David W. Sadler

Drug accumulation and elimination in Calliphora vicina larvae

Calliphora vicina larvae were fed on drug-laden muscle from three suicides involving amitriptyline, temazepam and a combination of trazodone and trimipramine; triplicate daily harvestings were analysed. The limit of detection for all four drugs was 0.01 micrograms drug/g larvae. Mean drug concentrations (microgram/g) in the initial muscle were:amitriptyline, 2.68; temazepam, 4.04; trazodone, 21.56; and trimipramine, 19.58. Larval rearings for days 4-8 (15 larval samples per drug) had mean and ranges of drug concentrations (microgram/g) of 0.10 (r, 0.02-0.24) for amitriptyline; 0.52 (r, 0.26-0.78) for temazepam; 0.13 (r, 0.05-0.32) for trazodone; and 0.28 (r, 0.10-0.59) for trimipramine. After day 8 there was a precipitous fall in larval drug concentrations associated with pupariation. At day 11 ranges of drug concentrations (microgram/g) were: amitriptyline, < 0.01-0.01; temazepam, 0.01-0.08; trazodone, < 0.01-0.01; and trimipramine, 0.04-0.04. Day 16 pupae had corresponding ranges (microgram/g) of < 0.01, 0.01-0.01, < 0.01 and < 0.01-0.02. Transfer to drug-free food at day 5 led to similar falls in drug concentrations (microgram/g) from day 5 to day 6: 0.08-0.03 for amitriptyline, 0.61-0.09 for temazepam, 0.13-0.01 for trazodone, and 0.30-0.02 for trimipramine. The results show considerable variation in larval drug concentrations, both at the same developmental stage and at different stages of the life cycle, under conditions which closely reflect case situations. In practice, the precipitous decrease in drug concentrations in non-feeding larvae and at pupariation make it desirable to sample only larvae actively feeding on a corpse.

Post mortem markers of chronic alcoholism.

We compared the post mortem diagnostic value of gamma-glutamyltransferase (GGT), carbohydrate-deficient transferrin (CDT), alcoholic liver disease (ALD), blood alcohol concentration (BAC), the presence of multiple bruises and poor hygiene of the feet as markers of chronic alcoholism (heavy continuous drinking) in 32 alcoholics with 32 age-sex matched controls drawn from a forensic autopsy population. Alcoholics and controls were selected on the basis of positive and negative medical history but controls were excluded if BAC exceeded 70 mg%. Femoral venous blood, urine and vitreous humour alcohol concentrations were determined by headspace gas chromatography (GC). BAC was positive in 19 alcoholics (mean 234 mg%, range 2-570 mg%) and six controls (mean 32 mg%, range 2-52 mg%). Serum GGT was measured by a kinetic photometric method, and CDT by both isoelectric focusing/laser densitometry and by a commercial radioimmunoassay kit (CDTect). Features of alcoholic liver disease were graded histologically using two weighted scoring systems. Eleven alcoholics tested positive for GGT, CDTq and ALD, nine were positive for two tests, five for one test and three were negative for all three tests. No controls were positive for all three tests but six were positive for two tests and nine for only one test; 17 were negative for all three tests. Using the normal clinical cut-off values GGT, CDTq and CDTect gave poor specificity which was improved at moderate cost to sensitivity by raising cut off values for each test. Comparison of receiver operating characteristic curves, likelihood ratios and post-test odds showed CDT to be the best individual test, followed by ALD and GGT. Quantitation of CDT by IEF/laser densitometry performed slightly better than MAEC/RIA by CDTect. CDT shows considerable promise as a post mortem marker of chronic alcoholism.

Death of a psychiatric patient during physical restraint. Excited delirium--a case report.

We report the case of a young man with a diagnosis of paranoid schizophrenia and multiple drug abuse who died in hospital following a period of prolonged physical restraint. The literature is reviewed, possible factors contributing to death discussed and measures which may reduce the incidence of such deaths in the future highlighted.

BARBITURATES AND ANALGESICS IN CALLIPHORA VICINA LARVAE

Calliphora vicina larvae were reared on artificial foodstuffs spiked with a range of concentrations of aspirin (acetylsalicylic acid), sodium salicylate, paracetamol, sodium aminohippurate, amphetamine sulfate, and the barbiturates thiopentone, phenobarbitone, amylobarbitone, barbitone, and brallobarbitone. Larvae were harvested at either day 6, 7, or 8 for analysis of drug content. Paracetamol, aspirin, amylobarbitone, and thiopentone were not detected in larvae fed on foodstuff containing drug concentrations equivalent to those expected in skeletal muscle from fatal human overdoses. Drug concentrations in larvae (expressed as larva: Foodstuff drug ratio) were 12–14% for phenobarbitone, 9–11% for sodium salicylate, 10% for aminohippurate, 18–19% for brallobarbitone, 41% for amphetamine, and 50–67% for barbitone. Amylobarbitone became detectable in larvae fed on higher drug concentrations (larva: Foodstuff drug ratio 2.6–21%). Higher levels of thiopentone and phenobarbitone were lethal to the larvae. Despite sharing similar basic structures, related drugs were each handled very differently by the larvae. We found it impossible to predict, on the basis of chemical structure, which drugs are likely to be detectable in Calliphora vicina larvae and in what ratio to the drug-spiked foodstuff. Drug concentrations in larvae are significantly lower than in their food source and the absence of a drug from feeding larvae does not necessarily imply its absence from the food source.

