Fatal doses and concentrations of drugs in biological objects

Information on the lethal doses and concentrations of drugs in biological objects is essential for the diagnosis of drug poisoning. Methods for measuring the concentrations of some drugs in the blood and urine have been developed and tables of lethal doses, concentrations, and metabolism coefficients for drugs most often occurring in forensic medical practice are offered. A method for estimating the drug dose which led to a lethal outcome is suggested.     

唾液中滥用药物分析及其与血液中药物浓度的相关性

唾液是一种成分简单、易于采集的体液,某些药物在唾液中的浓度可以反映其血药浓度。本文分析了滥用药物进入唾液的机制和影响因素,综述了唾液中滥用药物分析时样品的采集、前处理和检测方法以及唾液与血液中药物浓度的相关性。认为唾液是临床和法医学方面很有价值的分析样品,用唾液中滥用药物浓度来推测血药浓度具有一定的法医学意义。     

Fatal poisoning with alcohol and drugs in the Greater Amman County

A study of fatal poisoning due to alcohol and drugs was carried out, to examine the mortality resulting from alcohol and drugs in the Greater Amman County, Jordan. A retrospective review of all autopsy records and certified deaths issued by the Department of Forensic Medicine at Jordan University Hospital in the greater Amman county was undertaken. During the 18 years (1978-1996) 6109 postmortem cases were performed in our department. A total of 60 cases were identified and analyzed according to age, race, sex, manner of death of the victims along with blood alcohol concentration, the drug detected at autopsies, the scene circumstances, and the geographic location of the accident and death.     

Postmortem tissue concentrations of venlafaxine

Venlafaxine is a phenethylamine antidepressant which inhibits both serotonin and norepinephrine reuptake and is structurally unrelated to the serotonin reuptake inhibitors (SSRIs). Its major metabolite, O-desmethylvenlafaxine (ODV), also inhibits serotonin reuptake. Although metabolized by the cytochrome P-450 (CYP) system, venlafaxine inhibits CYP 2D6 and 3A4 to a far lesser extent than do the SSRIs. Mechanisms of drug action are reviewed and evaluated in the investigation of 12 fatalities occurring over a 6-month-period where venlafaxine was detected.Venlafaxine and ODV were identified by liquid chromatography-mass spectrometry (LC-MS) using atmospheric pressure ionization (API) electrospray in positive mode following an n-butyl chloride extraction. Postmortem tissue concentrations studied in each of 12 postmortem cases for venlafaxine and ODV, were 0.1-36 and <0.05-3.5mg/l (peripheral blood), <0.05-22 and <0.05-9.9mg/kg (liver), <0.05-10 and <0.05-1.5mg/l (vitreous), <0.05-53 and <0.05-6.8mg/l (bile), <0.05-55 and <0.05-21mg/l (urine), respectively, and 0.1-200mg of venlafaxine in the gastric contents. Venlafaxine was typically present with other drugs, including other antidepressants, alcohol, and benzodiazepines. The potential for interaction with each drug is discussed. Over the 6-month-period of this study, there were no deaths ascribed solely to venlafaxine intoxication.     

Fatal versus non-fatal heroin "overdose": blood morphine concentrations with fatal outcome in comparison to those of intoxicated drivers

