Postmortem concentrations of citalopram

The postmortem concentrations of citalopram in blood, bile, liver, and vitreous humour were investigated in 14 cases using a specially developed high performance liquid chromatography assay. Concentrations from drug and non-drug related deaths were categorized to determine a postmortem therapeutic and toxic range. Therapeutic citalopram concentrations for blood, bile, liver, and vitreous humour ranged to 0.4 mg/L, 2.1 mg/l, 6.6 mg/kg, and 0.2 mg/L, respectively. In one potentially fatal response to citalopram, concentrations were 0.8 mg/L, 6.0 mg/L, 0.3 mg/L for blood, bile and vitreous humour, respectively.     

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.     

Two tricyclic antidepressant poisonings: levels of amitriptyline, nortriptyline and desipramine in post-mortem biological samples

Two deaths due to amitriptyline and desipramine overdoses are reported. The first case deals with a 20-year-old Caucasian male who was found dead at his residence. Toxicological analysis of the blood, urine, liver and kidney revealed the presence of amitriptyline (1.7 mg/l, 0.13 mg/l, 36.0 mg/kg and 98.0 mg/kg) and nortriptyline (0.66 mg/l, 0.74 mg/l, 12.0 mg/kg and 37.0 mg/kg). The gastric content contained only 220 mg of amitriptyline. The urine also contained norverapamil, which was consistent with previous verapamil therapy. The second case involved a 19-year-old Caucasian male who attempted suicide earlier and was on desipramine medication. The blood, urine, liver and gastric content disclosed the presence of desipramine in the concentrations of 14.2 mg/l, 33.7 mg/l, 112.5 mg/kg and 180 mg, respectively. The levels of these tricyclics analyzed by high pressure liquid chromatography were in agreement with the levels reported in the literature. Though with the amitriptyline poisoning no significant anatomic changes were noted, the desipramine-caused death was further supported by the multisystem vascular congestion and ischemic changes consistent with cardiopulmonary failure.     

Postmortem atropine concentrations in resuscitation cases

The medications used during resuscitation are often in and of themselves toxic. Several reports have been published regarding toxicities of these drugs, including lidocaine, procainamide, and atropine. But how does a forensic pathologist or toxicologist differentiate a possible intoxication from therapeutic or resuscitory use especially given that the concentrations of such drugs, when used in the setting of resuscitation, have not been studied? Concentrations of a well-known resuscitation medication, atropine, were assessed in cases where it was administered before death during attempted resuscitation in an effort to address this deficiency. A review of deaths occurring in 2009 was undertaken to identify cases where drugs known to be used during resuscitation were present on toxicological analysis. Autopsy reports and medical records were examined to determine how much atropine was administered, the timing and route of administration, the time the sample was drawn (antemortem and postmortem), the source of the sample, and the ultimate cause of death. Eighty-nine cases were identified in which atropine was given before death during attempted resuscitation and was detected in the blood on postmortem toxicological screening; 11 cases were identified in which atropine was administered before death yet was not detected on the postmortem toxicological screening. Mean age was 41 years, and there were 65 males and 35 females. The overall median dose of atropine given was 3 mg, the median difference between the time of last administration of the atropine to the time of death (or draw for antemortem samples) was 15 minutes, and the median atropine concentration was 0.1 mg/L. Analysis failed to reveal significant differences in the atropine concentration based on the route of administration (intravenous or intraosseus), the cause of death, or the time since administration (within the first 2 hours). Analysis did reveal a difference between the atropine concentrations in peripheral versus central blood sources and with prolonged postmortem interval (>24 hours) suggesting postmortem redistribution.     

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.     

Postmortem hydroxychloroquine concentrations in nontoxic cases

Hydroxychloroquine (HCQ) is a 4-aminoquinoline compound used to treat malaria and chronic autoimmune disorders and is not uncommonly found in the medical examiner setting. Studies have shown HCQ to have a long half-life (32-56 days in blood), high volume of distribution (580-815 L/kg), and therapeutic concentrations ranging from 0.03 to 15 mg/L, depending on the chronicity of treatment. Previous reports have shown that the toxic concentration of HCQ ranges from 3 to 26 mg/L, whereas the lethal concentration ranges from 20 to 104 mg/L. A report addressing nontoxic postmortem concentrations of HCQ in individuals known to be taking the medication, and in whom there is no evidence of toxicity, has not been previously undertaken. This study found that postmortem concentrations in nontoxic cases can range from 0.3 to 39 mg/L, which is well within the reported range of both lethal and toxic concentrations. It is recommended that all investigative and autopsy data be considered and that the cause of death not be certified based purely on blood HCQ concentrations.     

Postmortem methemoglobin concentrations and their significance

Small concentrations of methemoglobin are present in the blood of normal individuals. Increased concentrations of methemoglobin can be formed by the action of certain chemicals or drugs, or in individuals with specific genetic defects. There is little information available concerning the validity of postmortem methemoglobin concentration as an indicator of antemortem methemoglobinemia. We measured blood concentrations of methemoglobin in 49 autopsy specimens. We conclude that postmortem methemoglobin concentrations are not valid indicators of antemortem methemoglobinemia.     

