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The optimum regimen to treat severe nosocomial pneumonia was 2 g of meropenem infused over 3 h every 8 h. This regimen achieved the highest pharmacodynamic targets both in plasma and in ELF.

In previous studies, we detected a dichlorodiphenyltrichloroethane (DDT) derivative in the serum of children with sexual precocity after migration from developing countries. Recently, we reported that DDT stimulated pulsatile gonadotropin-releasing hormone (GnRH) secretion and sexual maturation in the female rat. The aim of this study was to delineate the mechanisms of interaction of endocrine-disrupting chemicals including DDT with GnRH secretion evoked by glutamate in vitro. Using hypothalamic explants obtained from 15-day-old female rats, estradiol (E2) and DDT caused a concentration-related increase in glutamate-evoked GnRH release while p,p'-dichlorodiphenyldichloroethene and methoxychlor had no effect. The effective DDT concentrations in vitro were consistent with the serum concentrations measured in vivo 5 days after exposure of immature rats to 10 mg/kg/day of o,p'-DDT. Bisphenol A induced some stimulatory effect, whereas no change was observed with 4-nonylphenol. The o,p'-DDT effects in vitro were prevented partially by a selective antagonist of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) subtype of glutamate receptors. A complete prevention of o,p'-DDT effects was caused by an estrogen receptor (ER) antagonist as well as an aryl hydrocarbon receptor (AHR) antagonist and inhibitors of protein kinases A and C and mitogen-activated kinases. While an intermittent incubation with E2 caused no change in amplification of the glutamate-evoked GnRH release for 4 h, continuous incubation with E2 or o,p'-DDT caused an increase of this amplification after 3.5 h of incubation. In summary, DDT amplifies the glutamate-evoked GnRH secretion in vitro through rapid and slow effects involving ER, AHR, and AMPA receptor mediation.

A sensitive and reproducible method for the identification and the quantitative determination of bupropion (BUP) and its major metabolites, hydroxybupropion (OH-BUP) and threohydrobupropion (T-BUP), was developed in blood and urine. The three compounds were extracted with a solid-phase extraction procedure followed by LC-ESI-MS-MS separation and quantification using decadeuterated lidocaine as internal standard. BUP and its metabolites were satisfactorily identified by multiple reactions monitoring detection. The limits of detection and quantification were determined at 5 and 10 microg/L, respectively, for each analyte. The intraday and interday coefficients of variability were lower than 11.9% for BUP and its metabolites. This method was applied to the forensic case of a 35-year-old male who died after a suspected ingestion of 30 slow-release tablets of Zyban. As samplings were performed at least 72 h after the drug intake, BUP had disappeared from blood, but OH-BUP and T-BUP were present at the concentrations of 5.8 and 30.4 mg/L, respectively. In urine, concentrations ranged from 42.9 mg/L for BUP to 617 mg/L for T-BUP. These results agree with the hypothesis of a successful suicide attempt.

Tramadol is an opioid analgesic considered to induce fewer side effects than other compounds of this class. It has been extensively prescribed for two decades. However, serious complications may occur in case of intoxication. We report here two cases of fatal intoxication due to tramadol ingestion. Tramadol, O-desmethyltramadol (ODT), and N-desmethyltramadol (NDT) were quantitatively and qualitatively determined in postmortem blood and urine, respectively. An HPLC method coupled with fluorescence detection was validated using total error approach for the analysis of tramadol, ODT, and NDT in blood. In case 1, concentrations of tramadol and its metabolites were 7.7 mg/L (tramadol), 1.33 mg/L (ODT), and 0.6 mg/L (NDT). In case 2, concentrations found were 48.34 mg/L (tramadol), 2.43 mg/L (ODT), and 10.09 mg/L (NDT). The tramadol concentration found in case 2 is one of the highest ever described in the literature. Opposite ratios of ODT/NDT concentrations observed in different cases were suggested to be useful for the evaluation of the delay between ingestion and death. However, the changes in metabolites levels may also be explained by pharmacokinetic interactions and quantitative differences in the activity of the cytochrome-P450 2D6. Interestingly, norfluoxetine was detected in subtherapeutic levels in case 2. Most of these aspects in tramadol-related fatalities are reviewed in this paper, and an overview of fatal intoxications due to tramadol is presented.