Colchicine quantitation by high-performance liquid chromatography in human plasma and urine.
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Biomedical subjects
Publications and source records attributed to F Erb.
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Toxicity of copper, cadmium and zinc complexed by the EDTA and HPO4(2)- ligands has recently been studied by the use of the short-term daphnia test. In order to detect the toxicity due to very small quantities of metals present in water in free ionic state or in complexed species formed with humic matters, a medium term test on Daphnia magna has been developed for a better appreciation of lethal and sublethal effects. Collected data are statistically analysed with the use, for instance, of "Lowest Rejected Concentration Tested" previously proposed by Skalski. The test defined in our laboratory allows to point out cadmium concentrations as small as 5 micrograms.l-1.
A new technique of cell culture in gas phase may be used for the "in vitro" study of the effects of toxic gases on the alveolar macrophages responsible for phagocytic defence of the respiratory system. Macrophage cells deposited on a porous membrane applied to the surface of a reservoir filled with nutrient fluid, survive in direct contact with the atmosphere, retaining normal metabolic and functional activities for several days. It is then possible to analyse the effects exerted on these cells by various types of gaseous aerocontaminants. This "in vitro" technique is highly sensitive. Nitrogen dioxide and ozone have cytotoxic effects after 30 minutes exposure at concentrations at less than 1 p.p.m. Acrolein has a harmful effect only at concentrations of 8 to 35 p.p.m. A mixture of oxygen (95 p. cent) and of CO2 (5 p. cent) causes much slower cell destruction, in a period varying from 2 to 6 days. Information provided by this method must be interpreted taking two concepts into account: 1--"in vitro" cytotoxicity explores only one aspect of the harmfulness of a gas, since the latter may have pathological effects by other mechanisms: irritant action on the respiratory mucosa resulting in hypersecretion and bronchospasm, ciliary paralysis or destruction, changes in the alveolar wall also capable of disturbing the phagocytic intervention of alveolar macrophages; 2--"in vitro", certain gaseous aerocontaminants are fixed or neutralised in part in the upper airway or by secretions lining the respiratory mucosa. In addition, the constant supply of new cells from the interstitium or pulmonary capillaries, limits the consequence of any possible destruction of phagocytic cells exposed to toxic gases. However, these reservations are compensated by the new possibilities offered by the "in vitro" study of the cytotoxicity of gases in the following areas: establishment of a hierarchy of gaseous pollutants, evaluation of their mechanism of action and determination of methods of protection against their harmful effects.
Intoxication by pure polychlorobiphenyls and a commercial product is studied, in rats, after intraperitoneal and oral administration. Their fixation and excretion of their metabolites is greater by intraperitoneal than by oral administration. The only hydroxy metabolites, identified by means of synthesis, gas chromatography and mass spectrometry are, all, derivatives from trichlorobiphenyl. It appears that administration of commercial product induces a more rapid degradation of these compounds in animal organism.
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Dysregulation of free radical metabolism has been supposed to be involved in schizophrenia etiopathogeny. Recently, Wang et al. showed a red blood cell super oxide dismutase increase in positive schizophrenia (Crow's type I), but neither in negative schizophrenia (Crow's type II) nor in controls. The study included 28 in-patients suffering from acute positive psychosis who were compared with 15 controls. We confirmed the results of Wang. We found a significantly red blood cell Super oxide dismutase increase in positive psychosis, in comparison to negative psychosis and controls (p = 0.0001). This SOD increase was in relationship with the degree of clinical psychomotor excitement. After 21 days of neuroleptic treatment, SOD activity decreased and reached standard values. These results support the hypothesis of striking relationships between catecholaminergic hyper-metabolism and SOD increase, in positive psychosis. These could account for psychotic positive symptoms improvement with neuroleptic treatment, which blocks dopamine pathways.
Serum levels of haloperidol and reduced haloperidol as well as the reduced haloperidol/haloperidol ratios were determined in nine acute schizophrenics on oral haloperidol medication and correlated over 21 days with psycho pathology and extra-pyramidal symptom scores. We have investigated red blood cells haloperidol reductase activity in the group of patients. Significant correlations were found between haloperidol plasma levels and positive sub scale for each patient (r = 0.86 and p < 0.01; r = 0.70 and p < 0.05). We found a correlation between red blood cells reductase activity and the improvement of the psychotic anxiety scale (r = 0.64/and p < 0.05; r = 0.67 and p < 0.05), but not with reduced haloperidol/haloperidol ratios in plasma. The knowledge of reductase activity could predict the treatment response in acute schizophrenic patients. We suggest that the reported inter individual and inter ethnic differences in haloperidol and reduced haloperidol and in clinical response and adverse effects may be a reflection of genetic control of the two oxidative pathways mediated by cytochrome P450 isozyme and/or the reductase pathway mediated by haloperidol reductase in individual subject.
