Perimortem fixation of the gastric and duodenal mucosa: a diagnostic indication for oral poisoning

Two cases of fatal oral poisoning are presented. In the first case, a 40-year-old man died due to a lethal dose of mercury (blood concentration 113.8 μg/ml) and in the second, a 34-year-old man died of chloralhydrate overdose with a lethal blood concentration of trichloroethanol (52 μg/ml), the active metabolite of chloralhydrate. In both cases gross examination and histology showed an unusually well preserved gastrointestinal mucosa in addition to unspecific signs of intoxication. The two cases demonstrate that the phenomenon of perimortal fixation is a useful indication for the forensic pathologist and should direct the suspicion to oral poisoning. The detection of fixation facilitates toxicology screening by indicating that the relevant substance must have the capability to precipitate proteins. Received: 24 November 1998 / Received in revised form: 18 February 1999     

Evidence for the involvement of central alpha 2 mechanisms in intrathoracic volume expansion--induced diuresis: a study with clonidine and propranolol

Intravenous (10 micrograms/kg) or intracisternal (1 microgram/kg) clonidine inhibited the diuretic response to negative pressure breathing (NPB) and left atrial distension (LAD) in chloralose anesthetized dogs. The drug reduced the induced tachycardia, but not the increase in respiratory rate caused by NPB, and did not change the blood pressure. Propranolol (1 mg/kg i.v.) did not change the NPB-induced diuresis. Intravenous yohimbine (1 mg/kg i.v.) opposed the effects of intravenous or intracisternal clonidine, whereas prazosin (0.05 mg/kg i.v.) had no effect. These results show that the adrenergic receptor implicated in the volumetric control of vasopressin secretion could be of the alpha 2 subtype. This alpha 2 adrenoceptor could be centrally located. Clonidine might therefore be proposed to combat the dehydration observed after long-term weightlessness.     

Prostaglandin levels in human renal venous blood during renal arteriography

In view of the possible role of prostaglandins (PG) and thromboxane (TX) in the disturbances of renal function and blood flow after the injection of diatrizoate into the renal artery, we have determined the levels of PGE2, 6-keto-PGF1 alpha (a stable metabolite of prostacyclin) and TXB2 in the renal venous blood before, during and after renal arteriography in 12 patients. Radioimmunologically assayed PGE2 was the most abundant prostaglandin in renal venous blood. Lower basal levels of PGs were associated with renal adenocarcinomas or other tumours than non-tumour kidneys. The concentrations of 6-keto-PGF1 alpha and PGF2 alpha rapidly increased after diatrizoate injection and returned to the basal levels within 5 minutes. Slower elevation was noticed in the PGF2 level of 5 tumour kidneys. Renal plasma concentration of TXB2 remained unchanged throughout the study. The rapid elevation of renal venous prostacyclin and PGF2 alpha concentration after the contrast injection may reflect the enhanced intrarenal prostaglandin synthesis or may be secondary to hemodynamic changes in the kidney caused by hypertonic diatrizoate.     

Practical use of ethyl glucuronide and ethyl sulfate in postmortem cases as markers of antemortem alcohol ingestion

In postmortem toxicology, it could be difficult to determine whether a positive blood ethanol concentration reflects antemortem ingestion or postmortem synthesis of alcohol. Measurement of the nonoxidative ethanol metabolite ethyl glucuronide (EtG) has been suggested as a marker of antemortem ingestion of alcohol, but EtG might degrade postmortem which could make interpretation difficult. So far, the published articles concern EtG only. Another nonoxidative metabolite, ethyl sulfate (EtS), which is more stable, has therefore been included in this study. We present a material of 36 deaths where postmortem formation of ethanol was suspected and where both EtG and EtS were measured in blood and urine to assist the interpretation. In 19 cases, EtG and EtS were positive in the body fluids analyzed. The median concentration of EtG and EtS in blood was 0.4 (range 0.1–23.2) and 0.9 mg/L (range 0.04–7.9), respectively. The median concentration of EtG and EtS in urine was 35.9 (range 1.0–182) and 8.5 mg/L (range 0.3–99), respectively. In another 16 cases, there was no trace of EtG or EtS in the specimens analyzed. In one case, there was inconsistency between the results of EtG and EtS; they were both positive in urine, while only EtS was positive in blood. This study showed that, out of 36 cases, antemortem ingestion of alcohol was very likely in 19 and unlikely in 16, according to EtG and EtS results. In the last case, the interpretation was more difficult. One possible explanation would be postmortem degradation of EtG in blood.     

