Toxicity evaluation of α-pyrrolidinovalerophenone (α-PVP): results from intoxication cases within the STRIDA project.

CONTEXT: An increasing number of new psychoactive substances (NPS) of different chemical classes have become available through marketing and sale over the Internet. This report from the Swedish STRIDA project presents the prevalence, laboratory results, and clinical features in a series of intoxications involving the stimulant NPS α-pyrrolidinovalerophenone (α-PVP), a potent dopamine re-uptake inhibitor, over a 4-year period. STUDY DESIGN: Observational case series of consecutive patients with admitted or suspected intake of NPS presenting to hospitals in Sweden from 2012 to 2015. PATIENTS AND METHODS: In the STRIDA project, blood and urine samples are collected from intoxicated patients with admitted or suspected intake of NPS or unknown drugs presenting to hospitals over the country. Analysis of NPS is performed by mass spectrometry multicomponent methods. Clinical data are collected when caregivers consult the Swedish Poisons Information Centre (PIC), and retrieved from medical records. The severity of poisoning is graded retrospectively using the Poisoning Severity Score (PSS). The inclusion criteria for this study included absence of other stimulants than α-PVP. RESULTS: During the 4-year study period, 23 intoxications were originally coded as "α-PVP related" out of a total 3743 NPS-related inquiries (0.6%) at the PIC. The present study covered 42 analytically confirmed cases in which α-PVP was the only stimulant detected. The age range of patients was 20-58 (median 32) years, of which 79% were males. The α-PVP concentration in serum was 4.0-606 (median 64; n = 42) ng/mL and 2.0-41,294 (median 1782; n = 25) ng/mL in urine. There was no statistically significant association between the serum α-PVP concentration and urinary α-PVP/creatinine ratio in 25 cases, where both sets of data were available. In 14/42 (33%) cases, α-PVP was the only psychoactive substance identified. In the remaining cases, additional substances comprised opioids, benzodiazepines, and ethanol. The main clinical manifestations were tachycardia (80%), agitation (70%), hypertension (33%), hallucinations (20%), and delirium (18%). Classification of poisoning severity yielded 25 (60%) moderate (PSS 2), 7 (17%) severe (PSS 3), and 2 fatal cases (PSS 4). CONCLUSIONS: In analytically confirmed α-PVP intoxication cases involving no other stimulant drugs, the urine and serum concentrations showed high variability. The clinical features were consistent with a severe sympathomimetic toxidrome. The results further demonstrated that α-PVP prevailed as a drug of abuse after being classified as a narcotic substance, and despite a high incidence of severe poisonings and fatalities. However, the low prevalence of α-PVP cases registered at the PIC suggested that many were unaware of the actual substance they had taken.

Intoxications involving MDPV in Sweden during 2010-2014: Results from the STRIDA project.

