Long-term Cocaine Use Research Articles

Cognitive Decline in Ageing and Disease: Risk factors, Genetics and Treatments.

Aging is the primary risk factor for cognitive decline, impacting multiple cognitive domains and significantly elevating the risk of conditions such as mild cognitive impairment and dementia. In addition to aging, several diseases contribute to cognitive decline. Alzheimer's disease, a progressive neurodegenerative disorder, leads to the loss of neurons and synapses in the brain, resulting in a profound decline in cognitive abilities and functional capacity. Several studies provide compelling evidence that modifiable lifestyle factors play a crucial role in influencing cognitive health. Adopting healthier behaviors has been shown to significantly reduce the risk of cognitive decline. Genetic factors also play a crucial role in cognitive decline, with several genes being identified that influence the risk of developing conditions like Alzheimer's disease and other dementias. Long-term use of opioids and cocaine is also associated with cognitive decline, affecting functions such as memory and executive processes. Understanding the factors contributing to cognitive decline in aging and disease is essential for developing strategies to mitigate its impact. The drugs available to treat patients with cognitive decline due to advanced aging and drug abuse are also summarize.

Cocaine Induced Cardiac Arrhythmias

An addictive drug that provides pleasure and reward is more likely to attack various parts of the body and affect health. Dangerous substances are also involved in cocaine processing. Not just the high dosage of cocaine but a lower quantity may also lead to severe health issues, which ultimately cause panic attacks, violent behavior, and tremors. However, long-term use of cocaine may lead to heart attack and is likely to cause sudden death. Cardiac arrhythmia or irregular heartbeat is highly associated with cocaine use. The potential causes of cocaine-associated arrhythmias, including sodium channel blockade, ischemia, and potassium channel blockade, and clinical manifestations that are influenced by acidosis, hyperthermia, hypoxia, and electrolyte abnormalities will be discussed.

PET imaging of dopamine transporters and D2/D3 receptors in female monkeys: effects of chronic cocaine self-administration.

Brain imaging studies using positron emission tomography (PET) have shown that long-term cocaine use is associated with lower levels of dopamine (DA) D2/D3 receptors (D2/D3R); less consistent are the effects on DA transporter (DAT) availability. However, most studies have been conducted in male subjects (humans, monkeys, rodents). In this study, we used PET imaging in nine drug-naïve female cynomolgus monkeys to determine if baseline measures of DAT, with [18F]FECNT, and D2/D3R availability, with [11C]raclopride, in the caudate nucleus, putamen and ventral striatum were associated with rates of cocaine self-administration and if these measures changed during long-term (~13 months) cocaine self-administration and following time-off (3-9 months) from cocaine. Cocaine (0.2 mg/kg/injection) and 1.0 g food pellets were available under a multiplefixed-interval (FI) 3-min schedule of reinforcement. In contrast to what has been observed in male monkeys, baseline D2/D3R availability was positively correlated with rates of cocaine self-administration only during the first week of exposure; DAT availability did not correlate with cocaine self-administration. D2/D3R availability decreased ~20% following cumulative intakes of 100 and 1000 mg/kg cocaine; DAT availability did not significantly change. These reductions in D2/D3R availability did not recover over 9 months of time-off from cocaine. To determine if these reductions were reversible, three monkeys were implanted with osmotic pumps that delivered raclopride for 30 days.We found that chronic treatment with the D2/D3R antagonist raclopride increased D2/D3R availability in the ventral striatum but not in the other regions when compared to baseline levels. Over 13 months of self-administration, tolerance did not develop to the rate-decreasing effects of self-administered cocaine on food-reinforced responding, but number of injections and cocaine intake significantly increased over the 13 months. These data extend previous findings to female monkeys and suggest sex differences in the relationship between D2/D3R availability related to vulnerability and long-term cocaine use.

Cocaine Orbitopathy Complicated by Orbital Wall Defects, Bilateral Naso-Orbital Fistulas, Phthisis, and Bilateral Vision Loss.