Morphine in postmortem blood: its importance for the diagnosis of deaths associated with opiate addiction

Summary This article describes an analytical method for the determination of morphine, the active metabolite of heroin, in post-mortem blood by HPLC with electrochemical detection. An extraction technique allowing the determination of free and total morphine (free morphine + morphine glucuronide) was used. Blood morphine levels in postmortem cases are reported and the ratio of free to total morphine was measured in 52 cases obtained at autopsy. The importance of this ratio is discussed in relation to the circumstances of the death.     

Relationship of renal hemodynamic and functional changes following intravascular contrast to the renin-angiotensin system and renal prostacyclin in the dog

Deterioration in renal function has been observed after the use of intravascular contrast media. In an attempt to identify factors responsible for this phenomenon, meglumine iothalamate (Conray 60), in a dosage range of 2.5-3.3 ml/kg, was injected as a bolus into the aorta of dogs. Serial measurements were made of parameters of renal function as well as of changes in aortic and renal venous levels of angiotensin II, renin activity, and 6-keto-PGF1 alpha, the stable metabolite of prostacyclin. The major findings were (1) an initial, brief increase followed by approximately a 20% sustained decrease in renal blood flow and creatinine clearance, (2) no significant changes in angiotensin II and renin levels, and (3) a significant decline in the renal secretory rate of 6-keto-PGF1 alpha. These observations suggest that the suppression of prostacyclin, rather than the activation of the renin-angiotensin system, may contribute to the renal function changes attending the use of intravascular contrast media.     

Fatal dextropropoxyphene poisonings in Jutland (Denmark)

Summary For many years dextropropoxyphene (dxp) has been the medicament most frequently occurring in drug poisoning cases examined at the Institute of Forensic Medicine, University of Aarhus.This study includes 85 cases of acute fatal poisoning examined in the period 1985–1987 in which dxp alone (40 cases) or in combination with alcohol (29 cases) and/or other drugs (16 cases) contributed significantly to death. Two-thirds of the deceased were men and one-third women. The average age was 37 years for both sexes. More than half of the deceased were drug and/or alcohol misusers. Eighteen were drug addicts. Half of the deaths resulted from accidents, while 40% were suicides. Accidental deaths prevailed among younger men. In a majority of the cases the drug had been taken orally. In these cases the median total blood concentration of dxp and the metabolite nordextropropoxyphene (ndxp) was 17 mg/kg in the suicide cases and 7.1 mg/kg in the accident cases. The corresponding figures for dxp without metabolite were 9.4 mg/kg and 2.2 mg/kg, respectively. The median value of the quotient dxp/ndxp was 1.9 in the suicide cases and 0.5 in the accident cases. The quotient, together with the concentrations of the drug, may therefore indicate the manner of death in many cases.     

Methadone and methadone metabolites in postmortem specimens

We have determined drug/metabolite concentrations and ratios of methadone (METH) to two of its metabolites (EDDP, 2-ethylidene-1, 5-dimethyl-3, 3-diphenylpyrrolidine; and EMDP, 2-ethyl-5-methyl-3,3-diphenylpyrroline) in postmortem peripheral blood and liver tissue by liquid chromatography/tandem mass spectrometry. The assays employed deuterated internal standards and multiple reaction monitoring (MRM) techniques. The assay linear range was 0.01–2.0 mg/l for each analyte. METH, EDDP, and EMDP were determined in liver and peripheral blood from 46 methadone-positive cases. METH and EDDP were detected in all specimens, whether blood or liver. EMDP was detected, only in liver, and only 17 cases, at concentrations much lower than those of EDDP. Concentrations of METH and EDDP in blood and liver from EMDP-positive cases were in ranges higher than, but overlapping with, concentrations in blood and liver from EMDP-negative cases. These data suggest that although METH is readily demethylated and cyclized to EDDP, in vivo, conversion to EMDP may be less efficient and its accumulation in postmortem tissues may be highly individual.     