Urinary catecholamines as markers of hypothermia

Although raised urinary CA levels provide good supportive evidence of prolonged agonal stress in hypothermic deaths, the CA index is not, in our experience, of particular diagnostic significance.

Fatal air embolism occurring during consensual intercourse in a non-pregnant female

Death from air embolism during pregnancy has been reported following sexual activity, particularly vaginal insufflation. We report a death from air embolism in a non-pregnant woman during consensual penile intercourse, in a position with the pelvis elevated above heart level. Air is thought to have entered the veins via a vaginal laceration, which occurred during digital foreplay.

Organomegaly in chronic alcoholics.

We compared the weights of the brain, heart, spleen, lungs, liver, and kidneys, uncorrected and corrected for body surface area (BSA) and body mass index (BMI), of 50 alcoholics with 50 forensic controls matched for sex, age, and body weight. With the exception of combined renal weight corrected for BSA and BMI, no significant differences were found in organ weights between the two groups. Glomerular diameter corrected for BSA was significantly greater in alcoholics than controls. It appears that nephromegaly and glomerulomegaly are both population markers for alcoholism. In alcoholics, there was no correlation between the microscopic degree of steatosis and glomerulomegaly. In controls, renal glomerular diameter was greater with increasing severity of hepatic steatosis, probably as a reflection of obesity.

Unsuspected Self-Poisoning with Flecainide and Alcohol

The death of a 23-year-old man by suicidal flecainide and alcohol poisoning is reported. Flecainide was identified by ultraviolet (UV) spectrophotometry and gas chromatography-mass spectrometry (GC-MS). Flecainide levels, quantitated by high performance liquid chromatography (HPLC) with UV detection were: femoral blood 7.3 mg/L, urine 117 mg/L, stomach contents 19 mg and liver 302 mg/kg. Ethanol levels in femoral blood, urine and vitreous humor were 107, 136 and 113 mg%, respectively. The importance of carefully considering all the available pathological and toxicological data, together with the past medical history and circumstances surrounding the death in poisoning cases is emphasized.

Intra-individual and inter-individual variation in breath alcohol pharmacokinetics: Variation over three visits

Eleven male and 7 female student subjects underwent serial Breath Alcohol Concentration (BrAC) measurements after being given alcohol as 13% white wine (5.7 ml/kg for males and 4.7 ml/kg for females) in a fasting state on three separate occasions. BrAC versus time curves were constructed for each subject and the values of peak BrAC (Cmax), theoretical BrAC extrapolated at zero time (Co), time taken to reach peak (Tmax) and rate of elimination (ß) from breath were recorded directly from the curves. Average Intra-individual variation for each individual between the 3 visits (for males and females, respectively) was 5.6% and 8% for Co, 12% and 13% for Cmax, 42% and 37% for Tmax and 11% and 13% for ß. Inter-individual variation (for males and females) was 7.5% and 13% for Co, 16% and 15% for Cmax, 43% and 46% for Tmax and 21% and 15% for ß. Average elimination rates in males (5.3 μg/100 ml breath/h, range 4-7.7) and females (5.6 μg/100 ml breath/h, range 4-7) were not significantly different. Widmark factors calculated by various established mathematical methods were 0.71-0.81 in males and 0.59-0.68 in females, higher than the originally quoted mean experimental levels.

Intra-individual and inter-individual variation in breath alcohol pharmacokinetics: the effect of short-term variation.

Ten male and 8 female students underwent serial breath alcohol concentration (BrAC) measurements on a CAMIC Datamaster on two consecutive occasions, early evening and again the following morning. Subjects were fasted for 6 h before receiving alcohol as white wine (12.5% by volume) at doses of 38-45 g for males and 26-37 g for females, consumed over 10 min. Specific individual doses were calculated individually from height and weight (according to the Forrest Method) to give target C0 breath alcohol concentrations of 35 μg/100 ml breath in males and 31 μg/100 ml breath in females. BrAC versus time curves were constructed for each subject and the values of peak BrAC (Cmax), BrAC extrapolated at zero time (C0), time taken to reach peak (Tmax) and rate of elimination (ß) were recorded directly from the curves. Values of C0 taken from the BrAC-time curves varied widely, from 21 to 47 μg/100 ml on visit 1 and from 22 to 45 μg/100 ml on visit 2. Widmark Factors calculated from these C0 values averaged 0.74 (range, 0.59-1.06) in males and 0.73 (range, 0.58-1.05) in females. Elimination rate was higher in the morning than evening in both males (7.4 versus 5.7 μg/100 ml/h) and females (6.9 versus 5.8 μg/100 ml/h). Elimination rates in males and females were not significantly different. Total body water, measured by electronic scales, averaged 58.7% (range, 56.6-63%) in males and 48.3% (range, 40.9-57.6%) in females. Widmark Factors calculated by various established mathematical methods were 0.73-0.77 in males and 0.61-0.64 in females.