CONTEXT: In the recent years, there have been an increasing number of new psychoactive substances (NPS) available through marketing and sale on the Internet. The stimulant 3,4-methylenedioxypyrovalerone (MDPV) is a potent dopamine reuptake inhibitor, which can cause serious intoxications requiring intensive care and even fatality. This report from the STRIDA project presents the prevalence, laboratory results, and clinical features in a series of intoxications involving MDPV over a 5-year period. STUDY DESIGN: Observational case series of consecutive patients with admitted or suspected intake of NPS presented at hospitals in Sweden from 2010 to 2014. PATIENTS AND METHODS: Blood and/or urine samples were collected from intoxicated patients with admitted or suspected intake of NPS presenting at hospitals over the country. Analysis of NPS was performed by a liquid chromatography-tandem mass spectrometry multicomponent method. Clinical data were collected when caregivers consulted the Swedish Poisons Information Centre and also retrieved from medical records. The severity of poisoning was graded retrospectively using the poisoning severity score. RESULTS: During the 5-year study period, the number of MDPV-related inquiries to the Poisons Information Centre was 662 out of a total ∼4500 suspected NPS-related inquiries (∼15%), and 201 analytically confirmed MDPV intoxications were enrolled in the study. The study period covered the period when the use of MDPV in Sweden was at its peak and also the decline to an almost zero level. The age range of patients was 18-68 (mean 36, median 35) years, and 71% were males. The MDPV concentrations in serum ranged between 1.0 ng/mL and 1509 ng/mL (mean 63.6, median 20) and between 1.0 ng/mL and 81 000 ng/mL (mean 3880, median 1160) in urine. The urinary values were also creatinine corrected for variation in urine dilution, and the MDPV/creatinine ratio ranged between 0.10 ng/mmol and 2480 ng/mmol (mean 247, median 92.6). There was a statistically significant association between the serum MDPV concentration and the urinary MDPV/creatinine ratio, for 118 cases where both data were available (r = 0.764; p < 0.0001, Spearman's rank correlation). In 30 (15%) cases, MDPV was the single psychoactive substance identified in the serum or urine specimens. In the other 171 cases, other psychoactive substances were detected together with MDPV. The additional substances (n = 61) comprised of both conventional drugs of abuse, other NPS (n = 39), pharmaceuticals, and ethanol. The cathinone-derivative alpha-pyrrolidinovalerophenone (α-PVP) was the most frequent other NPS, and was detected in 58 (29%) cases, followed by methylone in 14 (7%) cases. The main clinical manifestations reported in patients testing positive for MDPV included agitation, tachycardia (≥100/min), and hypertension (systolic blood pressure ≥140 mmHg), which were observed in 130 (67%), 106 (56%), and 65 (34%) cases, respectively. Other symptoms included hallucinations (n = 31, 16%), delirium (n = 29, 15%), hyperthermia (>39°C/102.4°F; n = 18, 10%), and rhabdomyolysis (n = 16, 8%). In MDPV intoxications with serum levels >100 ng/mL, the cases were graded as more severe and hyperthermia was less common. CONCLUSIONS: In a large number of analytically confirmed MDPV intoxications from mostly polydrug users, the urine and serum MDPV concentrations showed a high variability. The clinical features were consistent with a severe sympathomimetic toxidrome. The results also demonstrated that MDPV prevailed as a drug of abuse for a long time, after its classification as a narcotic substance and despite a high incidence of severe poisonings.

Investigating the potential influence of cause of death and cocaine levels on the differential expression of genes associated with cocaine abuse.

The development of new therapeutic strategies for the treatment of complex brain disorders such as drug addiction is likely to be advanced by a more complete understanding of the underlying molecular pathophysiology. Although the study of postmortem human brain represents a unique resource in this regard, it can be challenging to disentangle the relative contribution of chronic pathological processes versus perimortem events to the observed changes in gene expression. To begin to unravel this issue, we analyzed by quantitative PCR the midbrain expression of numerous candidate genes previously associated with cocaine abuse. Data obtained from chronic cocaine abusers (and matched control subjects) dying of gunshot wounds were compared with a prior study of subjects with deaths directly attributable to cocaine abuse. Most of the genes studied (i.e., tyrosine hydroxylase, dopamine transporter, forkhead box A2, histone variant H3 family 3B, nuclear factor kappa B inhibitor alpha, growth arrest and DNA damage-inducible beta) were found to be differentially expressed in chronic cocaine abusers irrespective of immediate cause of death or perimortem levels of cocaine, suggesting that these may represent core pathophysiological changes arising with chronic drug abuse. On the other hand, chemokine C-C motif ligand 2 and jun proto-oncogene expression were unaffected in cocaine-abusing subjects dying of gunshot wounds, in contrast to the differential expression previously reported in cocaine-related fatalities. The possible influence of cause of death and other factors on the cocaine-responsiveness of these genes is discussed.

Prolonged lipemia and pancreatitis due to extended infusion of lipid emulsion in bupropion overdose.