Post-aggression suicide under the influence of new psychoactive substances AMB–FUBINACA and U-47700

The objective of the present study was the development and validation of the method for determining AMB-FUBINACA and its metabolite - AMB-FUBINACA O-desmethyl acid – in blood samples, followed by verification of the method in toxicological judicial and forensic medicine practice employing the example of post-aggression suicide. Most likely in consequence of development of adverse effects resulting in psychotic symptoms, a male being under the influence of the synthetic cannabinoid AMB-FUBINACA and the new synthetic opioid U-47700, mortally wounded his female partner and subsequently committed suicide. Identification and determination of the afore-mentioned xenobiotics in blood samples collected from the male and female victims were performed employing high performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS). The analytes were isolated from blood samples using the solid phase extraction (SPE) method. The blood samples collected from the male and female demonstrated respectively 110 and 196 ng/mL of AMB-FUBINACA O-desmethyl acid metabolite, 1935 and 357 ng/mL of U-47700, 250 and 200 ng/mL of N-desmethyl-U-47700, as well as 410 and 200 ng/mL of N,N-didesmethyl-U-47700. The concentration values of new psychoactive substances (NPS’s) in blood samples originating from the male and female were within the ranges encountered in cases of poisoning, including these resulting in death. Nevertheless, the evident signs of exsanguination proof that the woman was alive when she sustained lethal injuries. The presented cases illustrate the difficult to be anticipated effect exerted on the users by NPS’s.     

The possible involvement of PGI2 in the PEEP-induced changes in cardiac output and blood pressure

Ventilation with positive end-expiratory pressure (PEEP) is employed in clinical and aviation medicine. The widespread application of PEEP, however, is limited principally because of its adverse effect on cardiac output (CO) and systemic arterial blood pressure (BP). Recently, it has been suggested that this PEEP-induced cardiovascular depression may be mediated by vasoactive agents, possibly prostaglandin in nature. This study examined the possible involvement of PGI2 in the PEEP-induced decreases in CO and BP. Chloralose-anesthetized mechanically ventilated dogs were subjected to brief intervals (75 s) of PEEP 10 or 20 mm Hg. Arterial levels of 6-keto-PGF1 alpha (stable metabolite of PGI2) were monitored by radioimmunoassay. These parameters were compared before and during PEEP application. During PEEP, tracheal pressure-related decreases in both CO and BP were noted. Application of either PEEP 10 or 20 mm Hg resulted in an increase in circulating 6-keto-PGF1 alpha levels in three animals while a decrease was noted in two others. Overall, application of PEEP did not result in a significant change from baseline levels. Furthermore, there was no correlation between changes in either CO or BP with changes in arterial 6-keto-PGF1 alpha levels. These results do not support the hypothesis that the short term PEEP-induced changes in CO or BP are mediated by endogenously released PGI2.     

Lack of effect of helium breathing on catecholamine levels in the adrenal vein blood of the rabbit

Catecholamine levels were measured in the adrenal vein blood of the chloralose anesthetized rabbit during periods of helium-oxygen breathing (50% He-50% O2) and of air breathing. Blood samples were taken from the T-arm of a venous shunt made by cannulating the renal vein proximally to the orifice of the adrenal vein and connecting the distal end of the cannula to one in the femoral vein. Adrenal vein blood flow varied from 0.09-0.30 g/min in five animals, and catecholamine release from 10-92 ng/min. There were large differences between levels from animal to animal but no significant differences in any one animal between levels measured while breathing helium and levels measured while breathing air. The same held true for respiratory rate, blood pressure, heart rate, and percent change in blood pressure during a simulated valsalva maneuver. Although there were changes seen in catecholamine release during some of these experiments, they could not be related to an effect of gases breathed. It is concluded that if there was an effect of helium breathing on catecholamine release in these anesthetized rabbits it was masked by other conditions with stronger action on the sympatho-adrenal system.     

