Chiaki Fuke

POSTMORTEM DIFFUSION OF DRUGS FROM GASTRIC RESIDUE : AN EXPERIMENTAL STUDY

Postmortem drug diffusion from gastric residue was assessed in a human cadaver model. Fifty milligrams of amitriptyline (Ami) and 5 g of paracetamol (Par) suspended in 350 ml of 10% methanol, 0.1 N HCl, and 50 ml urograffin with 5 g lithium carbonate (alkaline model) or without lithium (acidic model) was instilled into the stomach through an esophageal tube via a neck dissection. Multiple samples were obtained after 48 h at room temperature (range in mean hourly room temperature: 15.6-20.7 degrees C, n = 9). The pH of the gastric contents (alkaline model range = 8.3-8.9, n = 5; acidic model range = 3.4-3.8, n = 5) had no significant effect. Drug diffusion was most marked in the left lung base, with drug concentrations (micrograms/g) of 0.1-13.9 for Ami, 65-524 for Par, and 13-161 for lithium. Similarly affected were the left lobe of the liver (Ami, 0.1-54.9; Par, 7-218; lithium, 7-39), the spleen (Ami, 0.6-24.3; Par, 104-663; lithium, 27-106), and pericardial fluid (Ami, 0-4.5; Par, 48-641; lithium, 12-56). Diffusion into gallbladder bile, cardiac blood, aortic blood, and blood of the inferior vena cava was less severe. The left kidney and left lung were more severely affected than the right kidney and lung, and similarly the left and right psoas muscles. Least affected was the right anterior lobe of the liver and the lung apexes. This phenomenon may significantly influence drug concentrations in liver and in blood samples obtained from the torso, and consequently liver/blood drug ratios. To circumvent the problem of postmortem drug diffusion from the stomach, it is recommended that blood be sampled from a peripheral vessel, skeletal muscle from a limb, liver from deep within the right lobe, and lung from the apex rather than the base.

Site to site variability of postmortem drug concentrations in liver and lung

We evaluated postmortem diffusion of gastric drug residue into tissues and blood in eight suicidal overdoses. Analyses were performed on liver (five sites), lung (four sites), spleen, psoas muscle and kidney (left and right), blood (peripheral and torso), vitreous, pericardial fluid, bile and, urine as well as residual gastric contents. Standard analytical techniques and instrumentation gas chromatograph/mass spectrometer and high performance liquid chromatography (GC-MS and HPLC) were used throughout. These case studies confirm previous studies of an animal and human cadaver model of gastric diffusion, in that in several instances there was drug accumulation in the left posterior margin of the liver and, to a lesser extent, the left basal lobe of the lung. Uncontrollable variables, such as postmortem interval, refrigeration before autopsy, and position of the body appear to influence significantly drug accumulation in a specific site. We suggest that autopsy sampling techniques should be standardized on blood taken from a ligated peripheral (preferably femoral or external iliac) vein, and liver from deep within the right lobe.

Haloperidol treatment induces tissue- and sex-specific changes in DNA methylation: a control study using rats

BackgroundWe previously found that there is a subtle difference in the global methylation state of blood leukocyte DNA between male subjects with and without schizophrenia. The aim of the current study was to determine whether this difference was a primary effect of the disease state, or a secondary effect of antipsychotics administered to these patients.MethodsWe examined the methyl cytosine (mC) content of DNA from the leukocytes, brain, and liver of rats using high performance liquid chromatography. A total of 40 male and female rats received for 21 days daily injection of haloperidol or vehicle solution alone.ResultsIn control rats injected with buffer only, there was a sex-dependent difference in mC content in leukocyte DNA (male > female; P = 0.028, n = 10), similar to our previous observations in human peripheral leukocytes. No difference in mC content between the sexes was observed in the brain or liver in buffer-treated animals. Haloperidol treatment slightly decreased the mC content of leukocytes in male rats, but unexpectedly, increased the mC content of leukocytes in females. We observed a trend toward a higher level of mC in the liver in both sexes following haloperidol treatment, compared to buffer-treated animals. In contrast, haloperidol treatment resulted in a decrease in mC content in the brain in females, and this difference was statistically significant (P = 0.026).ConclusionThese results indicate that haloperidol can affect DNA methylation states in the brain, as well as in certain other tissues, and raise the possibility that antipsychotic drugs play a role in the observed disparity in mC content in male subjects with and without schizophrenia.

Regional brain distribution of toluene in rats and in a human autopsy.

Toluene concentrations in 9 brain regions of acutely exposed rats and that in 11 brain regions of a human case who inhaled toluene prior to death are described. After exposure to toluene by inhalation (2000 or 10000 ppm) for 0.5 h or by oral dosing (400 mg/kg), rats were killed by decapitation 0.5 and 4 h after onset of inhalation and 2 and 10 h after oral ingestion. After each experimental condition the highest range of brain region/blood toluene concentration ratio (BBCR) was in the brain stem regions (2.85–3.22) such as the pons and medulla oblongata, the middle range (1.77–2.12) in the midbrain, thalamus, caudate-putamen, hypothalamus and cerebellum, and the lowest range (1.22–1.64) in the hippocampus and cerebral cortex. These distribution patterns were quite constant. Toluene concentration in various brain regions were unevenly distributed and directly related blood levels. In a human case who had inhaled toluene vapor, the distribution among brain regions was relatively similar to that in rats, the highest concentration ratios being in the corpus callosum (BBCR: 2.66) and the lowest in the hippocampus (BBCR: 1.47)

Analysis of paraquat, diquat and two diquat metabolites in biological materials by high-performance liquid chromatography

