Journal de toxicologie clinique et experimentale最新文献

In the biotechnology development, the biohazard become an important field of environmental medicine. After evaluation of biological agents, the laboratory organization in different security steps in achieved. One chapter "Health and Security" must be included in every scientific or industrial scheme of procedures. One example is given with the schedule for Hepatitis B and AIDS prevention.

The effect to paraquat in normobaric conditions and hyperbaric conditions with either a normal or low (10%) oxygen percentage was investigated in rats. Results showed that hyperbaric conditions increased the toxic effect of paraquat on the lung. By contrast, in hypoxic-hyperbaric conditions, the toxic effect of paraquat was decreased either clinically or macro-/microscopically, and lung injury was reduced.

NDMA, one of the most widely occurring carcinogenic compounds in the environment, is present in human food (meat, vegetables, cheese and alcohol beverages), in drinking water, in drugs, in cosmetics, in tobacco and its smokes. Furthermore NDMA may be synthesized from nitrates and nitrites and endogen or exogen amines. Since the first observations of MAGEE and BARNES in 1956 on the carcinogenicity of NDMA, this compound was reported to be carcinogenic in a large number of animal species including mammals, birds, amphibia and fish. NDMA requires metabolic activation for its cytotoxic and carcinogenic actions. The major activation step is believed to be the oxygenation of the alpha-carbon catalysed by a Cytochrome P-450-dependent enzyme system commonly know as NDMA-demethylase. Studies on the enzymology of NDMA metabolism show that some Cytochrome P-450 isozymes exhibit significant NDMA-demethylase activity only at high NDMA concentrations. The form of P-450 inducible by factors such as, fasting, diabetes, ethanol consumption and pretreatment with acetone, pyrazole or isopropanol has the higher affinity for NDMA. The gene coding for this isozyme belongs tho the P-450 II E subfamily. Because NDMA-demethylase activity is decreased by monoamine oxidase inhibitors, some authors have suggested a possible role of MAO in NDMA demethylation. This view is not supported by others who don't find evidence for an involvement of MAO in NDMA metabolism. Likewise, there are contradictory reports about the existence of some NDMA demethylase activity in cytosol, nuclei and mitochondria. NDMA demethylation, followed by nonenzymatic cleavage of the hydroxylated methyl group gives formaldehyde and methyldiazohydroxide and then leads to the formation of, a methonium ion, which is able to methylate nucleophilic sites of cellular macromolecules such as, proteins, RNA and DNA. A lot of studies suggest the existence of an alternative pathway to the formation of a methylating agent, denitrosation. Although the nature of mechanisms of denitrosation is not completely known, authors think that the formation of nitrite may represent a detoxification pathway rather than an activation pathway.

The authors report three cases of diltiazem overdose with hypotension and atrio-ventricular conduction disturbances. Hemodynamic study in 2 cases showed a hyperkinetic state with a decrease of systemic vascular resistances. Diltiazem kinetics studied in 2 cases showed a plasma half life of 5.4 and 8.3 hours, a prolonged absorption until the 28th hours in one case. Treatment included gastric lavage, oral activated charcoal (2 cases), plasma expanders and in 2 cases vasopressors with alpha effects. All three patients recovered.

A study, that was realized by the French Association of Poison Control Centers, tried to estimate the toxicity of Dihydropyridine derivatives towards human beings, in comparison with other calcium antagonists, said to be more toxic. Though, the toxicity of the Dihydropyridine derivatives happens to be far less important considering the rarity or absence of their cardiac effects, it must not however be underestimated in the case of a mass ingestion, or if they are taken simultaneously with psychotropic or cardiotropic drugs.

A 41 year old man with overdose of nicardipine is reported. Quickly after the poisoning, he developed a cardiovascular collapse picture with renal failure and myocardium ischemia. The clinical picture improved with injection of dobutamine and dopamine. The hemodynamic study showed a fall of the systemic resistances. The recovery was complete 40 hours after the ingestion.

Calcium antagonists decrease the intracellular concentration of calcium ions. They act essentially on the smooth vascular muscle, on the cardiac muscle and on the automatic and conducting cells in the heart. At toxic doses these effects induce hypotension, shock and disturbances of sinusal automatism and atrio-ventricular conduction. The toxicity of the different calcium antagonists varies according to their tissue specificity. The treatment of overdose includes gastric lavage, oral activated charcoal, cardiorespiratory support, especially alphamimetic vasopressors for shock or hypotension, adrenaline or cardiac pacing for atrio-ventricular block.

Unlabelled: The end-points of this study upon 134 cases reports by the french Poison Centers from 1979 to 1988 (10 years) were to specify the acute toxicity of diltiazem (DTZ). There were 83 self-poisonings in adults, with diltiazem alone (36 cases) or associated with other non cardiotoxic drugs (47), the doses of DTZ ranging from 300 to 5400 mg, and 51 acute accidental overdose in children, the doses of DTZ ranging from 60 to 420 mg. One case of hypotension was observed in a child, without rhythmic disorder, occurring twelve hours post-ingestion of 180 mg of DTZ. In adults, the clinical effects were observed following 360 mg of dose DTZ, occurring 1 1/2 hour post-ingestion. There were discomfort, brady-cardia in 16% of the cases, hypotension in 23% of the cases, cardiogenic shock in 4% of the cases and cardiac arrest in 2.4% of the cases. The rhythmic disorders occurred 2 to 15 hours post-ingestion. There were conduction defects like atrio-ventricular heart bloc I degree in 9% of the cases, II degree in 2.4% of the cases and III degree in 9% of the cases. Less frequently, sinusal bradycardia in 11% of the cases or sino-auricular heart block in 4% of the cases with sometimes auriculo ventricular heart block. These cardiac disorders occurred with 600 mg of DTZ. A cardiac arrest happened in a young healthy man who had absorbed 5400 mg of DTZ. The cardiogenic shocks occurred in patients with an history of coronary on heart disease. The poison removal is likely to prevent the occurrence of clinical or EKG effects when performed within 2 hours post-ingestion, whatever toxic the dose is. The inotropic drugs have been used in 18% of the cases; a percutaneous ventricular pacing was always effective in patients with II or III degree atrio-ventricular block or/and cardiogenir shock. These data confirm the data in thirteen patients of the literature.

In conclusion: The acute diltiazem poisoning can occur after 600 mg of DTZ and can induce severe cardiac disorders which can be prevented with poison removal or treated with supportive care.

Six cases of acute verapamil poisoning are reported. The dose ingested ranged between 1.2 and 9.6 g. In all cases other drugs had also been ingested and especially betablockers in two cases. Symptomatology included a cardiogenic shock in two cases and an atrioventricular block in four cases. A hemodynamic study in one case showed a cardiogenic shock with increased systemic vascular resistances. The treatment of cardiogenic shock included artificial ventilation, several vasopressors and inotropic agents and cardiac pacing in one case. All patients recovered without sequelae. A toxicokinetic study performed in two cases showed plasma half lives of 7.9 and 13.2 hours, total body clearances of 425 and 298 ml/min. Only 2 to 4.2 per cent of the dose ingested were eliminated in urine. These results confirm the severity of verapamil overdose and the efficacy of symptomatic treatment by inotropic agents. The high rate of spontaneous elimination by hepatic metabolism does not justify drug removal by extra-corporeal methods.