Cocaine postmortem distribution in three brain structures: A comparison with whole blood and vitreous humour

The presence of cocaine (COC) in fluids or tissues does not prove that death was due to drug consumption and the interpretation of postmortem concentrations is more complex than attempts at making such correlations in the living. The purpose of this study was to investigate the distribution of cocaine and its metabolite benzoylecgonine in brain and compare with whole blood and vitreous humour. The distribution in three brain structures (prefrontal cortex, basal ganglia and cerebellum) was homogeneous. There is a strong correlation for cocaine concentrations between vitreous humour and brain, vitreous humour and whole blood, and whole blood and brain in overdose cases. In addition, the comparison of COC/benzoylecgonine (BE) ratios in different experimental specimens proved to be more appropriate for evaluating cocaine-related death than individual drug values. These findings suggest that the comparison of cocaine levels in different compartments is essential to assess the cause of death.     

Lipid peroxides, prostacyclin, and thromboxane A2 in runners during acute exercise

We studied the effect of physical activity on lipid peroxidation and on the production of antiaggregatory, vasodilatory prostacyclin (epoprostenol, PGI2) and its endogenous antagonist, thromboxane A2 (TxA2) in 10 well-trained long-distance runners before, during, and after maximal exercise on a cycle ergometer. Pre-exercise levels of lipid peroxides (2.0 +/- 0.4 mumol X l-1, means +/- SD), plasma immunoreactive 6-keto-prostaglandin F1 alpha (i 6-keto-PGF1 alpha, a metabolite of PGI2) (192.8 +/- 51.7 pmol X l), and serum immunoreactive thromboxane B2 (i TxB2, a metabolite of TxA2) (703.3 +/- 290.1 nmol X l) did not differ from those of 10 non-athletic controls. Plasma i 6-keto-PGF1 alpha was increased at the seventh minute of the exercise test, but not any more at the end of the exercise or 30 min later. Lipid peroxides or i TxB2 did not change. Our data suggest that the changes of the PGI2/TxA2-ratio induced by long-term or acute physical exercise are too small to explain the protective effect of physical fitness against coronary heart disease.     

Characterization of the radiolabeled metabolite of tau PET tracer <Superscript>18</Superscript>F-THK5351

Purpose

¹⁸F-THK5351 is a novel radiotracer developed for in vivo imaging of tau pathology in the brain. For the quantitative assessment of tau deposits in the brain, it is important that the radioactive metabolite does not enter the brain and that it does not bind to tau fibrils. The purpose of the study was to identify a radiolabeled metabolite of ¹⁸F-THK5351 in blood samples from human subjects and to characterize its pharmacological properties.

Methods

Venous blood samples were collected from three human subjects after injection of ¹⁸F-THK5351 and the plasma metabolite was measured by high performance thin layer chromatography. In addition, mass spectrometry analysis and enzymatic assays were used to identify this metabolite. Mice were used to investigate the blood–brain barrier permeability of the radioactive metabolite. Furthermore, the binding ability of the metabolite to tau aggregates was evaluated using autoradiography and binding assays using human brain samples.

Results

About 13 % of the unmetabolized radiotracer was detectable in human plasma at 60 min following the injection of ¹⁸F-THK5351. The isolated radiometabolite of ¹⁸F-THK5351 was the sulphoconjugate of THK5351. This metabolite could be produced in vitro by incubating THK5351 with liver but not brain homogenates. The metabolite did not penetrate the blood–brain barrier in mice, and exhibited little binding to tau protein aggregates in post-mortem human brain samples.

Conclusions

These results suggest that the sole metabolite detectable in plasma seems to be generated outside the brain and does not cross into the brain, which does not affect quantitative analysis of PET images.