The study was performed to distinguish fatal from non-fatal blood concentrations of morphine. For this purpose, blood levels of free morphine and total morphine (free morphine plus morphine conjugates) in 207 cases of heroin-related deaths were compared to those in 27 drivers surviving opiate intoxication. The majority of both survivors and non-survivors were found to show a concomitant use of depressants including alcohol or stimulants. Blood morphine levels in both groups varied widely, with a large area of overlap between survivors (free morphine: 0-128 ng/ml, total morphine: 10-2,110 ng/ml) and non-survivors (free morphine: 0-2,800 ng/ml, total morphine: 33-5,000 ng/ml). Five (18.5%) survivors and 87 (42.0%) non-survivors exhibit intoxication only by morphine. In these cases, too, both groups overlapped (survivors-free morphine: 28-93 ng/ml, total morphine: 230-1,451 ng/ml; non-survivors-free morphine: 0-2,800 ng/ml, total morphine: 119-4,660 ng/ml). Although the blood levels of free or total morphine do not allow a reliable prediction of survival versus non-survival, the ratio of free/total morphine may be a criterion to distinguish lethal versus survived intoxication. The mean of the ratio of free to total morphine for all lethal cases (N=207) was 0.293, for those that survived (N=27) 0.135, in cases of intoxication only by morphine 0.250 (N=87) and 0.080 (N=5), respectively. Applying a cut-off of 0.12 for free/total morphine and performing ROC analyses, fatal outcome can be predicted in 80% of the cases correctly, whereas 16% of the survivors were classified as dead. Nevertheless, in this study, all cases with a blood concentration of 200 ng/ml and more of free morphine displayed a fatal outcome.     

Codeine and morphine blood concentrations increase during blood loss

During extensive blood loss, a plasma volume refill will take place by transfer of extravascular fluid into the circulation. Drugs present in this fluid may follow and cause a rise or a drop in blood drug concentration, depending on their levels and accessibility in the restoration fluid. This study explored the possible changes of codeine, and its metabolite morphine, in whole blood during a standardized exsanguination in the rat. Three doses containing 5 mg codeine were given orally. In eight rats, blood loss was accomplished by slowly withdrawing 0.8 mL blood at 10 min intervals during 70 min. In control rats, blood was withdrawn only at 0 and 70 min. At 70 min, the final/initial codeine and morphine concentration ratios were 0.70 +/- 0.38 and 0.88 +/- 0.47, respectively, in controls, but increased to 1.28 +/- 0.44 (p = 0.014) and 1.41 +/- 0.34 (p = 0.021), respectively, in exsanguinated rats. It is concluded that blood loss can affect blood drug concentrations.     

Postmortem oxycodone and hydrocodone blood concentrations

There is limited data on postmortem oxycodone concentrations, consisting of three published reports with a total of 11 cases, many of which were polypharmacy cases. This report presents the results of a review of autopsy and coroner's reports from 10 counties for the years 2000 and 2001 to locate cases with oxycodone or hydrocodone exposure as a leading cause of death. Eighty-eight cases were located. Twenty-four deaths were attributed to oxycodone alone. Mean and median postmortem oxycodone blood concentrations were 1.23 mg/L and 0.43 mg/L, respectively. The range was 0.12 to 8.0 mg/L, with 13 cases (54%) < or = 0.5 mg/L. Seventeen deaths were attributed to hydrocodone alone. Mean and median postmortem hydrocodone blood concentrations were 0.53 mg/L and 0.40 mg/L, respectively. The range was 0.12 to 1.6 mg/L, with 11 cases (65%) < or = 0.5 mg/L. There were seven cases where the cause of death was attributed to the effects of a combination of hydrocodone and oxycodone. Mean oxycodone and hydrocodone blood concentrations were 0.34 mg/L and 0.14 mg/L, respectively. Forty cases involved polysubstance overdoses with significant involvement of other drugs and ethanol. Mean oxycodone and hydrocodone blood concentrations were 0.18 mg/L and 0.29 mg/L, respectively. The list of other substances involved was extensive but included ethanol, amitriptyline, methadone, codeine, propoxyphene, and acetaminophen. The findings of this study report oxycodone values associated with a fatality at blood concentrations lower than previously reported. This may represent enhanced information because of the larger sample group. Hydrocodone values associated with a fatality were similar to previously published values.     