A 64-year-old male with a 40-year history of daily intranasal cocaine use presented with painless, gradually worsening binocular diplopia. External examination showed a severe saddle-nose deformity. Ophthalmologic exam was notable for visual acuity of 20/40 in OU, with restrictive strabismus, esotropia, and hypotropia in the OD. Neuroimaging revealed extensive nasal septal destruction with erosion of bilateral medial and orbital floors. The patient was lost to follow-up and presented 3 years later with progression of vision loss, now light perception vision OD and count fingers vision OS. There was now complete absence of the nasal bridge and medial orbital walls with large naso-orbital fistulas bilaterally, and phthisis of the right globe with complete corneal neovascularization. Laboratory work-up, including perinuclear anti-neutrophil cytoplasmic antibodies, cytoplasmic anti-neutrophil cytoplasmic antibody, erythrocyte sedementation rate, c-reactive protein, and chest X-ray, were unremarkable. The patient continually refused drug testing. Repeat neuroimaging revealed progression of the nasal midline destruction and further loss of the medial and orbital floors (panels A and B). These findings were consistent with anatomic destruction of the orbital bony walls and subsequent ocular necrosis, perforation, and ischemia related to long-term cocaine use (panel C). Cocaine use can result in tissue damage through its alpha agonist and inflammatory properties leading to a prothrombotic state, vasoconstriction, and subsequent ischemia. The authors present a severe case of presumed cocaine orbitopathy resulting in extensive midline structural loss, destruction of the medial and inferior orbital walls, naso-orbital fistulas, and subsequent phthisis bulbi resulting in vision loss.

Simultaneous determination of cocaine, cocaethylene, benzoylecgonine and ethyl glucuronide in hair from the cocaine and alcohol abusers by LC-MS/MS

In general, cocaine (COC) is hydrolyzed to benzoylecgonine (BZE) in the human body and the presence of COC and BZE in biological matrix such as blood, urine or hair is usually associated with the illegal use or exposure of COC. In addition, the additional metabolite, cocaethylene (CE), is produced when COC is consumed with alcohol. CE found in hair is a strong marker for the long term use of COC and alcohol. Recently, the COC trafficking and abuse have been slightly increased in Republic of Korea and the aim of this study was to find out the COC and alcohol consumption patterns in our country by quantifying COC, CE, BZE, and EtG in hair samples from COC-alcohol abusers by LC-MS/MS. Hair samples were examined to the determination of COC, CE, BZE, and EtG by LC-MS/MS. Mechanical pulverization of hair (30 mg), ultrasound-assisted extraction, and Oasis MAX solid-phase extraction techniques were used for obtaining improved extraction efficiency and effective sample purification. Target compounds were separated on Xselect HSS T3 C18 column (2.5 μm, 2.1 × 150 mm) and detected on polarity-switching electrospray ionization mode. Positive ionization mode was performed for COC and its metabolites, whereas EtG was operated in negative ionization mode. The method was validated for precision, accuracy, selectivity, recovery, matrix effect, and stability. Lower limit of quantification for COC, CE, BZE and EtG were 2, 10, 1, and 7 pg/mg, respectively. The calibration ranges were 2–200 pg/mg, 10–1000 pg/mg, 1–100 pg/mg, and 7–700 pg/mg, respectively. All the determination coefficients (r2) were greater than 0.9967. The intra-day and inter-day precision of the analytes was within 5.9%, 10.0%, 8.4%, and 14.4%, while the intra-day and inter-day accuracy was −6.1%–4.0%, −4.1%–9.7%, −4.4%–8.5%, and −9.3%–4.5%, respectively. The recoveries were 85.1–100.9%. The autosampler stability was 96.6–109.7% for target compounds. The developed method was successfully applied to forensic hair samples (n = 2). In one sample (262–3), only EtG was found with a concentration of 63.7 pg/mg while other sample (562-2) showed COC, CE, BZE, and EtG concentrations of 292.0 pg/mg, 118.5 pg/mg, 102.2 pg/mg, and 29.3 pg/mg, respectively. This study performed LC-MS/MS method development and optimization for determining COC consumption with alcohol and the method successfully applied to simultaneous qualification and quantification of CE and EtG as well as COC and BZE from hair. In conclusion, these results suggest that the method can be helpful for investigation of violent crimes involving COC and alcohol use. In future, more detailed abusing patterns of COC and alcohol use in Republic of Korea will be investigated as the number of positive sample accumulated.

Transcranial Magnetic Stimulation for the Treatment of Cocaine Addiction: A Systematic Review.