     

Evaluation of a bromine-76-labeled progestin 16alpha,17alpha-dioxolane for breast tumor imaging and radiotherapy: in vivo biodistribution and metabolic stability studies

INTRODUCTION: Progesterone receptors (PRs) are present in many breast tumors, and their levels are increased by certain endocrine therapies. They can be used as targets for diagnostic imaging and radiotherapy. METHOD: 16alpha,17alpha-[(R)-1'-alpha-(5-[(76)Br]Bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione ([(76)Br]16alpha,17alpha-[(R)-1'-alpha-(5-bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione (3)), a PR ligand with relative binding affinity (RBA)=65 and log P(o/w)=5.09+/-0.84, was synthesized via a two-step reaction, and its tissue biodistribution and metabolic stability were evaluated in estrogen-primed immature female Sprague-Dawley rats. RESULTS: [(76)Br]16alpha,17alpha-[(R)-1'-alpha-(5-bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione 3 was synthesized in 5% overall yield with specific activity being 200-1250 Ci/mmol. [(76)Br]16alpha,17alpha-[(R)-1'-alpha-(5-bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione 3 demonstrated high PR-mediated uptake in the target tissue uterus (8.72+/-1.84 %ID/g at 1 h) that was reduced by a blocking dose of unlabeled progestin R5020, but the nonspecific uptake in blood and muscle (2.11+/-0.14 and 0.89+/-0.16 %ID/g at 1 h, respectively) was relatively high. [(76)Br]16alpha,17alpha-[(R)-1'-alpha-(5-bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione 3 was stable in whole rat blood in vitro, but it was not stable in vivo due to the fast metabolism that occurred in the liver, resulting in the formation of a more polar radioactive metabolite and free [(76)Br]bromide. The level of free [(76)Br]bromide in blood remained high during the experiment (2.11+/-0.14 %ID/g at 1 h and 1.52+/-0.24 %ID/g at 24 h). The tissue distribution of [(76)Br]16alpha,17alpha-[(R)-1'-alpha-(5-bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione 3 at 1 and 3 h was compared with that of the (18)F analogs, [(18)F]FFNP fluoro furanyl norprogesterone (FFNP) 1 and ketal 2. CONCLUSION: [(76)Br]16alpha,17alpha-[(R)-1'-alpha-(5-bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione 3 may have potential for imaging PR-positive breast tumors at early time points, but it is not suitable for imaging at later times or for radiotherapy.     

Carbon-monoxide poisoning in young drug addicts due to indoor use of a gasoline-powered generator

We report six fatal cases of unintentional carbon-monoxide poisoning which occurred in a house occupied by young people. The source of carbon monoxide was a gasoline-powered generator. For all victims, an external body examination was carried out and blood and urine samples collected. Blood carboxyhaemoglobin (COHb) was performed using an automated visible spectrophotometric analysis. Blood-alcohol level quantification was performed using gas chromatography and drug screening in urine was performed by a one-step manual qualitative immunochromatography (Syva Rapid test, Behring Diagnostics Inc.) for benzoylecgonine (the main metabolite of cocaine in urine), morphine, 11-nor-Delta(9)-THC-9-COOH (cannabinoids) and d-methamphetamine. In all victims the COHb value was as high or higher than 65%. No alcohol was found in blood samples, but urine samples were positive for methamphetamine, cocaine and cannabis in five cases and for opiates in one case. In four victims, the urine sample was positive for at least three drugs. The availability and accuracy of rapid toxicological screening is an important tool for the medical examiner at the immediate scene of a clinical forensic examination.     

Sudden death after isobutane sniffing: a report of two forensic cases

The intentional inhalation of a volatile substance (“sniffing”) causing euphoria and hallucinations is an under-recognised form of substance abuse in children and adolescents with a high morbidity and mortality. Sudden death can be caused by cardiac arrhythmia, asphyxia or trauma. Two fatal cases of isobutane sniffing of cigarette lighter refill containing isobutane are reported. Toxicological investigations revealed the presence of isobutane in the heart blood and brain tissue of both cases (case 1: heart blood 0.1 μg/g, brain tissue 2.3 μg/g; case 2: heart blood 4.6 μg/g, brain tissue 17.4 μg/g) and the presence of its metabolite 2-methyl-2-propanol in the heart blood of both cases (0.5 and 1.8 μg/g, respectively). The histological investigations of the inner organs showed similar results in both victims. Autopsy findings, results of the histological and immunohistochemical investigations, toxicological findings and analytical procedures are discussed.     

Superior mesenteric angiography and blood flow following intra-arterial injection of prostaglandin F2alpha.

