, (2) decrease in the energy of the lowest unoccupied molecular orbital, (3) insertion of a methylene group between the amide carbonyl and the aromatic ring, (4) replacement of the amide oxygen by sulfur. The affinity remained, however, weaker than that of the specific inhibitor 9-amino-1,2,3,4-tetrahydroacridine (tacrine). The association of anti-inflammatory and cholinesterase inhibiting activities within the same compound may prove useful for the treatment of Alzheimer's disease.

Applications of liquid chromatography--mass spectrometry in analytical toxicology: a review.

Liquid chromatography-mass spectrometry (LC-MS), after long-term development that has introduced seven major interfacing techniques, is finally suitable for application in the field of analytical toxicology. Various compound classes can be analyzed, and sensitivities for more or less polar analytes that are as good as or better than those of gas chromatography-mass spectrometry can be obtained with modern interfaces. In addition, because ionization is often softer than classical electron impact, some LC-MS interfaces are able to handle fragile species that are otherwise not amenable to MS. This review is intended to present LC-MS to less familiarized readers and to give an extensive overview of the application of the different coupling techniques to doping agents, drugs of abuse, forensic analysis, toxic compounds of various nature, and several toxicologically relevant therapeutic drugs. Experimental parameters such as the interfaces used, ionization methods, detection limits, and experimental details for exemplary applications are given.

Determination of haloperidol and its reduced metabolite in human plasma by liquid chromatography-mass spectrometry with electrospray ionization.

A sensitive and accurate liquid chromatographic-electrospray mass spectrometric (LC-ES-MS) method for the determination of haloperidol (H) and reduced haloperidol (RH) in human plasma is presented, using chlorohaloperidol as the internal standard. A 2-ml volume of plasma was subjected to basic (NaOH) extraction, acid (HCl) back-extraction, acid wash and basic (NaOH) re-extraction. The extraction solvent was hexane-isoamyl alcohol (99:1, v/v) for the whole procedure. A Nucleosil C18 column (150 x 1 mm) was used for high-performance liquid chromatography, together with 2 mM HCOONH4-acetonitrile (55:45, v/v; pH 3.0) as the mobile phase. For each drug, four characteristic ions were monitored. Linearity was assessed in the ranges 0.1-50 and 0.25-50 ng/ml for H and RH, respectively. Recoveries were 58 and 70% and detection limits were 0.075 and 0.100 ng/ml for H and RH, respectively. Correlation coefficients were better than 0.999 for both compounds. R.S.D.s for repeatability and reproducibility at 0.25 ng/ml were 11.1 and 8.5% for H and 9.4 and 11.2% for RH, respectively. One of the main advantages of (LC-ES-MS) over other detection systems is the increase in selectivity obtained by monitoring three ions of confirmation for each of the drugs.

Trypanosoma brucei brucei: antitrypanosomal evaluation of stilbamidinium hexachloroiridiate on the murine CNS model and iridium serum kinetics in infected sheep.

Stilbamidinium hexachloroiridiate was found trypanocidal in vitro against Trypanosoma brucei brucei IPP at 600 microM after a 1 h incubation period and 30 microM after 24 h. This activity was confirmed in mice with a subcutaneous treatment at 20 mg/kg in a single dose. It was then evaluated on T.b. brucei murine CNS model. At the early stage, a subcutaneous treatment at 2 mg/kg/day x 5 cured 50% mice where-as one single dose at 10 mg/kg was completely inactive. Higher doses failed to cure the mice. Nevertheless, hexachloroiridiate salt of stilbamidine was 3.3 fold less toxic than dihydrochloride salt. Although the compound appeared inactive at the late stage of the murine trypanosomiasis, the difference of toxicity justified its evaluation on the early stage of sheep trypanosomiasis. The compound was trypanocidal at 2 mg/kg in a single dose when administered 8 days after infection. The study of iridium serum kinetic showed that stilbamidinium hexachloroiridiate was distributed rapidly according to a monocompartmental model. Moreover, iridium persisted in serum for a long time. The compound in aqueous suspension with 1% carboxymethylcellulose acted therefore as a controlled release system with a bioavailability allowing its trypanocidal action at the early stage.

Trypanocidal activity and platinum plasma kinetics of cis-Pt pentamidine iodide in Trypanosoma brucei sheep model.