Effect of post-mortem changes on peripheral and central whole blood and tissue clozapine and norclozapine concentrations in the domestic pig (Sus scrofa)

Interpretation of the results of psychoactive or other drug measurements in post-mortem blood specimens may not be straightforward, in part because analyte concentrations in blood may change after death. There is also the issue of comparability of plasma (or serum) results to those obtained in whole blood. To investigate these problems with respect to clozapine, this drug (10mg/kg daily) was given orally to two pigs. Blood was collected 3h post-dose on day 7, the animals were sacrificed, and blood taken from central and peripheral veins for up to 48 h after death. Tissue samples were also collected immediately after death and at 48 h. Ante-mortem whole blood clozapine/N-desmethylclozapine (norclozapine) concentrations were 0.86/1.07 and 1.11/1.15 mg/l in pigs 1 and 2, respectively. Blood clozapine and norclozapine concentrations generally increased after death (central vein: clozapine up to 300%, norclozapine up to 460%; peripheral vein: clozapine up to 155%, norclozapine up to 185%). Initial blood and kidney clozapine and norclozapine concentrations were comparable in both animals, but were some two-fold higher in heart, liver and striated muscle in pig 2. In both animals, the heart and striated muscle clozapine and norclozapine concentrations had increased some two- to three-fold at 48 h, whilst the liver and kidney concentrations were essentially unchanged. The reason for the increase in heart and striated muscle concentrations at 48 h is unclear, but could be simple variation in sample site. The plasma:whole blood distribution of clozapine and norclozapine was studied in vitro. In human blood (one volunteer donor, haematocrit 0.50) the plots of plasma versus whole blood concentration were linear for both analytes across the range 0.1-1.5mg/l, although clozapine favoured plasma (plasma:whole blood ratio=1.12), whereas norclozapine favoured whole blood (ratio 0.68). In pig blood, the plots of plasma versus whole blood were non-linear in both cases, although clozapine favoured plasma to a greater extent than norclozapine. This may be due to lower plasma clozapine and norclozapine protein binding capacity in the pig as compared to man.     

Analysis of blood and tissue for amoxapine and trimipramine

A method for the identification and quantitation of two tricyclic antidepressants, amoxapine (Asendin) and trimipramine (Surmontil) is presented here. Samples were extracted with hexane at pH 10, back-extracted with 1.0N sulfuric acid. The acidic layer was adjusted to pH 10 and re-extracted with hexane. Electron impact mass spectra were obtained. The base peak and molecular ion for amoxapine were at m/z 245 and 313, respectively. The base peak and molecular ion for trimipramine were at m/z 58 and 294, respectively. There were three forensic toxicology cases involving amoxapine in Cook County, IL, in 1980 and 1981. The concentrations of amoxapine in blood for these three cases were 1.66 mg/L, 7.16 mg/L, and 2.95 mg/L, respectively.     

The temporal fate of drugs in decomposing porcine tissue

Drug levels in decomposed individuals are difficult to interpret. Concentrations of 16 drugs were monitored in tissues (blood, brain, liver, kidney, muscle, and soil) from decomposing pigs for 1 week. Pigs were divided into groups (n = 5) with each group receiving four drugs. Drug cocktails were prepared from pharmaceutical formulations. Intracardiac pentobarbital sacrifice was 4 h after dosing, with tissue collection at 4, 24, 48, 96, and 168 h postdosing. Samples were frozen until assay. Detection and quantitation of drugs were through solid phase extraction followed by gas chromatograph/mass spectrometer analysis. Brain and kidneys were not available after 48 h; liver and muscle persisted for 1 week. Concentration of drugs increased during decomposition. During 1 week of decomposition, muscle showed average levels increasing but concentrations in liver were increased many fold, compared to muscle. Attempting to interpret drug levels in decomposed bodies may lead to incorrect conclusions about cause and manner of death.     

