Gary D. Christian

Postmortem Forensic Toxicology of Selective Serotonin Reuptake Inhibitors: A Review of Pharmacology and Report of 168 Cases

This paper reviews the complex pharmacology of the new class of antidepressant medications exhibiting selective inhibition of serotonin reuptake. The four selective serotonin reuptake inhibitors (SSRIs) considered--fluoxetine, fluvoxamine, sertraline and paroxetine--can result in toxicity and death through contributing to serotonergic excess resulting in serotonin syndrome, inhibiting the metabolism of other centrally acting drugs, leading to accumulation of toxic concentrations, and exerting complex vasoactive effects on the vascular smooth muscle. This latter feature is of particular concern in patients with preexisting heart disease. An analytical method involving isolation of the drugs by liquid/liquid extraction at alkaline pH into n-butyl chloride, and analysis by gas chromatography/mass spectrometry (GC/MS) is described, together with some of its limitations. Toxicologic and cause and manner of death data were examined in 60 deaths involving fluoxetine, 5 involving fluvoxamine, 75 involving sertraline, and 28 involving paroxetine. Deaths involving drug toxicity were generally a result of ingestion of multiple drugs, and in only a small number of the cases was death attributed principally to the SSRI involved. The potential for drug interactions between members of this class of drugs is discussed as well as their metabolites and a variety of other therapeutic and abused drugs which can contribute to their toxicity. In the absence of other risk factors, the lowest concentrations determined to have resulted in death were 0.63 mg/L for fluoxetine, 0.4 mg/L for paroxetine, and 1.5 mg/L for sertraline. We had insufficient data to make even this crude assessment for fluvoxamine. Drug-induced elevation of serotonin concentrations may be a significant risk factor for patients with atherosclerotic cardiovascular disease (ASCVD). Other factors including preexisting disease and the presence of other drugs and their pharmacology need to be carefully considered before determining the appropriate cause and manner of death in these cases.

Stopped-flow injection simultaneous determination of phosphate and silicate using molybdenum blue.

Kinetic information for the phosphate-molybdate-ascorbic acid reaction can be obtained by making use of a very simple manually operated stopped-flow injection (FI) system. Various parameters (concentrations of reagents, flow rate, mixing coils, and volume of flow cell) were investigated for determination of phosphate. A stopped-FI system should be arranged for low degree of mixing (of reactants) and low dispersion so that good signals of rate changes will be observed. Simultaneous determination of phosphate and silicate by the stopped-FI technique is proposed, using a laboratory-made semi-automatic stopped-FI Analyzer with LED-based photometer. It is based on kinetic separation of phosphate and silicate using molybdenum blue. The proposed procedure has been demonstrated for the application to water samples. The results obtained agree with that of a standard method.

Sequential injection redox or acid–base titration for determination of ascorbic acid or acetic acid

Two sequential injection titration systems with spectrophotometric detection have been developed. The first system for determination of ascorbic acid was based on redox reaction between ascorbic acid and permanganate in an acidic medium and lead to a decrease in color intensity of permanganate, monitored at 525 nm. A linear dependence of peak area obtained with ascorbic acid concentration up to 1200 mg l(-1) was achieved. The relative standard deviation for 11 replicate determinations of 400 mg l(-1) ascorbic acid was 2.9%. The second system, for acetic acid determination, was based on acid-base titration of acetic acid with sodium hydroxide using phenolphthalein as an indicator. The decrease in color intensity of the indicator was proportional to the acid content. A linear calibration graph in the range of 2-8% w v(-1) of acetic acid with a relative standard deviation of 4.8% (5.0% w v(-1) acetic acid, n=11) was obtained. Sample throughputs of 60 h(-1) were achieved for both systems. The systems were successfully applied for the assays of ascorbic acid in vitamin C tablets and acetic acid content in vinegars, respectively.

Determination of trace iron in beer using flow injection systems with in-valve column and bead injection

Three flow injection (FI) systems were investigated for the determination of trace iron in beer: an FI-in-valve column-flame atomic absorption spectrophotometry (FI-FAAS) system, a spectrophotometric FI system with a column placed at the detection point, and an FI-spectrophotometric system with bead injection (FI-BI). Cationic exchange resin Dowex 50W X8 and iminodiacetate chelating resin, Chelex-100, were employed for the FI-spectrophotometric and FI-FAAS systems, respectively. The FI-in-valve column, packed with the resin, enhances the FAAS performance. The spectrophotometric FI system with a column (packed with Chelex-100) placed at the detection point (in a cell holder of a spectrophotometer) is based on the formation of iron (II)-1,10-phenanthroline complex sorbed onto the resin. No eluent has been found to be suitable. The FI-BI for renewable microcolumn has been proven to be an alternative. The FI-FAAS and FI-BI procedures provide online sample preseparation and preconcentration for the determination of iron in beer. Both are simple, rapid, and economical. The procedures also involve sample preparation (decarbonation and suppression of tannin interference by adding ascorbic acid) and standard addition. The results obtained by FI-FAAS and FI-BI agree with those of AOAC spectrophotometric method.

