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.

Postmortem investigation of lamotrigine concentrations.

Lamotrigine is a relatively new anticonvulsant. Therapeutic plasma concentrations generally range from 1 to 4 mg/L, although several studies have shown that good control of epilepsy has been achieved with concentrations reaching 10 mg/L generally, with little toxicity. In overdose, however, the drug has been linked to ECG changes that may suggest a possible arrythmogenic effect and hence cardiac toxicity. Lamotrigine has also been shown to cause encephalopathy and thus neurotoxicity. There is no information concerning postmortem lamotrigine concentrations and their interpretation. We describe lamotrigine concentrations in postmortem specimens including blood, liver, bile, vitreous humour, and urine from eight cases. A high performance liquid chromatography (HPLC) method is described with extraction procedures for the various tissues. Two possible groups were identified. The first being the "broader therapeutic" group with blood concentrations ranging from 0.9 to 7.2 mg/L and corresponding liver concentrations ranging from 16 to 36 mg/kg. The second being a "supratherapeutic" group with blood concentrations ranging from 20 to 39 mg/L and corresponding liver concentrations ranging from 53 to 350 mg/kg. Although none of the eight cases described were attributed to overdose by lamotrigine alone, the cause of death for one of the three cases in the "supratherapeutic" group was given as mixed drug toxicity. Cause of death for the remaining two cases in this group was reported as epilepsy. However, both these cases showed elevated concentrations of lamotrigine and both were co-medicated with valproic acid. Such co-administration has been shown in the literature to lead to elevated lamotrigine concentrations and a reduction in lamotrigine dose has been recommended. With such data, we highlight the importance of monitoring lamotrigine concentrations in cases co-medicated, particularly with valproic acid.

A study involving venlafaxine overdoses: comparison of fatal and therapeutic concentrations in postmortem specimens.

The distribution and redistribution of venlafaxine were investigated in two overdoses and several cases involving the therapeutic use of venlafaxine. Blood, liver, bile vitreous humor, urine and gastric contents were analyzed using high performance liquid chromatography with ultraviolet detection. Blood concentrations of venlafaxine in the two overdose cases were 53 mg/L and 78 mg/L. Comparison of venlafaxine concentrations in blood samples taken at different times after death revealed increases in concentrations over time, suggesting the possible postmortem redistribution of venlafaxine.

Training initiative list scheme (TILS) for minimal access therapy: the MATTUS experience.

The objective of the MATTUS intercollegiate exercise was to set up and audit a training initiative list scheme (TILS) by which funds are awarded to Trust hospitals for operative sessions used specifically for the training of staff in minimal access therapy (MAT). A prospective centralized audit of TILS involving nine Trust hospitals in Scotland over a 12-month period (1 March 1995-end of February 1996) was carried out. These hospitals had contracted for 510 4-h training sessions (389 for minimal access surgery, 121 for allied interventional techniques) by MATTUS accredited consultant tutors. The scheme covered training in technical competence for Minimal Access Surgery (MAS), interventional flexible endoscopy and interventional radiology within Scottish Hospitals. The main outcome measures used in the audit were trainee completion rates, conversion rates, morbidity and mortality, assessment of training received by trainees and assessment of aptitude by the trainers. The results were as follows. Of 510 sessions, 482 (95%) were completed within the deadline. Of these, 463 sessions were audited (367 for MAS, 69 for flexible endoscopy and 27 for interventional radiology). During these sessions, 817 operations/procedures were performed (781 training and 36 developmental). A total of 544 operations were performed during 339 MAS training sessions and 237 radiological/flexible endoscopy procedures in 96 MAT training sessions. The trainee was the principal operator in 643 (82%) procedures and completed the task in 581 (74%) cases. Four per cent of the MAS operations (22/544) required conversion. Post-operative complications occurred in 42 out of 817 patients (5%). Four patients, all with advanced malignancy, died within 30 days of the procedure. Trainees graded 355 sessions as excellent, 109 good, two as average and one as unsatisfactory. The tutors graded their trainees' aptitude to perform the operation as excellent in 34%, good in 53%, average in 11% and poor in < 1%. The training initiative list scheme which allows unhurried training in MAT by consultant tutors using operating sessions that are extra to the service lists is operationally and educationally viable. Furthermore, it can be implemented within a pre-determined budget. The audit of TILS has also demonstrated that the immediate clinical outcome of patients is not compromised by this type of training.