BACKGROUND: Lipid emulsion is gaining popularity as an antidote for lipophilic drug overdose, and is generally considered safe at doses recommended for antidotal therapy. We report a case of asymptomatic pancreatitis following extended infusion lipid emulsion. CASE REPORT: A 14-year-old female presented to the emergency department actively seizing after ingesting 9 g of bupropion and unknown amounts of hydroxyzine and citalopram. She was intubated for airway protection, and gastrointestinal decontamination was performed with activated charcoal. She was treated with potassium and magnesium for a prolonged QT interval and sodium bicarbonate for metabolic acidosis and QRS complex widening. Upon transfer to the pediatric intensive care unit, she seized again, became hypotensive, and developed a junctional cardiac rhythm. A lipid emulsion bolus was recommended which improved her hypotension and conduction abnormalities. The lipid emulsion was continued for several hours and she received a total dose of 46 mL/kg in less than 12 h. She developed lipemia, which interfered with laboratory analysis, a severe elevation in her triglycerides, as well as a mild pancreatitis that resolved over several days, although she was asymptomatic. CASE DISCUSSION: Large doses of lipid emulsion may result in lipemia, severe hypertriglyceridemia, interference in laboratory analyses, and pancreatitis. This is the third reported adverse event due to lipid emulsion therapy used for overdose.

A case series of patients with lamotrigine toxicity at one center from 2003 to 2012.

INTRODUCTION: Lamotrigine is a phenyltriazine compound that inhibits voltage-gated sodium channels, decreasing release of glutamate and aspartate, and inhibits serotonin, norepinephrine and dopamine reuptake. Reports of toxicity in the literature are limited to case reports and primarily involve coingestants. This case series is intended to report the clinical manifestations of lamotrigine toxicity. METHODS: This retrospective case series from 2003 to 2012 studies the effects of lamotrigine toxicity when not confounded by coingestants. Admission records at an inpatient toxicology center were reviewed for lamotrigine-only exposure based on history with supporting laboratory data when available. After identification, these charts were reviewed again to characterize vital signs, neurological examination findings, specific laboratory and electrocardiography parameters, and complications. RESULTS: Fifty-seven patients were identified with possible lamotrigine toxicity. Nine patients, including three toddlers, had lamotrigine-only ingestions. Three of these patients had seizures, four were hypertensive, five were tachycardic, and four experienced tachypnea. Mental status was altered in all nine (depressed (n = 4), agitated (n = 5) or both (n = 3)). Five patients were hyperreflexic and experienced intermittent myoclonus, and two had inducible clonus. On electrocardiogram, two patients experienced QRS prolongation (114-116 ms), and four had QTc prolongation (463-586 ms). No patient had life-threatening symptoms or signs. Serum levels of lamotrigine were available in seven patients, and averaged 35.4 mg/L (17-90 mg/L). The therapeutic range for sLTG is 3-14 mg/L. CONCLUSIONS: Lamotrigine toxicity manifested with minor-moderate neurologic and/or electrocardiographic effects. Toxicity reflects the known pharmacologic actions of lamotrigine: serotonin, norepinephrine and dopamine reuptake inhibition, and sodium channel blockade.

Dopamine transporter DAT and receptor DRD2 variants affect risk of lethal cocaine abuse: a gene-gene-environment interaction.

Epistatic gene-gene interactions could contribute to the heritability of complex multigenic disorders, but few examples have been reported. Here, we focus on the role of aberrant dopaminergic signaling, involving the dopamine transporter DAT, a cocaine target, and the dopamine D2 receptor, which physically interacts with DAT. Splicing polymorphism rs2283265 of DRD2, encoding D2 receptors, were shown to confer risk of cocaine overdose/death (odds ratio ∼3) in subjects and controls from the Miami Dade County Brain Bank.(1) Risk of cocaine-related death attributable to the minor allele of rs2283265 was significantly enhanced to OR=7.5 (P=0.0008) in homozygous carriers of the main 6-repeat allele of DAT rs3836790, a regulatory VNTR in intron8 lacking significant effect itself. In contrast, carriers of the minor 5-repeat DAT allele showed no significant risk (OR=1.1, P=0.84). DAT rs3836790 and DRD2 rs2283265 also interacted by modulating DAT protein activity in the ventral putamen of cocaine abusers. In high-linkage disequilibrium with the VNTR, DAT rs6347 in exon9 yielded similar results. Assessing the impact of DAT alone, a rare DAT haplotype formed by the minor alleles of rs3836790 and rs27072, a regulatory DAT variant in the 3'-UTR, occurred in nearly one-third of the cocaine abusers but was absent in African American controls, apparently conferring strong risk. These results demonstrate gene-gene-drug interaction affecting risk of fatal cocaine intoxication.

The outcome of unintentional pediatric bupropion ingestions: a NPDS database review.