Characterization and use of a Raman liquid-core waveguide sensor using preconcentration principles

A novel Raman sensor using a liquid-core optical waveguide is reported, implementing a Teflon-AF 2400 tube filled with water. An aqueous analyte mixture of benzene, toluene and p-xylene was introduced using a 1000 microl sample loop to the liquid-core waveguide (LCW) sensor and the analytes were preconcentrated on the inside surface of the waveguide tubing. The analytes were then eluted from the waveguide using an acetonitrile-water solvent mixture injected via a 30 microl eluting solvent loop. The preconcentration factor was experimentally determined to be 14-fold, in reasonable agreement with the theoretical preconcentration factor of 33 based upon the sample volume to elution volume ratio. Raman spectra of benzene, toluene and p-xylene were obtained during elution. It was found that analytically useful Raman signals for benzene, toluene and p-xylene were obtained at 992, 1004 and 1206 cm(-1), respectively. The relative standard deviation of the method was 3% for three replicate measurements. The limit of detection (LOD) was determined to be 730 ppb (parts per billion by volume) for benzene, exceptional for a system that does not resort to surface enhancement or resonance Raman approaches. The Raman spectra of these test analytes were evaluated for qualitative and quantitative analysis utility.

Flow analysis and its role and importance in the analytical sciences

Flow Analysis was started in 1979, first held in Amsterdam. A brief history of the conference is presented, along with the important roles flow analysis plays in analytical measurements. Flow analysis comprises numerous techniques that encompass much of what we do as analytical chemists. It includes operations and techniques such as segmented, continuous or stopped flow, chromatography, and electrophoresis. Flow methods are used for handling and treating solutions, and for separations, and are applicable for all sorts of wet chemical operations and measurements. They provide rapid, precise, and automated measurements, using small samples, with low reagent consumption. They form the basis of total microanalysis systems.

Recovery of morphine from biological samples by hydrolysis and solvent extraction.

Quantitative recovery of drugs from biological samples is important when a response is to be related to the amount of drug present in a tissue sample. Morphine is one drug of interest in this regard because of its widespread use and its chemical peculiarities. Its relatively low dosage, amphoteric nature, and metabolism to a water-soluble product, 3-morphine monoglucuronide [1,2], make morphine relatively difficult to analyze in biological samples. Most quantitative analytical schemes of analysis require that the glucuronide be cleaved to free morphine for extraction into an organic solvent. Acid hydrolysis [3] and enzymatic cleavage [4] are the most popular methods for freeing the morphine. We report here a study of the recoveries of radioactively tagged morphine from biological samples of morphine-treated dogs by using hydrolysis and solvent extraction. It is possible to recover more than 90% of the morphine contained in a sample with acid hydrolysis and about 80% with enzymatic cleavage.

Novel flow injection analysis systems for drug analysis.

Flow injection analysis (FIA) has become a versatile tool for rapid and automated analyses. As its capabilities have increased, so have the complexity and operation of the apparatus. We have been investigating ways to simplify both the apparatus and the application of injection techniques. A novel cam-driven syringe pump and the development of sequential injection analysis (SIA) are reviewed, and some applications presented. Flow injection coulometric titrations are presented as a means to further alleviate reagent stability and calibration problems. These systems have potential for automatically carrying out many drug assays.

PRINCIPLES AND CAPABILITIES OF ELECTROINJECTION ANALYSIS

Electroinjection analysis, its principles, and its applications are reviewed. The signal-enhancing effect of kinematic focusing is explained, and new results to demonstrate the effect are presented. The potential of electroinjection analysis for investigation of the complex-forming ability of natural samples is illustrated by the reaction of copper and lead with peat samples; the fraction of uncomplexed metal is reacted in the column with EDTA for detection. Reaction kinetic studies with EIA are presented, along with the novel ability to detect reaction intermediates. Electroinjection analysis is compared with flow injection analysis, capillary electrophoresis with precolumn reaction, electrophoretically mediated microanalysis, and affinity capillary electrophoresis. *Presented at Warsaw Technical University Chemical Forum, May 15, 2001.