The authors, after having performed the preparation of a few pure trichlorobiphenyl isomers, proceeded with a preliminary toxicological study of the rat which should then facilitate study for a commerical product. The fixation level of these compounds is considerably higher in lipids and in the spleen than in the other organs. Urinary elimination is very low compared with faecal excretion; furthermore, chromatographic analysis makes it possible to shed light on phenolic products of transformation in the excreta, some of which it was possible to identify with hydroxylated trichlorobiphenyls synthesized in the laboratory.
A toxicity and bioaccumulation study was carried out in Colpidium campylum with sixteen pure isomers of mono-, di-, tri-, tetra-, penta-, hexa- and heptachlorobiphenyls and a commercial product: Pyralene 3010, dissolved in alcohol, after factorial study of the summation of effects between PCB and solvent. The position of chlorine atoms on the aromatic rings and their number influence toxicity, probably in relationship to the possibilities of hydroxylation of these molecules. The experimental conditions must be very carefully respected to obtain reproducible results.
Haloperidol (HAL) is a widely used and clinically effective neuroleptic. Its metabolism differs in various animal species. In humans, reduced haloperidol (RHAL), a hydroxy metabolite of HAL, is produced by a cytosolic ketone reductase. Interconversion is known to occur whereby HAL is found in the plasma after administration of RHAL in vivo. Interconversion of HAL and RHAL has been observed in man. However, the capacity for reductive HAL is greater than its oxidation back from RHAL. RHAL, the resulting metabolite of HAL, is reported to be about 10-25% as active as HAL in an animal model. Large intersubject variation has been observed in the pharmacokinetics of HAL and RHAL. A wide variation in reductive drug-metabolizing has been observed in schizophrenic patients treated with HAL. Both high and low RHAL/HAL ratios or RHAL levels were reported to be linked to poor response in HAL-treated patients and might be correlated with the therapeutic window effect of HAL treatment. It is conceivable, therefore, that subjects with high reductive capacity relative to oxidative capacity may have less therapeutic response from the same dose of HAL than those with a low reductive capacity relative to oxidative capacity. This aim of this study was to investigate the HAL reduction among a sample of HAL-treated schizophrenic patients. Because ketone reductases are generally not tissue specific, we investigate the reductase activity in Red blood cells (as described by Inaba), before and during the treatment. Steady-state plasma drug levels during 2 weeks of treatment were quantified. We examined the relationships between fixed doses of HAL treatment, Red blood cells ketone reductase activity, plasma HAL and RHAL levels and the percentage of change of the Positive and Negative Syndrome Scale for Schizophrenia. The participants in this study were 15 inpatients consecutively being treated in the adult psychiatric wards of the University of Lille. All subjects met DSM III-R criteria for schizophrenia (paranoid form). Upon induction subjects were evaluated clinically by trained raters using the Positive and Negative Syndrome Scale for Schizophrenia (PANSS). Subjects were required to score 40 or higher on the general psychopathology subscale of the PANSS to continue participation. All subjects were drug free. Haloperidol was administered orally at three times daily dose. Patients were randomized to treatment at three orally fixed doses: 6 mg per day, 10 mg per day and 15 mg per day. Patients were treated for 2 periods of one week. At the end of each period, dosages could be modified according to the clinic evolution of the patient. PANSS was repeated by the same raters blinded to the haloperidol dosage, plasma concentration and Rbc haloperidol ketone reductase activity, at the beginning and at the end of each period. Blood samples were collected on the same day that clinical assessment were made. Multiple regression analysis (forward stepwise) revealed that Red blood cells reductase activity at D0 is an important variable predicting haloperidol plasma levels at week 2. Similarly Red blood cells reductase activity at D0 and D7 predicted Reduced haloperidol plasma concentrations at week 2. In this sample, no parameter was found to be consistency predicted the percentage change in the PANSS positive subscale from baseline, at week 2. Nevertheless, Red blood cells reductase activity at D0, Reduced haloperidol/haloperidol ratio at week 2, haloperidol plasma levels at week 2 and the dose of haloperidol at week 1 were important variables predicting the percentage change in the PANSS general subscale from baseline at week 2. These results suggest that the knowledge of reductase activity could predict the treatment response in acute schizophrenic patients.