Unintentional bupropion pediatric exposures uncommonly report severe clinical effects such as seizures. We sought to determine the clinical effects and case outcomes for unintentional bupropion ingestions in children age

Bupropion induced serotonin syndrome: a case report.

Although there are no documented cases of serotonin syndrome (SS) following bupropion ingestion alone in the literature, the ability of bupropion to potentiate serotonin levels and lead to SS is known. A 15-year-old boy was found at home hallucinating. He then developed tonic-clonic activity. Upon arrival in the emergency department, he was confused and restless. On exam, he had tachycardia, hypertension, dilated pupils and dry oral mucosa, normal tone and reflexes in his arms, but rigidity and +4 reflexes in his legs with sustained clonus at his ankles. He was admitted and treated with intravenous fluids and lorazepam for his agitation. A urine drug screen (via gas chromatography/mass spectrometry) was positive only for naproxen and bupropion. Serum bupropion and hydroxybupropion levels drawn 17 h after his reported ingestion were 280 (therapeutic range 50-100) and 3,100 ng/mL (therapeutic range <485), respectively. Within 24 h of his admission, the patient was awake with normal vital signs and neurologic exam. To our knowledge, there are only three reported cases demonstrating SS in conjunction with bupropion toxicity; however, none of these were secondary to bupropion alone.

Unintentional ingestion of bupropion in children.

BACKGROUND: The incidence of seizures after unintentional bupropion ingestion in children aged < 6 years has been reported as 0.2%. However, in many poison centers, > 80% of these patients are referred to the Emergency Department (ED) for evaluation. OBJECTIVE: To evaluate if all unintentional pediatric bupropion ingestions require referral to a health care facility (HCF), or what fraction of these could be managed safely at home. METHOD: A retrospective chart review was conducted of all bupropion ingestions in children aged < 6 years for 2000-2006 from four regional poison centers. Exclusion criteria were lack of follow-up or multiple drug ingestion. RESULTS: Of 407 patients, 209 (51%) were male. Mean age was 2.2 years (SD +/- 1.0). There were 329 patients (81%) seen in a HCF, of which 143 (35%) were hospitalized; 77 patients (19%) were observed at home. Symptoms occurred in 73 patients (18%): sinus tachycardia (n = 50), nausea/vomiting (n = 32), hyperactivity (n = 17), seizure (n = 3), hallucinations (n = 2), and hypertension (n = 2). The mean heart rate of patients with sinus tachycardia (n = 50, 12.3%) was 137 beats/min (SD +/- 13), with a range of 112-172 beats/min. Mean dosage of those with tachycardia was 24 mg/kg. In the 2 patients with hypertension, the maximum recorded blood pressures were 145/80 mm Hg (2-year-old boy) and 137/90 mm Hg (2-year-old girl), with heart rates of 122 and 125 beats/min, respectively. Dose ingested and patient weight was known for 218 patients. Mean dosage ingested was 12.2 mg/kg, with a range of 2.6-64 mg/kg. Eighty-eight percent of patients with a known dosage ingested < 20 mg/kg. DISCUSSION: A high percentage of children continue to be seen in a HCF. Concern from the higher incidence of severe effects seen with intentional adult exposures may be one of the reasons for this cautious approach. CONCLUSION: Unintentional pediatric bupropion ingestions resulted in clinical effects that rarely required any HCF intervention. Isolated unintentional bupropion ingestion of

Incidence and onset of delayed seizures after overdoses of extended-release bupropion.

BACKGROUND: Delayed seizures have been reported with overdoses of bupropion extended-release (XL). This study systematically evaluates the frequency and timing of seizures and an association between other toxic effects (ie, agitation, tremors, and hallucinations) and seizures. METHODS: A 3-year multi-poison center observational study of hospitalized patients with ingestion of bupropion XL >or=600 mg in adults and >or=4 mg/kg in children was performed. Patients with coingestants or a medical history that could affect seizure occurrence were excluded. Data collection forms captured onset time of seizure(s), other symptoms, and treatment. RESULTS: One hundred seventeen patients met inclusion criteria: median age of 22 years (range, 1.3-65 years) with 16 children 8 hours. Subsequent seizures occurred in 49%. Children ages 1.3, 3, and 7 years, developed seizures. In patients >or= 13 years of age, median dose with seizures was 4350 mg (range, 600-54 000) compared to 2400 mg (range, 600-9000) in patients without seizures. Agitation, tremors, and hallucinations occurred in 29.7%, 40.5%, and 18.9% of patients with seizures, respectively, compared with 12.5 %, 17.5%, and 10% in patients without seizures. The neurologic effects agitation (P = .045) and tremors (P = .005) occurred more frequently. CONCLUSION: Delayed seizure onset suggests a minimum observation period of 24 hours after bupropion XL overdose. Although patients experiencing agitation or tremors may be at greater risk, seizures can occur without preceding central nervous system toxicity.