Postmortem stability and interpretation of beta 2-agonist concentrations.

This paper describes a series of stability and redistribution studies aimed at understanding the presence and significance of beta 2-agonists in asthma deaths. Salbutamol and terbutaline were shown to be stable in postmortem blood at 23 degrees C for 1 week, 4 degrees C for 6 months and -20 degrees C for 1 to 2 years. However, fenoterol was shown to degrade at 23 degrees C (83% loss), 4 degrees C (93% loss) and -20 degrees C (66% loss) over the same time. Salbutamol concentrations detected in blood taken at the time of body admission to the mortuary were not significantly different from the concentrations detected in blood taken from the same cases at the time of autopsy (45 h later). This suggests that significant postmortem redistribution of salbutamol is unlikely to occur during this period. Postmortem blood concentrations of at least salbutamol are likely to reflect the concentration of these drugs in the body at the time of death.     

Postmortem evaluation of serum and urine neopterin concentrations

Cellular immune response is accompanied by the release of neopterin. Increased neopterin levels in urine and serum are observed in patients during viral infections, autoimmune diseases, and allograft rejections and certain malignant diseases. We investigated postmortem neopterin concentrations in urine and serum samples taken from 32 corpses 3 to 69 h (mean 19.3 h) after death. Urine neopterin concentrations in corpses are similar to those of healthy live controls and are independent of the time after death. In contrast, serum neopterin concentrations are frequently greatly increased in corpses, and the levels are higher in sera collected more than 10 h after death in comparison with samples obtained earlier. Neopterin measurement in urine and serum samples of corpses is feasible. It appears likely that urine neopterin concentrations could aid the diagnosis of inflammatory diseases in corpses.     

Postmortem interval estimation by creatinine levels in human psoas muscle.

A new method was tested for estimating time after death in the middle range of postmortem interval (weeks). Creatinine muscular concentration in human cadaver is positively correlated to postmortem estimation. Temperature should be mainly related to the creatinine transformation rate. A stronger correlation was found at 11 degrees C up to 30 days and at 20 degrees Celsius up to 15 days.     

Clocapramine-related fatality. Postmortem drug levels in multiple psychoactive drug poisoning

A suicide caused by ingestion of multiple psychoactive drugs is reported. A 42-year-old man with a history of psychosis was found dead in a blood pool in his room. The forensic autopsy revealed two stab wounds on his chest. However, these wounds could not explain the cause of death. Eighty-six tablets were found in his stomach. Four psychoactive drugs; clocapramine (CC), chlorpromazine (CP), promethazine (PM) and clotiazepam (CT) were detected in blood and tissues. The concentrations of CC, CP, PM and CT in the femoral vein (FV) blood were 0.39, 0.61, 1.23 and 0.09 microg/ml, respectively. The cause and manner of death were attributed to suicidal multiple psychoactive drug poisoning.Postmortem drug redistribution showed great site-dependent variations with the lowest level in the FV blood. Remarkable variations were observed in CC, CP and PM, but not in CT compared to other three drugs. The variations were dependent on the volume of distribution (Vd) of the drugs. Our human case has demonstrated drugs with higher Vd values showed higher degree of postmortem redistribution of the drug and vice versa.     

Postmortem citalopram concentrations: alone or along with other compounds

Citalopram, an antidepressant whose use has become more widespread in Spain in recent years participates directly and indirectly in the lethal mechanism in voluntary and involuntary poisonings. There were 30 cases of autopsies in the Madrid region where citalopram and other psychoactive substances (psychotropic drugs, alcohol, opiates) were detected in the corpses. The postmortem citalopram levels in relation to the manner and mechanism of death were evaluated, and a significant difference between the toxic and nontoxic cases (p < 0.01) was found. We studied the citalopram blood levels alone and along with other psychoactive products, and these cases were then further divided into those where the compounds were at deadly levels and those which were not. We found a range of citalopram levels between 0.37 and 0.83 microg/mL in which some cases were associated with citalopram toxicity and others were not. Citalopram blood levels of less than 0.35 microg/mL did not lead to fatal poisoning when it was the sole substance detected.     

Postmortem changes in the levels of monoamine metabolites in human cerebrospinal fluid.

Four monoamine metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG) and 5-hydroxyindoleacetic acid (5-HIAA), were determined in the cerebrospinal fluid (CSF) of cadavers, whose causes of death had been suicidal hanging (SH) or ischemic heart failure (IHF). The concentration of DOPAC increased in parallel with the increment of the postmortem interval (PMI) (r = 0.626), whereas the concentrations of HVA, MHPG and 5-HIAA did not. The correlation coefficient was further increased by considering each cause of death separately: i.e., SH, r = 0.761; IHF, r = 0.705. These findings suggest the possible usefulness of the DOPAC level in CSF for estimating PMI.     

Postmortem pink teeth.