血中碱性药物的高效液相色谱分析

利用高效液相色谱法，ODS柱，二极管阵列紫外检测器，测定了血中常见吩噻嗪类、三环类等碱性药物．实验以赛庚啶为内标物，血样经沉淀蛋白后，用固相小柱提取，或直接用乙醚液液提取，以甲醇：水：三乙胺为流动相，考察了血中碱性药物的提取及定性、定量方法．     

The association of alcohol-induced blackouts and grayouts to blood alcohol concentrations

The primary aim of this study was to investigate the association between measured blood alcohol concentration (BAC) and the presence and degree of amnesia (no amnesia, grayout, or blackout) in actively drinking subjects. A secondary aim was to determine potential factors other than BAC that contribute to the alcohol-induced memory loss. An interview questionnaire was administered to subjects regarding a recent alcohol associated arrest with a documented BAC greater than 0.08 g/dL for either public intoxication, driving under the influence, or under age drinking was administered. Demographic variables collected included drinking history, family history of alcoholism, presence of previous alcohol-related memory loss during a drinking episode, and drinking behavior during the episode. Memory of the drinking episode was evaluated to determine if either an alcohol-induced grayout (partial anterograde amnesia) or blackout (complete anterograde amnesia) occurred. Differences in (1) mean total number of drinks ingested before arrest, (2) gulping of drinks, and (3) BAC at arrest were found for those having blackouts compared with no amnesia; while differences in drinking more than planned were found between the no amnesia and grayout groups. A strong linear relationship between BAC and predicted probability of memory loss, particularly for blackouts was obvious. This finding clinically concludes that subjects with BAC of 310 g/dL or greater have a 0.50 or greater probability of having an alcoholic blackout.     

Passive exposure in detection of low blood and urine cannabinoid concentrations

Whenever small amounts of drugs are present in blood or urine samples, especially of substances that are preferentially smoked such as cannabinoids, the discrimination between active and passive inhalation may cause severe problems. The statement of a passive exposure by marijuana smoke has been scrutinized reviewing the literature. The pharmacokinetics of smoked marijuana as well as experimental data on cannabinoid concentrations in plasma and urine samples following passive exposure are summarized. As a conclusion it seems urgent to enlarge the existing data base.     

Concentration of drugs in blood of suspected impaired drivers

Analytical records concerning 440 living drivers suspected of driving under the influence of drug (DUID) were collected and examined during a 2 years period ranging from 2002 to 2003 in canton de Vaud, Valais, Jura and Fribourg (Switzerland). This study included 400 men (91%) and 40 women (9%). The average age of the drivers was 28+/-10 years (minimum 16 and maximum 81). One or more psychoactive drugs were found in 89% of blood samples. Half of cases (223 of 440, 50.7%) involved consumption of mixtures (from 2 to 6) of psychoactive drugs. The most commonly detected drugs in whole blood were cannabinoids (59%), ethanol (46%), benzodiazepines (13%), cocaine (13%), amphetamines (9%), opiates (9%) and methadone (7%). Among these 440 cases, 11-carboxy-THC (THCCOOH) was found in 59% (median 25 ng/ml (1-215 ng/ml)), Delta(9)-tetrahydrocannabinol (THC) in 53% (median 3 ng/ml (1-35 ng/ml)), ethanol in 46% (median 1.19 g/kg (0.14-2.95 g/kg)), benzoylecgonine in 13% (median 250 ng/ml (29-2430 ng/ml)), free morphine in 7% (median 10 ng/ml (1-111 ng/ml)), methadone in 7% (median 110 ng/ml (27-850 ng/ml)), 3,4-methylenedioxymethamphetamine (MDMA) in 6% (median 218 ng/ml (10-2480 ng/ml)), nordiazepam in 5% (median 305 ng/ml (30-1560 ng/ml)), free codeine in 5% (median 5 ng/ml (1-13 ng/ml)), midazolam in 5% (median 44 ng/ml (20-250 ng/ml)), cocaine in 5% (median 50 ng/ml (15-560 ng/ml)), amphetamine in 4% (median 54 ng/ml (10-183 ng/ml)), diazepam in 2% (median 200 ng/ml (80-630 ng/ml)) and oxazepam in 2% (median 230 ng/ml (165-3830 ng/ml)). Other drugs, such as lorazepam, zolpidem, mirtazapine, methaqualone, were found in less than 1% of the cases.