Bupropion-associated QRS prolongation unresponsive to sodium bicarbonate therapy.

We describe a case of bupropion-associated QRS prolongation that was unresponsive to intravenous bolus therapy of sodium bicarbonate. Bupropion may cause seizures and conduction delays similar to tricyclic antidepressants in the overdose setting by an unknown mechanism.

Accidental drug deaths in Fulton County, Georgia, 2002: characteristics, case management and certification issues.

BACKGROUND AND OBJECTIVES: Historically, the duty of the medical examiner in assigning cause and manner of death in drug-related death cases has been fraught with controversial challenges. The lack of standardization in certifying drug-related deaths may involve differences among practicing forensic pathologists in their approach to such cases. The central objectives of the present study include characterization of current drug death patterns and the variability among medical examiners with respect to autopsy performance and death certification practices in one county medical examiner's office. MATERIALS AND METHODS: Death certificates, scene information/investigative reports, autopsy reports, and toxicological laboratory results for each of the 100 cases of drug-related death occurring in 2002 in Fulton County, Georgia were reviewed. Comparison of overall autopsy rates and autopsy rates in drug-related death cases for each medical examiner individually and for the group collectively was performed. In examining cocaine-related deaths (most common), statistical analysis was performed for comparison of drug concentrations (cocaine and benzoylecgonine) between deaths certified as cocaine toxicity (poisoning) versus cocaine-complicating disease or causing an adverse event such as cerebral hemorrhage. RESULTS: Causes of accidental drug deaths included cocaine 40%, mixed drug intoxication 37%, opioids 10%, ethanol 7%, and prescription medication (nonopioid) 5%. Overall total autopsy rates in 2002 for each of the 6 independent medical examiners ranged from 51% to 69% (mean 64%), whereas autopsy rates in drug-related death ranged from 55% to 91% (mean 81%). In review of the subset of 40 cocaine-related deaths, 25% were certified as cocaine toxicity (poisoning), with the remaining 75% certified as cocaine-complicating disease or causing and adverse event. Autopsy rates in cocaine-related deaths were as follows: cocaine toxicity 80%, cocaine-complicating disease 77.3%, and cocaine causing adverse event 62.5%. Thirty-eight percent of cocaine-related deaths were considered to be of "low suspicion" for drug involvement at the time the death was reported to the medical examiner with the remaining 62% being of "high suspicion". Autopsy rates were somewhat lower in the low suspicion group (67%) versus the high suspicion group (72%). Comparison of drug levels between cocaine-related death certification groups was performed. No statistically significant difference was shown in drug levels (cocaine, P > 0.3; benzoylecgonine, P > 0.2) between deaths certified as cocaine toxicity versus those certified as cocaine-complicating disease or causing adverse event. CONCLUSIONS: In Fulton County, accidental drug deaths in 2002 most often involved cocaine either alone or in combination with opiates and/or alcohol. Cocaine, opiates, or both were involved in greater than three-fourths (77%) of all drug-related deaths. The majority of all decedents were black (57%) and male (76%) with an average age of 42.2 years. Cocaine and ethanol were more frequently detected in black decedents, whereas opiates and polydrug abuse were more common in white decedents throughout the period studied. Preliminary investigation showed a high index of suspicion for the specific drug involved in virtually all opiate and alcohol cases, and in 62% of cocaine-related cases. Overall, the 100 accidental drug deaths in 2002 accounted for 7.5% of all deaths investigated and certified by the Fulton County Medical Examiner's Office. Our study provides further evidence to support the lack of correlation between serum drug levels and the mechanism of drug toxicity in cocaine-related deaths. No statistically significant differences were shown in parent cocaine or benzoylecgonine concentrations between those cases certified as toxicities or poisonings versus those cases certified as aggravating underlying disease or causing an adverse event. In addition, 62% of the cocaine-related death cases were considered initially to be of high suspicion for drug-related death, thus emphasizing the strong importance of scene information/investigative reports in evaluating drug-death cases and in formulating plans of action to handle each individual case. Among the drug-death cases handled by 6 staff medical examiners at the Fulton County Medical Examiner's Office, variation existed in autopsy performance and death certification practices. These issues are discussed in the context of the National Association of Medical Examiners' (NAME) Position Paper on Cocaine, NAME Forensic Autopsy Performance Standards, and other relevant literature. Most variations relate to completeness of the cause-of-death statement (whether or not comorbid conditions are included) rather than classification of manner of death within the office. However, specific wording in the cause of death may have significant ramifications regarding drug-related mortality statistics processed by the vital statistics system, with possible under-representation of drug-related deaths in single-cause mortality data.