Incidence of persistent symptoms after laparoscopic cholecystectomy: a prospective study.

BACKGROUND AND AIMS: Laparoscopic cholecystectomy is the standard treatment for symptomatic gall stone disease. This study aimed to assess the effect of the operation on patients' symptoms. METHODS: One hundred consecutive patients undergoing laparoscopic cholecystectomy between June 1994 and June 1995 were evaluated using standard questionnaires examining demographic details, indication for laparoscopic cholecystectomy, characteristics of pain, and other associated dyspeptic and colonic symptoms. A history of psychiatric disturbances and of hysterectomy were also recorded. The same questionnaires were administered again six months after the operation. Operation notes and histological reports were reviewed. RESULTS: Three patients were converted to open surgery and were excluded from analysis. The median age of the remaining 97 patients was 50.9 (19-85) years; 19 were men. There was one complication each of bleeding and biliary leak. Indications for laparoscopic cholecystectomy were biliary type pain (66 patients) and complicated gall stone disease (acute cholecystitis 21, cholestatic jaundice six, and pancreatitis four). Thirteen patients (13%) had persistent pain and two (3%) developed diarrhoea at follow up. Only one patient with persistent pain after laparoscopic cholecystectomy originated from the complicated gall stone disease group. Logistic discriminant analysis showed that bloating (p < 0.001), constipation (p < 0.05), and previous and current use of psychotrophic drugs (p < 0.001) were significantly more common among those with a poor outcome after laparoscopic cholecystectomy. Heartburn was unaffected. Of patients with persistent symptoms after cholecystectomy 77% had no or mild histological changes of cholecystitis as compared with 30% in the pain free group. CONCLUSIONS: The incidence of persistent pain after laparoscopic cholecystectomy was 13%. Abdominal bloating and psychiatric medications were predictive for persistence of pain after laparoscopic cholecystectomy.

Extraction of psychotropic drugs from human scalp hair.

A comparison of techniques for the extraction of antidepressant and antipsychotic drugs in human scalp hair is described. Human scalp hair was obtained from cadavers known to be taking psychotropic drugs prior to their death. Following a washing step, hair was either solubilized in sodium hydroxide, or treated with dilute hydrochloric acid, methanol or subtilisin. Digests were treated with a solvent and the extracted drugs quantified by high performance liquid chromatography. The alkaline digestion procedure was found to be significantly more effective (P < 0.01) in recovering a range of antidepressant and antipsychotic drugs from hair than either the acidic, methanolic or enzymatic treatments.

Detection of antidepressant and antipsychotic drugs in postmortem human scalp hair.

The presence of therapeutic drugs in postmortem human scalp hair was investigated. Hair samples from 21 cadavers known to have taken antidepressant and antipsychotic drugs were solubilized in 1 M sodium hydroxide. Drugs were extracted using solvent extraction procedures and analyzed by gas chromatography-mass spectrometry (GC-MS) and high performance liquid chromatography (HPLC). Antidepressant drugs detected were amitriptyline, dothiepin, doxepin, imipramine, trimipramine, and mianserin. Antipsychotic drugs detected were haloperidol, chlorpromazine and thioridazine. Concentrations of these drugs and their metabolites ranged from 1.3 to 242 ng/mg hair. Segmental analysis demonstrated that the drug concentrations detected were either consistent with the known dosing regime of the deceased, or were able to provide an indication of drug use within the last few months prior to death. This study reinforces the potential of hair as a useful tissue in forensic investigations, in establishing a history of past exposures to therapeutic drugs.

A fatality due to flurazepam.

A fatality attributed to suicidal ingestion of up to 2.2 grams of flurazepam is described. The deceased was a 52-year old female with a history of depression and suicidal attempts. No significant pathology was found at autopsy. Full toxicological analyses detected only flurazepam and metabolites in her tissues. The concentrations of flurazepam in femoral blood, liver, bile, vitreous humor and urine were 5.5 mg/L, 130 mg/kg, 33 mg/L, 1.3 mg/L and 3.3 mg/L, respectively. Analysis of gastric contents showed 600 mg of flurazepam. Desalkylflurazepam was also detected in blood, liver, bile and vitreous, but at much lower concentrations than the parent compound.