Long-term cocaine use is associated with cognitive deficits and neuro-psychiatric pathologies. Repetitive transcranial magnetic stimulation (rTMS) is an emerging therapeutic strategy relating to changes in brain activity. It stimulates the prefrontal cortex and is involved in inhibitory cognitive control, decision making and care. This systematic review aims to evaluate and synthesize the evidence on the safety, effectiveness, and cost-effectiveness of rTMS for the treatment of cocaine addiction. A systematic review of the literature was carried out. The following electronic databases were consulted from inception to October 2020: MEDLINE, Embase, CINAHL, PsycINFO, Cochrane Central Register of Controlled Trials and Web of Science. Randomised controlled trials, non-randomised controlled trials and case-series and full economic evaluations were included. Twelve studies were included. No identified study reported data on cost-effectiveness. Significant results of the efficacy of TMS have been observed in terms of the reduction of craving to consume and the number of doses consumed. No serious adverse effects have been observed. Despite the low quality of the studies, the first results were observed in terms of reduction of cocaine use and craving. In any case, this effect is considered moderate. Studies with larger sample sizes and longer follow-ups are required.

Cocaine and Cardiotoxicity: A Literature Review.

Long-term cocaine use, as well as acute cocaine use, is associated with adverse cardiovascular consequences, including arrhythmias, angina, myocardial infarction, heart failure, and other conditions. Over the long term, cocaine can result in structural changes to the heart such as increased left-ventricular mass and decreased left-ventricular end-diastolic volume. Patients arriving with cocaine-associated cardiovascular complaints may not be forthcoming about their cocaine or polysubstance abuse or may be unresponsive. The role of beta-blockers, a first-line treatment for many forms of heart disease, is controversial in this population. Cocaine is a powerful sympathomimetic agent, and it was thought that beta-blockade would result in unopposed alpha-adrenergic stimulation and adverse consequences. A number of small, single-center, retrospective and observational studies suggest that beta-blockers may be safe, effective, and beneficial in this population. Further study is needed to clarify the role of beta-blockers in this population.

Effects of long-term cocaine self-administration on brain resting-state functional connectivity in nonhuman primates

Long-term cocaine use is associated with a variety of neural and behavioral deficits that impact daily function. This study was conducted to examine the effects of chronic cocaine self-administration on resting-state functional connectivity of the dorsal anterior cingulate (dACC) and putamen—two brain regions involved in cognitive function and motoric behavior—identified in a whole brain analysis. Six adult male squirrel monkeys self-administered cocaine (0.32 mg/kg/inj) over 140 sessions. Six additional monkeys that had not received any drug treatment for ~1.5 years served as drug-free controls. Resting-state fMRI imaging sessions at 9.4 Tesla were conducted under isoflurane anesthesia. Functional connectivity maps were derived using seed regions placed in the left dACC or putamen. Results show that cocaine maintained robust self-administration with an average total intake of 367 mg/kg (range: 299–424 mg/kg). In the cocaine group, functional connectivity between the dACC seed and regions primarily involved in motoric behavior was weaker, whereas connectivity between the dACC seed and areas implicated in reward and cognitive processing was stronger. In the putamen seed, weaker widespread connectivity was found between the putamen and other motor regions as well as with prefrontal areas that regulate higher-order executive function; stronger connectivity was found with reward-related regions. dACC connectivity was associated with total cocaine intake. These data indicate that functional connectivity between regions involved in motor, reward, and cognitive processing differed between subjects with recent histories of cocaine self-administration and controls; in dACC, connectivity appears to be related to cumulative cocaine dosage during chronic exposure.

Long-term cocaine use is associated with increased coronary plaque burden – a pilot study