Screening for cocaine metabolite fails to detect an intoxication.

Testing for the presence of cocaine (COC) is common in postmortem and clinical laboratories. COC use may be detected by screening urine specimens for COC metabolite. In the forensic arena, screening positive results are confirmed by a more specific and sensitive technique, such as gas chromatography-mass spectrometry. This article reports the case of an individual who died of COC intoxication but whose immunoassay screen (EMIT) for COC metabolite was negative. Gas chromatography-mass spectrometry analysis of the urine detected benzoylecgonine (BE) at a concentration of 75 ng/mL and COC at 55 ng/mL. These concentrations explain the negative screening result since the cutoff concentration of the assay was 300 ng/mL for BE. The reported cross reactivity with COC was 25,000 ng/mL. However, heart blood concentrations of COC and BE were 18,330 and 8640 ng/mL, respectively. The results from this case provide evidence that an EMIT test alone may fail to detect COC use. Individuals utilizing results of drug screening by immunoassay must be aware of the limitations of this testing methodology.

Cocaine-related deaths: an enigma still under investigation.

In recent years there has been an increase interest in cocaine-related death reflecting the rising trend in cocaine use in Europe. Nevertheless it is still now very difficult to attribute a death to cocaine. We can affirm that cocaine can be responsible for the cause of death only when there is a reasonably complete understanding of the circumstances or facts surrounding the death. Isolated blood cocaine levels are not enough to assess lethality, and should be always considered and evaluated in relation to concentrations of cocaine and benzoylecgonine concentrations in body tissue compartments, especially in brain and blood. We have reanalyzed all of our cocaine-related cases from 1990 to 2005, applying the methodology used by Spielher and Reed over 30 years ago. Our aim was to try to validate this model and verify its applicability and effectiveness after 20 years.

Cardiotoxicity associated with accidental bupropion ingestion in a child.

Bupropion, an atypical antidepressant commonly used for depression and smoking cessation, is well known to cause seizures in both therapeutic use and overdose, but cardiac effects have been reported as minimal, usually sinus tachycardia. We describe an ingestion of bupropion estimated to be greater than 2 g by a 3-year-old boy that resulted in seizures. The child was decontaminated with whole bowel irrigation (WBI), and he experienced aspiration of polyethylene glycol and electrolyte solution used for the WBI. The patient ultimately developed hypotension and bradycardia requiring cardiopulmonary resuscitation due to the effects of the bupropion combined with the complications of WBI. In contrast to previous literature, which showed few clinical effects aside from seizures from ingestion of bupropion by children, our case highlights the dangers of pediatric bupropion ingestion and highlights risks of WBI.

The fatal case of a cocaine body-stuffer and a literature review - towards evidence based management.

The case of a 50-year old female body-stuffer who collapsed and died more than 10h after swallowing a plastic wrap of cocaine is reported. The case is discussed together with a review of the literature in order that guidelines on managing body-stuffers in police custody can be evidence based.

Cytosolic proteomic alterations in the nucleus accumbens of cocaine overdose victims.