The determination of paraquat, diquat and two metabolites of diquat in biological materials was developed using high-performance liquid chromatography combined with UV and fluorescence detectors. Paraquat, diquat and internal standards (ethyl viologen and o-acetamidophenol) were detected by the UV detector. Diquat-monopyridone and diquat-dipyridone were monitored by the fluorescence detector. Paraquat, diquat, diquat-monopyridone and ethyl viologen were effectively extracted from blood, liver and brain, using a Sep-Pak C(18) cartridge. Diquat-dipyridone and o-acetamidophenol were extracted with methanol. Paraquat and diquat at a concentration range of 0.1-10 microg/ml (or g), and diquat-monopyridone and diquat-dipyridone at a concentration range of 0.01-1 microg/ml (or g) in biological material were determined with high accuracy and precision. The detection limits of paraquat, diquat, diquat-monopyridone and diquat-dipyridone were 1, 1, 0.02 and 0.02 ng, respectively, as an injection amount. This method was applied for toxicological examination of a case of suspected paraquat and diquat intoxication. The analysis of the metabolites of diquat was helpful for the estimation of the elapsed time from ingestion to death.

A fatal case considered to be due to cardiac arrhythmia associated with butane inhalation.

An autopsy case of a 14-year-old boy whose death is considered to be a result of cardiac arrhythmia after butane inhalation and sample preservation for butane analysis are reported. The electrocardiogram taken in the ambulance revealed ventricular fibrillation. There were no autopsy findings as to the cause of death. n-Butane, isobutane and propane were identified in the blood, brain and lung of the cadaver by headspace gas chromatography. Based on these results, the cause of death was concluded to be cardiac arrhythmia due to butane inhalation. As a follow-up, n-butane, isobutane and propane concentrations in the blood kept at -30 degrees C showed the unchanged values with a coefficient of variation of within 10% for 2 weeks.

A fatal case of oral ingestion of toluene

A 51-year-old male ingested orally a large quantity of toluene and died about 30 min later. The presence of toluene in body fluids and tissues was confirmed by gas chromatography and gas chromatography/mass spectrometry. Tissue distribution of toluene showed that the liver detected the highest content of toluene (433.5 micrograms/g), except for the stomach contents, followed by pancreas (88.2 micrograms/g), brain (85.3 micrograms/g), heart (62.6 micrograms/g), blood (27.6 micrograms/g), fat (12.2 micrograms/g) and finally cerebrospinal fluid (11.1 micrograms/g).

Characteristic features of injuries due to shark attacks: A review of 12 cases

Shark attacks on humans might not occur as often as is believed and the characteristic features of shark injuries on corpses have not been extensively reviewed. We describe the characteristic features of shark injuries on 12 corpses. The analysis of these injuries might reveal the motivation behind the attacks and/or the shark species involved in the attack. Gouge marks on the bones are evidence of a shark attack, even if the corpse is decomposed. Severance of the body part at the joints without a fracture was found to be a characteristic feature of shark injuries.

Different distribution of paraquat and diquat in human poisoning cases after ingestion of a combined herbicide

This report describes a slight difference in the rate of decrease of serum paraquat and diquat concentrations in eight human cases of poisoning by the herbicide PreegloxL (containing paraquatCl2, 5% and diquatBr2, 7%) and the distribution of each in three autopsied cases. There was no variation between the serum concentrations of paraquat and diquat within 24 h after ingestion, but paraquat remained at a slightly higher concentration than diquat after more than 24 h. The decrease of urinary paraquat and diquat concentrations was almost the same during the 24-h determination period. In three autopsied cases, diquat concentrations in the tissues were relatively lower than those of paraquat, except in bile. Paraquat and diquat were unevenly distributed in various tissues and fluids, but the distribution patterns of each in any particular tissues were quite similar. As no difference was observed in the decrease of urinary paraquat and diquat, the much higher concentration of diquat in bile indicates that bile may be one of the effective factors in lowering the concentration of diquat in serum and in tissues of the human body long after ingestion.

Postmortem diffusion of ingested and aspirated paint thinner

Post mortem diffusion of paint thinner (toluene/ethyl acetate/isobutanol 8:1:1 v/v) from gastric residue (25 ml or 100 ml) and airways contamination (25 ml) was assessed in a human cadaver model, with sampling after 24 h at room temperature. Four torso blood samples showed less toluene diffusion after gastric instillation (0.5-3.8 micrograms/ml) than after tracheal instillation (10.5-421 micrograms/ml). Isobutanol diffused more readily than toluene with four torso blood samples 1.8-256 micrograms/ml after gastric instillation and 26-576 micrograms/ml after tracheal instillation. Following 25 ml gastric instillation, toluene concentrations (microgram/ml or microgram/mg) were: pericardial fluid 0.7-4.0; bile 0.5-0.6; urine 0-0.6; brainstem 1.1; lung 0.4-4.4; liver 0-162; spleen 0.6-0.7; kidneys 0.4-0.6; peri-renal fat 0.3-30.3; psoas muscle 0.3-0.8; concentrations of toluene and isobutanol were markedly higher in the left lobe of the liver than the right. Ethyl acetate was mostly undetectable in tissue samples but variably present in five blood samples: 0-21.2 micrograms/ml following 25 ml or 100 ml gastric instillation and 0-198 micrograms/ml following 25 ml tracheal instillation. Ethyl acetate was always detectable in pericardial fluid but not always detectable in gastric contents. We conclude that post mortem diffusion of toluene from gastric residue or airways contamination is unlikely to compromise the analytical validity of femoral venous blood samples, brain, or liver from deep within the right lobe. Analysis of pericardial fluid and gastric contents allows identification of ethyl acetate and isobutanol thus implicating thinner solution.