ABSTRACT Background: There is a lack of research regarding whether prolonged use of cocaine would lead to increase of coronary plaque burden. Objectives: To study the effects of cocaine use on the coronary artery plaque volume. We hypothesize the longer the cocaine use, the greater the plaque burden. Methods: We used coronary computed tomography angiography to evaluate plaque volumes. The study included chronic (N = 33 with 27 HIV+) and non-cocaine users (N = 15 with 12 HIV+). Chronic cocaine use was defined as use by any route for at least 6 months, administered at least 4 times/month. The Student’s t-test was used to compare the plaque volumes between chronic and non-cocaine users. Multivariable regression analysis adjusted for age, sex, body mass index, HIV status, cigarette smoking, diabetes, and total cholesterol was performed to determine the relationship between years of cocaine use and plaque volumes. Results: The total plaque volumes between groups showed no difference (p = .065). However, the total left anterior descending artery (LAD) plaque volume in the chronic cocaine group was significantly higher than that in the non-cocaine group (p = .047). For each year increase in cocaine use, total plaque volume and total LAD plaque volume increased by 7.23 mm3 (p = .013) and 4.56 mm3 (p = .001), respectively. In the multivariable analyses, both total plaque volume and total LAD plaque volume were significantly associated with years of cocaine use (p = .039 and 0.013, respectively). Conclusion: Prolonged cocaine use accelerates the development of sub-clinical atherosclerosis.

Impact of cocaine use on protease inhibitor-associated dyslipidemia in HIV-infected adults.

Previous studies have demonstrated a link between protease inhibitor (PI)-based therapy and lipid dysregulation. The main objective of this study was to examine whether cocaine use may modify PI-associated dyslipidemia in adults. Between June 2003 and June 2014, 957 human immunodeficiency virus (HIV)-infected participants in Baltimore, Maryland were enrolled in a study that investigated HIV/antiretroviral therapy-associated comorbidities. Multiple linear and logistic regression models were fitted to examine the associations between PI therapy and lipid profiles for the pooled sample and cocaine use subgroups, respectively. Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), TC/high-density lipoprotein cholesterol (HDL-C) ratio, and atherogenic index of plasma (AIP) levels were positively associated with duration of PI-based therapy in long-term cocaine users (all p < 0.05). However, longer-term PI therapy was significantly associated with increased HDL-C in non-chronic cocaine users (β = 0.109, SE = 0.042, p < 0.05). The participants who received PI therapy ≥12 months and used cocaine ≥15 years were more likely to have hypertriglyceridemia (OR = 2.82, 95% CI = 1.63, 4.88) and abnormal AIP (OR = 1.73, 95% CI = 1.08, 2.79) as compared to their counterparts. Our findings showed that long-term cocaine use may exacerbate adverse effects of PI therapy on lipid metabolism, suggesting that reduced cocaine use may be considered an alternative approach to managing PI-associated dyslipidemia in chronic cocaine users with HIV infection.

Cocaine and coronary artery diseases: a systematic review of the literature.

Cocaine is associated with important cardiac complications such as sudden death, acute myocarditis, dilated cardiomyopathy, life-threatening arrhythmias, and myocardial ischemia as well as infarction. It is well known that cocaine may induce vasospasm through adrenergic stimulation of the coronary arteries. Moreover, cocaine may promote intracoronary thrombosis, triggered by alterations in the plasma constituents, and platelet aggregation, leading to subsequent myocardial infarction. The long-term use of cocaine may stimulate atherosclerosis, probably through endothelial cell dysfunction. Significant and severe coronary atherosclerosis is common in young chronic cocaine users and there is probably a relationship between the duration and frequency of cocaine use and the extent of coronary disease.

MRI assessment of cerebral oxygen metabolism in cocaine-addicted individuals: hypoactivity and dose dependence.

Long-term cocaine use is known to negatively impact neural and cerebrovascular systems. However, the use of imaging markers to separately assess these parameters remains challenging. The primary reason is that most functional imaging markers, such as cerebral blood flow, functional connectivity, and task-evoked functional MRI, are known to reflect a complex interplay between neural and vascular components, thus the interpretation of the results is not straightforward. The goal of the present study is to examine neural-activity-specific changes in cocaine addiction, using cerebral metabolic rate of oxygen (CMRO2) as a surrogate marker of aggregated neural activity. We applied a recently developed CMRO2 technique in 13 cocaine-addicted subjects and 13 age- and gender-matched control subjects, and examined the impact of long-term cocaine use on CMRO2. Our results showed that CMRO2 in cocaine-addicted subjects (152 ± 16 µmol/100 g/min) is significantly lower (p = 0.031) than that in controls (169 ± 20 µmol/100 g/min). Furthermore, the severity of this decreased metabolism is associated with lifetime cocaine use (p = 0.05). Additionally, the CMRO2 reduction was accompanied by a trend of decrease in cerebral blood flow (p = 0.058), but venous oxygenation was unaffected (p = 0.96), which suggested that the CMRO2 change may be attributed to a vascular deficiency in chronic cocaine users. To our knowledge, this is the first study to measure CMRO2 in cocaine-addicted individuals. Our findings suggest that CMRO2 may be a promising approach for assessing the long-term effects of cocaine use on the brain.

