This paper reports a series of 20 fatalities involving a high-dose, sublingual buprenorphine (BUP) formulation recently marketed in France for the substitutive therapy of opiate addicts. The files were recorded over a 16-month period from five different urban areas in France. All subjects but one were male, aged 14-48 (mean 26.6). BUP and its primary metabolite norbuprenorphine (norBUP) were assayed in postmortem fluids and viscerae by HPLC-MS. Blood levels for BUP and norBUP ranged from 1.1 to 29.0 ng/mL (mean 8.4 ng/mL) and 0.2 to 12.6 ng/mL (mean 2.6 ng/mL), respectively, that is, within or slightly over the therapeutic range. BUP exhibited extensive tissue distribution, with average postmortem concentrations of 6.0, 35.0, 45.5, and 80.0 ng/g in the myocardium, kidney, brain, and liver, respectively. In blood, as in viscerae, norBUP levels were generally lower than BUP. The highest concentrations were found in the bile for both BUP (range 575-72,650 ng/mL) and norBUP (range 41-30,000 ng/mL). Therefore, bile may represent a sample of choice for postmortem screening. BUP was identified in 9 of the 11 hair samples assayed at concentrations ranging from 6 to 597 ng/g (mean 137 ng/g), whereas norBUP was never detected. Intravenous injection of crushed tablets, a concomitant intake of psychotropics (especially benzodiazepines), and the high dosage of the BUP formulation available in France appear to be the major risk factors for such fatalities.

For many years, toxicologists have detected the presence of drugs of abuse in biological materials using blood or urine. In recent years, remarkable advances in sensitive analytical techniques have enabled the analysis of drugs in unconventional samples such as sweat. In a study conducted in a detoxification center, sweat patches were applied to 20 known heroin abusers. Subjects wore the patch with minimal discomfort for five days. During the same period, two urine specimens were also collected. Target drugs analyzed either by gas chromatography-mass spectrometry (GC-MS) or liquid chromatography-mass spectrometry (LC-MS) included opiates (heroin, 6-monoacetylmorphine, morphine, codeine), cocaine (cocaine, benzoylecgonine, ecgonine methyl ester), delta 9-tetrahydrocannabinol, benzodiazepines (nordiazepam, oxazepam), amphetamines (amphetamine, methamphetamine, methylenedioxyamphetamine [MDA], methylenedioxymethamphetamine [MDMA], methylenedioxyethylamphetamine [MDEA]), and buprenorphine. Patches were positive for opiates in 12 cases. Heroin (37-175 ng/patch) and/or 6-acetylmorphine (60-2386 ng/patch) were identified in eight cases, and codeine exposure (67-4018 ng/patch) was determined in four cases. When detected, heroin was always present in lower concentrations than 6-acetylmorphine, which was the major analyte found in sweat. Cocaine (324 ng/patch) and metabolites were found in only one case. delta 9-Tetrahydrocannabinol (4-38 ng/patch) was identified in nine cases. Benzodiazepine concentrations were very low, ranging from 2 to 44 and from 2 to 15 ng/patch for nordiazepam and oxazepam, respectively. MDEA (121 ng/patch) and its metabolite, MDA (22 ng/patch), were detected in one case. Buprenorphine, which was administered as therapy under close medical supervision, was detected in the range 1.3-153.2 ng/patch with no apparent relationship between the daily dose and amount excreted in sweat. All the urine tests were consistent with the sweat findings, but to identify the same drugs it was necessary to test two urine specimens along with only one sweat specimen. It was concluded that sweat testing appears to offer the advantage of being a relatively noninvasive means of obtaining a cumulative estimate of drug exposure over the period of a week. This new technology may find useful applications in the treatment and monitoring of substance abusers, as the patch provides a long-term continuous monitor of drug exposure or noncompliance.

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Our observation is the first demonstration of a relationship between high intracerebral manganese levels, radiologic abnormalities, and neurologic disorders during long-term PN. Moreover, serum manganese levels are not a good indicator of cerebral levels. In fact, in our patient, serum manganese levels returned to normal, whereas those of cerebral manganese remained increased.

Aldicarb (2 ethyl-2 (methylthio) propanal o-[(methlamino)-carbonyl] oxime) is a pesticide manufactured since 1965. This carbamate ester is sold under the tradename, Temiks, and is used as insecticide and nematicide. The Environmental Protection Agency has classified aldicarb in the highest toxicity category and has defined a strict control for its delivery and use. In Brazil and the Caribbean island, aldicarb is illegally used as a household rodenticide with a widespread risk of poisoning. Our study presents the first review of aldicarb poisoning circumstances associated with cliical and analytical findings. Moreover, the oxime treament is discussed. Eighteen patients with cholinergic symptoms admitted to the Emergency Unit and two deceased with a history of aldicarb poisoning were included in the study. As agricultural workers, only two of them could legally use Temikg. Seventy percent of the patients was managed by the Emergency Mobil Unit. Serum cholinesterase activity was always lower than 30% of the normal range and aldicarb was identified by UV spectra and retention time after liquid chromatogrphy separation. The most common muscarinic effect was diarrhea, the main nicotinic sign fasciculation and almost half of the poisoned patients had central nervous system (CNS) depression (Glasgow Coma Score lower than 8). Four patients had serious conduction abnoralities and two of them died. These results suggest that aldicarb intoxication is always severe. Oxime treatment did not produce side effects and should be recommended whenever the pesticide involved is unknown. Effective measures should be implemented to stamp out the illicit use of aldicarb.