Simultaneous determination of morphine and codeine in blood and bile using dual ultraviolet and fluorescence high-performance liquid chromatography.

The separation and identification of morphine and codeine from postmortem blood and bile was accomplished using a liquid-phase extraction method followed by reversed-phase high-performance liquid chromatography with combined UV and fluorescence detection. Identification of morphine and codeine was based on relative retention time matching with calibration standards, together with their fluorescence-to-UV response ratios. Linear calibration curves for morphine and codeine ranged from 0.10 to 3.0 mg/L for blood and 5.0 to 100 mg/L for bile. Morphine concentrations (in autopsy cases), where the intravenous use of heroin or morphine was suspected as the cause of death, were 0.10-0.89 mg/L (mean, 0.29 mg/L) for blood and 3.3-112 mg/L (mean, 38 mg/L) for bile. Codeine concentrations, where therapeutic use or overdosage of codeine occurred, were 0.06-6.4 mg/L (mean, 1.5 mg/L) in blood and 0.22-89 mg/L (mean, 24 mg/L) in bile. This method allowed simultaneous detection of morphine and codeine from blood and bile with little interference from extraneous peaks. The procedure described provides a selective, sensitive, accurate, and reliable method suitable for both clinical and forensic toxicology.

Postmortem clomipramine: therapeutic or toxic concentrations?

Postmortem blood and liver concentrations of clomipramine were determined in ten cases by high performance liquid chromatography (HPLC). Blood concentrations ranged from 0.21 to 4.9 mg/L, and liver concentrations from 7.0 to 320 mg/kg. Two cases associated with clomipramine toxicity were clearly differentiated from other cases by the analysis of liver. The concentrations of clomipramine in these two cases were 3.3 and 1.8 mg/L in blood, and 280 and 320 mg/kg in liver. The liver concentrations were 10 to 30 fold greater in the deaths associated with drug toxicity compared with the other cases. One case, where cardiac blood was collected in place of femoral blood, showed a high blood concentration (4.9 mg/L), but an arguably therapeutic liver concentration (13 mg/kg). The analysis of femoral blood together with liver provides the best guide as to the significance of post-mortem clomipramine concentrations.

Death following colchicine poisoning.

A 45-year-old male was admitted to hospital after 2 to 3 days of vomiting, nausea, and diarrhea following an apparent overdose of colchicine tables. During hospitalization his white blood cell count fell dramatically. At death, 33 h following initial hospitalization, pleural effusion with bilateral bronchopneumonia was evident, together with numerous bacterial colonies and marked hypocellularity of bone marrow and reduced megakaryocytes, erythroid, and myeloid cells. The most striking histological findings were numerous metaphasic mitotic figures in gastric and small bowel epithelia. Colchicine was detected, confirmed by high pressure liquid chromatography with photodiode array detection, and quantitated in antemortem plasma collected 3.3 h following hospitalization and in postmortem blood and bile. Colchicine was not detected in liver, vitreous humor, or stomach contents.

Chronic effect of the irreversible and reversible selective MAO-A inhibitors on rat pineal melatonin biosynthesis.

Acute administration of the irreversible MAO-A inhibitor, clorgyline (2.0 mg/kg, s.c.) and the reversible MAO-A inhibitor, moclobemide (10 mg/kg, s.c.), increased rat pineal melatonin and related indoles content (HPLC-fluorimetric method). Chronic (21 days) administration of clorgyline attenuated the acute effect of clorgyline on pineal melatonin biosynthesis. The acute effect of moclobemide on melatonin biosynthesis was not affected by chronic moclobemide administration. The observed difference in the chronic effects of irreversible and reversible selective MAO-A inhibitors on melatonin biosynthesis could have clinical implications.

Dual ultraviolet wavelength high-performance liquid chromatographic method for the forensic or clinical analysis of seventeen antidepressants and some selected metabolites.

A sensitive method suitable for the determination of tricyclic and other antidepressants in postmortem and clinical specimens is presented. The procedure, which utilizes reversed-phase HPLC combined with dual ultraviolet wavelength detection, enables the separation of 17 commonly prescribed antidepressants and some selected metabolites in a single extraction. Peak purity was confirmed using absorbance ratios at 220 nm and 254 nm wavelengths and revealed little interference from other eluting analytes. The blood detection limit for most antidepressants was 50 ng/ml. The most commonly observed antidepressants in 281 forensic cases analysed over a two-year period with the described method were dothiepin, amitriptyline, nortriptyline and doxepin.