Chronic cocaine use in humans and animal models is known to lead to pronounced alterations in neuronal function in the nucleus accumbens (NAc), a brain region associated with drug reinforcement. Two-dimensional gel electrophoresis was used to compare protein alterations in the NAc between cocaine overdose (COD) victims (n=10) and controls (n=10). Following image normalization, spots with significantly differential image intensities (P<0.05) were identified, excised, trypsin digested and analyzed by matrix-assisted laser desorption ionization-time of flight-time of flight. A total of 1407 spots were found to be present in a minimum of five subjects per group and the intensity of 18 spots was found to be differentially abundant between the groups, leading to positive identification of 15 proteins by peptide mass fingerprinting (PMF). Of an additional 37 protein spots that were constitutively expressed, 32 proteins were positively identified by PMF. Increased proteins in COD included beta-tubulin, liprin-alpha3 and neuronal enolase, whereas decreased proteins included parvalbumin, ATP synthase beta-chain and peroxiredoxin 2. The present data provide a preliminary protein profile of COD, suggesting the involvement of novel proteins and pathways in the expression of this complex disease. Additional studies are warranted to further characterize alterations in the differentially regulated proteins. Understanding the coordinated involvement of multiple proteins in cocaine abuse provides insight into the molecular basis of the disease and offers new targets for pharmacotherapeutic intervention for drug abuse-related disorders.

Effects of cocaine intoxication on the threshold for stun gun induction of ventricular fibrillation.

OBJECTIVES: This study sought to assess cocaine's effects on Taser-induced ventricular fibrillation (VF) threshold in a pig model. BACKGROUND: Stun guns are increasingly used by law enforcement officials to restrain violent subjects, who are frequently intoxicated with cocaine and other drugs of abuse. The interaction of cocaine and the stun gun on VF induction is unknown. METHODS: We tested five adult pigs using a custom device built to deliver multiples of standard neuromuscular incapacitating (NMI) discharge that matched the waveform of a commercially available electrical stun gun (Taser X-26, Taser International, Scottsdale, Arizona). The NMI discharges were applied in a step-up and step-down fashion at 5 body locations. End points included determination of maximum safe multiple, minimum VF-inducing multiple, and ventricular fibrillation threshold (VFT) before and after cocaine infusion. RESULTS: Standard NMI discharges (x1) did not cause VF at any of the 5 locations before or after cocaine infusion. The maximum safe multiple, minimum VF-inducing multiple, and VFT of NMI application increased with increasing electrode distance from the heart. There was a 1.5- to 2-fold increase in these values at each position after cocaine infusion, suggesting decreased cardiac vulnerability for VF. Cocaine increased the required strength of NMI discharge that caused 2:1 or 3:1 ventricular capture ratios at all of the positions. No significant changes in creatine kinase-MB and troponin-I were seen. CONCLUSIONS: Cocaine increased the VFT of NMI discharges at all dart locations tested and reduced cardiac vulnerability to VF. The application of cocaine increased the safety margin by 50% to 100% above the baseline safety margin.

Toxicologic findings in suicide: a 10-year retrospective review of Kentucky medical examiner cases.

Toxicologic analysis is an integral component in the investigation of suicide and requires correlation with a detailed scene inspection, with an extensive exploration into the decedent's medical and social background to uncover suicidal ideation or intent and a postmortem examination of the body. In this review, the authors analyzed 2864 cases classified as suicide upon autopsy and toxicologic examinations between 1993 and 2002 in the Kentucky Division of Medical Examiner's Services. Blood and urine were collected in 95.0% and 72.3% of cases, respectively. A total of 32.5% of the victims had negative blood toxicologic results, and 52.7% of urine toxicology screens yielded no drugs. Analysis of the data indicated that 3 times as many women had taken antidepressants and more than twice as many had consumed opioids. Drug toxicity ("overdose") ranked as the third (9.9%) leading cause of suicide after firearm injury (67.5%) and hanging (13.7%). Women succumbed to drug toxicity more than men (27.5% versus 5.9%). Of the overdose deaths, 66.5% had a negative blood alcohol concentration (BAC), while antidepressants, opioids, and benzodiazepines were detected in blood in 54.4%, 37.4%, and 29.2% of the subjects, respectively. The collection of these data serves the goals of public health and clinicians in devising strategies for suicide prevention.