The trypanocidal properties of cis-Pt pentamidine iodide have been studied on the T. b. brucei sheep model. The compound was evaluated on the lymphatic-plasma phase of the disease and appeared to be active on the circulating parasites. Cis-Pt pentamidine iodide was active at 5 mgl.kg-1 in one single dose both in mouse and sheep trypanosomiasis models. The chemotherapeutic index was about 200 in the mouse. As we observed previously with the chloride derivative, platinum plasma values for cis-Pt pentamidine iodide were rather constant between 24 and 48 hours. The nature of the salt associated to cis-Pt pentamidine had a direct effect on the compound kinetics. The iodide compound was distributed quickly and largely within deep compartments according to a monocompartmental model. The theoretical volume of distribution was 6.41.kg-1 for a 100% absorbed fraction. The two iodide ions of the complex probably played an important role in the compound kinetics mainly due to the extended release effect. The iodide salt of cis-Pt pentamidine could therefore be used in chemoprophylaxis of African trypanosomiasis.

[Plasma kinetics of a spiroarsorane trypanocidal agent in sheep trypanosomiasis]. / Cinétique plasmatique d'un spiroarsorane trypanocide chez le mouton parasité.

In a previous study, spiroarsoranes were very effective against both the two pathogenic phases of the experimental sheep trypanosomiasis. In this paper, the authors had studied the plasmatic pharmacokinetics of these compounds. Data had shown one peak 10 min after injection of a 3 months inoculated sheep, and 90 min for the control sheep. Spiroarsorane had a good diffusion into the central nervous system, but the trypanocidal activity, during the second phase of the disease, was effective only after repeated treatment. The spiroarsorane low toxicity could allow its direction against nervous trypanosomiasis.

[Trypanocidal activity and plasma kinetics of cis-Pt(II) pentamidine in the parasitized sheep]. / Activité trypanocide et cinétique plasmatique de la cis-Pt(II) pentamidine chez le mouton parasité.

The trypanocidal activity of cis-Pt(II) pentamidine had been demonstrated during the first phase of Trypanosoma brucei brucei sheep experimental trypanosomiasis. But a subcutaneous treatment with 5 mg.kg-1 (+2 x 12 mg.kg-1) was not effective during the brain phase of trypanosomiasis. The blood pharmacokinetics of this compound had a plasmatic peak between 45 and 60 min, followed by a low decreasing phase along several days. The curve shape allowed an important interval before the following injection, and showed a compound storage in internal organs and extravascular sites. A model of cis-Pt(II) pentamidine metabolism had been studied: this product could be used as a chemoprophylactic medicine against African trypanosomiasis and American leishmaniasis.

Acetylcholinesterase inhibition by two phosphoric 4-nitroanilides.

Two phosphoric 4-nitroanilides Z2P(O)NH-phi-NO2 (A, Z = Me; B, Z = NMe2) have been prepared and purified by chromatographic techniques. Their spectral data (uv, ir and 1H-nmr) have been determined, and compared with those of other similar compounds. Their ability to inhibit acetylcholinesterase has been measured by a modification of Ellman's method. The data, as computed according to the Michaelis scheme, indicate that A is not an inhibitor, whereas B is a reversible mixed one. These differences are discussed in terms of hydrophobic interactions.

[Comparative study of the toxicity of metal chlorides and a synthetic organic molluscacide, N-tritylmorpholine, in 2 fresh-water amphipods, Gammarus pulex and Echinogammarus berilloni]. / Action comparée de la toxicité de chlorures métalliques et d'un molluscicide organique de synthése, la N-trityl-morpholine, sur deux amphipodes dulcaquicoles Gammarus pulex et Echinogammarus berilloni.

The effects of three metal salts (BaCl2, CuCl2, ZnCl2) and of N-trityl-morpholine (Triphenmorph) were studied on two aquatic amphipod species, Gammarus pulex and Echinogammarus berilloni. Experiments were made up in eucalcic and oligocalcic waters for determining the LC50 at different exposure times. The order of toxicity was the same in eucalcic water with the two species: Triphenmorph greater than Cu2+ greater than Zn2+ greater than Ba2+. This order was the same in oligocalcic water with Echinogammarus berilloni; with Gammarus pulex, CuCl2 was more toxic than Triphenmorph.

[Pharmacokinetics and urinary metabolism of albendazole in man]. / Pharmacocinétique et métabolisme urinaire de l'albendazole chez l'homme.

Albendazole, a new broad spectrum benzimidazole anthelmintic, has been administered in 10 male volunteers. Administration was randomized using 100 mg tablets, 200 mg tablets and a 2% suspension. Blood samples were obtained 0.5; 1; 1.5; 2; 2.5; 3; 3.5; 4; 5; 6; 8; 12; 24; 72 h after treatment. Albendazole sulfoxide, one of the mains albendazole blood metabolites, was assayed by HPLC and the blood half life was calculated as 8 1/2 h. The three different pharmaceutical formulations were considered bioequivalent. Urines were collected, and using T. L. C. Technics, main metabolites were identified and characterized. Hydrolysis of the carbamate function and oxidation of the sulfur atom, the alkyle chain and the aromatic ring were the main biotransformations observed.