Simultaneous HPLC gradient analysis of 15 benzodiazepines and selected metabolites in postmortem blood.

The simultaneous identification and quantitation of 15 benzodiazepines and selected metabolites in postmortem blood, serum, or liver homogenate is described. The assay involves extraction with diethylether, followed by an acid clean-up step of the ether. Chromatographic separation was achieved on a Nova-Pak phenyl 18 column using ultraviolet detection at 240 nm. A gradient HPLC system was developed to improve separation of nitro-reduction metabolites from the solvent front and endogenous peaks. The mobile phases consisted of a gradient from 15 to 28% acetonitrile in 40 mM potassium phosphate buffer. Within-run and day-to-day precision were generally 10-15%. The method described is sensitive and reproducible for the analysis of benzodiazepine concentrations in postmortem tissues.

A class-independent drug screen in forensic toxicology using a photodiode array detector.

A class-independent drug screen, that is suitable for use in clinical and forensic toxicology and uses gradient-elution high-performance liquid chromatography and photodiode array detection, is presented. The assay is capable of detecting and identifying therapeutic and toxic amounts of barbiturates, anti-convulsants, diuretics, non-steroidal anti-inflammatory drugs, sulfonylurea anti-diabetic drugs, theophylline, and analgesic drugs. The assay has been successfully used to screen over 1000 postmortem blood specimens.

Simultaneous determination of 6-monoacetylmorphine, morphine and codeine in urine using high-performance liquid chromatography with combined ultraviolet and electrochemical detection.

A method is described for the simultaneous determination of 6-monoacetylmorphine (6-MAM), morphine and codeine in post-mortem urine specimens using reversed-phase high-performance liquid chromatography with dual ultraviolet spectrophotometric and electrochemical detection. The limits of detection for a 1-ml urine sample were 0.04 mg/l for 6-MAM and 0.05 mg/l for both morphine and codeine. The presence of 6-MAM in urine indicates prior use of heroin and enables differentiation between morphine- and heroin-related deaths.

Alterations to plasma melatonin and cortisol after evening alprazolam administration in humans.

Six healthy volunteers were given a 2-mg dose of alprazolam at 21:00 h and hourly blood samples were collected until 08:00 h the following morning. A control night of hourly blood sampling was undertaken 7 days before Plasma was analyzed for melatonin, cortisol, and alprazolam concentrations. Melatonin concentrations were significantly suppressed by alprazolam at 23:00, midnight, 01:00, 06:00, and 07:00 h. A trend toward suppression was evident from 02:00 to 05:00 h. Cortisol concentrations were also suppressed by alprazolam at several times throughout the night (01:00-04:00 h). Plasma alprazolam levels showed a peak at 3 h and remained relatively high 19-20 h after the dose. The significance of melatonin suppression by alprazolam is discussed in terms of benzodiazepine binding sites and GABA minergic transmission in the human pineal gland, suprachiasmatic nuclei, and retina. Plasma cortisol suppression has been reported for other benzodiazepine drugs, but conflicting data exist for alprazolam. The present results do not support the proposed inhibitory effect of melatonin on the hypothalamic-pituitary-adrenal (HPA)-axis. It is suggested that there is no simple direct relationship between melatonin and the HPA axis in humans.

A death involving probenecid.

A death following deliberate ingestion of approximately 75 g of probenecid in a 36-year-old man is described. Tissue concentrations of probenecid were highest in serum (710 mg/L) and liver (550 mg/kg). Probenecid was also detected in vitreous and bile. Ethanol was also detected in blood at 0.13 g/100 mL.

Melatonin, cortisol and prolactin response to acute nocturnal light exposure in healthy volunteers.

An investigation of the cortisol and prolactin responses accompanying acute melatonin suppression by light (600 lux) in humans is described. Light given from midnight to 0300h suppressed nocturnal plasma melatonin concentrations by 65%. Despite this significant suppression of melatonin, no significant effect on plasma cortisol or prolactin concentrations was observed. These data support recent studies which argue that, if there is a relationship between melatonin, the hypothalamo-pituitary, and the hypothalamo-pituitary-adrenal axis in humans, it is neither direct nor simple.