A series of cases is reported in which pink teeth were observed during the postmortem period. Most cases were associated with decomposition in a moist environment. Experimental procedures led to the extraction of pink material from dentin and demonstration that hemoglobin and serum proteins were present. The pink-tooth phenomenon was duplicated in human teeth by instilling into the pulp chambers whole blood and blood with the red cells hemolyzed. The change was manifested in teeth of dogs after freezing, heating, and decomposition in a moist environment. The authors postulate that pink teeth occur as a result of breakdown of red blood cells in the pulp chamber of the tooth and diffusion of hemoglobin and other serum proteins into the dentin via the dential tubules. Histochemical studies show that the brown or gray material in some teeth subjected to postmortem aging is probably hemoglobin and serum proteins. Factors of age, vascularity of the pulp chamber, and postmortem conditions are discussed in relation to the postmortem development of pink teeth.     

Postmortem blood free and total morphine concentrations in medical examiner cases

This purpose of this study was to determine the relationships between postmortem free morphine and total morphine levels in a large series of medical examiner morphine and heroin related deaths. Free morphine, total morphine, and 6-monoacetylmorphine (6-MAM) concentrations were measured by gas chromatography-mass spectrometry (GC-MS) in 87 medical examiner cases over 20 months. The mean total morphine concentration, mean free morphine concentration, and mean percent free morphine for all cases were: 2.3 mg/L (SD 5.2 mg/L), 0.5 mg/L (SD 1.6 mg/L), and 19.4% (SD 22.8%); respectively. Regression analyses showed weak correlations between total and free morphine concentrations over the entire concentration range (0 to 36.6 m/L, r = 0.603, n = 91) and over a subset concentration range of 0 to 1.0 mg/L (r = 0.369, n = 54). Twenty-three out of 56 (41%) tested positive for 6-MAM, indicative heroin abuse cases. Lower total and free morphine concentrations and a higher percent free morphine were found in individuals with detectable 6-MAM. Comparing blood concentrations for cases with and without detectable 6-MAM demonstrated mean total morphine concentrations of 0.9 mg/L versus 2.1 mg/L (p = 0.05), mean free morphine concentrations of 0.3 mg/L versus 0.4 mg/L (p = 0.21), and mean percent free morphine of 34.7% versus 13.7% (p < 0.003), respectively. Our findings demonstrate higher free to total morphine ratios in individuals with detectable 6-MAM than in individuals without 6-MAM. The database established in this study may assist medical examiners in the evaluation of postmortem blood opiates regarding the cause of death in opiate related ingestion cases.     

Postmortem serum catecholamine levels in relation to the cause of death

Catecholamines are major humoral factors and neurotransmitters that contribute to various stress responses. However, they have been considered unstable due to agony, terminal medical care and postmortem interference. The present study was a comprehensive investigation of postmortem serum levels of adrenaline (Adr), noradrenaline (Nad) and dopamine (DA) with regard to the cause of death in serial medicolegal autopsy cases (n=542) including fatalities from various traumas and diseases. There was a slight tendency toward postmortem increases of Nad and DA in cardiac blood as well as Adr and Nad in peripheral blood, a slight age-dependent decrease in Adr and DA in right heart blood, and a marked increase in serum DA due to administration during critical medical care. When these factors were taken into consideration, significantly higher cardiac blood levels were observed for Adr and Nad in injury and asphyxiation cases and for Adr in fatal methamphetamine (MA) abuse and other poisoning cases, whereas those levels were lower in fatal hypothermia. Drowning, fire fatality, acute cardiac death and cerebrovascular disease showed intermediate Adr and Nad levels. The DA level was elevated in cases of injury, hyperthermia, MA fatality and other poisoning. Topographical analyses suggested that the major sources of increased serum catecholamines in cases of injury was abdominal viscera including adrenal glands, and that in cases of asphyxiation, drowning, fire fatality, hyperthermia, MA fatality, other poisoning, acute cardiac death and cerebrovascular disease was the extremities in addition to abdominal viscera. However, there was in part a large case-to-case difference in each marker related to individual causes of death. These findings differed markedly from clinical observations and suggest that the postmortem serum catecholamine levels may reflect the magnitude of physical stress responses during the process of death in individual cases.     

Postmortem decrease in brain temperature.

The postmortem decrease in central brain temperature in a small number of forensic cases is presented. Each case shows a simple exponential fall during the time of the measurements. The data reported by Brinkmann et al. (1978), when plotted in semilogarithmic coordinate system, also show--after an initial "plateau" of about 2 h--a strictly one-term exponential temperature fall for several hours post mortem. The curve of brain temperature fall allows conclusions about the time of death without considering clothing, body stature, and weight. The interval temperature measurements which are required may be obtained on the spot, and the calculations needed are very simple. The method, therefore, seems preferable to those depending on rectal temperature measurements.     

Lethal effects of normeperidine.

Normeperidine, having a longer half-life than meperidine, can accumulate faster. Its excitatory neurotoxicity is manifest with administration of multiple meperidine doses or in cases of renal failure. This is a report of the lethal effects of normeperidine in a patient with renal failure who had abused meperidine.