The effect of intra-arterially administered prostaglandin F2alpha(PGF2alpha) on venous demonstration in angiography of the superior mesenteric artery was compared to that of bradykinin in 10 patients, and the flow increase in this vessel following PGF2alpha was measured by a dye dilution technique in another 8 patients. The angiographic demonstration of veins was similarly improved by the 2 drugs, the effect of 60 mug. of PGF2alpha being roughly equivalent to that of 10 mug. of bradykinin. The loss of arterial detail was less marked after PGF2alpha which, however, had a longer duration of action. The flow studies indicated that 80 mug. of PGF2alpha increased the superior mesenteric blood flow 103 +/- 16 per cent. There was no influecne on blood pressure or pulse rate. The patients experienced a sensation of warmth in the abdomen for a few seconds following the injection of drugs, but no other side effect was noted. It is concluded that PGF2alpha causes a rapid increase of the superior mesenteric blood flow in man making it suitable for pharmacoangiography of this vascular bed.     

PET-based human dosimetry of 18F-galacto-RGD, a new radiotracer for imaging alpha v beta3 expression.

(18)F-Galacto-RGD is a new tracer for PET imaging of alpha v beta3, a receptor involved in a variety of pathologic processes including angiogenesis and metastasis. Our aim was to study the dosimetry of (18)F-galacto-RGD in humans. METHODS: Eighteen patients with various tumors (musculoskeletal tumors [n = 10], melanoma [n = 5], breast cancer [n = 2], or head and neck cancer [n = 1]) were examined. After injection of 133-200 MBq of (18)F-galacto-RGD, 3 consecutive emission scans from the thorax to the pelvis were acquired at 6.7 +/- 2.9, 35.6 +/- 7.6, and 70.4 +/- 12.2 min after injection. Blood samples (n = 4) for metabolite analysis were taken 10, 30, and 120 min after injection. The OLINDA 1.0 program was used to estimate the absorbed radiation dose. RESULTS: Reversed-phase high-performance liquid chromatography of serum revealed that more than 95% of tracer was intact up to 120 min after injection. (18)F-Galacto-RGD showed rapid clearance from the blood pool and primarily renal excretion. Background activity in lung and muscle tissue was low (percentage injected dose per liter at 71 min after injection, 0.56 +/- 0.15 and 0.69 +/- 0.25, respectively). The calculated effective dose was 18.7 +/- 2.4 microSv/MBq, and the highest absorbed radiation dose was in the bladder wall (0.22 +/- 0.03 mGy/MBq). CONCLUSION: (18)F-Galacto-RGD demonstrates high metabolic stability, a favorable biodistribution, and a low radiation dose. Consequently, this tracer can safely be used for noninvasive imaging of molecular processes involving the alpha v beta3 integrin and for the planning and monitoring of therapeutic approaches targeting alpha v beta3.     

Prostaglandins in diagnostic and therapeutic superior mesenteric artery pharmacoangiography

The hemodynamic effects of prostaglandins PGA1, PGE1, PGE2, and PGF2 alpha on the splanchnic circulation were evaluated in five chronic dogs with portal hypertension, periportal fibrosis, and portosystemic venous shunting. The maximum effect was achieved with dosages of 2 micrograms/kg/min after bolus injection into the superior mesenteric artery. With this dosage a monophasic increase of portal blood flow and pressure was found with PGA1, PGE1, and PGE2, whereas PGF2 alpha caused a biphasic response: an initial decrease in portal blood flow and pressure was followed by an increase in these parameters. The average peak increase in portal blood flow and pressure was similar for PGE1 and PGF2 alpha, and significantly smaller for PGA1 and PGE2. Average peak iodine concentrations in the portal blood after superior mesenteric angiography were highest with PGF2 alpha, similar for PGE1 and tolazoline, and lowest in controls. The vasoconstrictor effect of PGF2 alpha is, overall, reduced and less reproducible when compared with vasopressin. This investigation suggests that both PGE1 and PGF2 alpha are effective for improved arterial portography, the latter agent appearing superior. On the other hand, PGF2 alpha cannot be recommended as a therapeutic agent for the treatment for gastrointestinal and particularly variceal bleeding.