Preliminary findings of the effects of rivastigmine, an acetylcholinesterase inhibitor, on working memory in cocaine-dependent volunteers

Long-term cocaine use is a risk factor for the onset of neurocognitive impairment. This study sought to determine whether the cholinesterase inhibitor rivastigmine could improve neurocognitive performance in cocaine-dependent individuals. Cocaine-dependent individuals who were not seeking treatment at the time of enrollment in the study were randomly assigned to receive placebo (n=16), rivastigmine 3mg (n=13), or rivastigmine 6mg (n=12). The baseline neurocognitive assessment, which included measures of attention/information processing (as measured by the Continuous Performance Task-II (CPT-II)), verbal learning/episodic memory (as measured by the Hopkins Verbal Learning Test-Revised (HVLT-R)), and working memory (as measured by the Dual N-Back Task), was conducted prior to the administration of study medication (Day 0). The follow-up assessment was conducted on Day 8 after the participants had received rivastigmine or placebo for 7days (Day 2-8). Rivastigmine administration significantly improved performance on one measure of working memory span (mean n-back span). This study provides additional data showing that cocaine-associated neurocognitive impairment, specifically working memory deficits, can be remediated, at least to some degree.

P.6.d.005 Differential effects of short- and long-term cocaine use on cortical volume, thickness and surface area

The effect of allelic variants of the studied genes on the results of treatment was determined first by the uncertainty coefficients calculated for the event ‘completion of the treatment program’ for each of three treatment groups separately and analyzed second by Kaplan-Meier survival for the overall study sample (regardless of type of therapy) taking into consideration allelic variants of the studied genes. Result: The average age in the study sample was 28±4 years (M±SD), the majority of patients were male (73%); the average duration of opiate dependence 8±4 years; the number of past treatments averaged from 3.8 to 4.9. The results of the analysis of influence of the alleles of opiate receptors genes and COMT gene on retention in treatment (Kaplan-Meier survival analysis) showed that carriers of AAAGTT or AGAGTT alleles of genes OPRM13, OPRK1 and COMT, correspondingly, and also CCAGTT or CTAGTT alleles of genes OPRM11, OPRK1 and COMT had significantly better retention and chance to complete treatment − regardless of the medication group. The probability of completing treatment program by carriers of all these above mentioned alleles (compared to those with other alleles of these genes) analyzed by uncertainty coefficients for each of the treatment group separately was higher for oral naltrexone and double placebo, but not for placebo-implant. Conclusion: The study showed that genetic analysis is useful for determining potential responders to naltrexone treatment of opioid dependence.

Imaging Glutamate Homeostasis in Cocaine Addiction with the Metabotropic Glutamate Receptor 5 Positron Emission Tomography Radiotracer [11C]ABP688 and Magnetic Resonance Spectroscopy

Preclinical studies demonstrate that glutamate homeostasis in the striatum is disrupted following cocaine exposure, including a decrease in metabotropic glutamate receptor type 5 (mGluR5) expression and reduced glutamate turnover. The goal of this study was to use imaging of the human brain to investigate alterations in the glutamate signaling in cocaine addiction. Positron emission tomography imaging with the radiotracer [(11)C]ABP688 was used to measure mGluR5 binding and magnetic resonance spectroscopy was used to measure glutamate-glutamine levels in the striatum of cocaine-addicted participants (n = 15) compared with healthy control subjects (n = 15). Following the scans, the cocaine-addicted volunteers performed cocaine self-administration sessions to investigate the correlation between cocaine-seeking behavior and mGluR5 receptor binding. The results of the study showed that cocaine addiction was associated with a 20% to 22% reduction in [(11)C]ABP688 binding in the striatum. A secondary analysis of cortical and subcortical regions other than the striatum showed a similar reduction in [(11)C]ABP688 binding, suggesting that the decrease was widespread. No between-group differences were seen in the magnetic resonance spectroscopy measures of glutamate-glutamine in the left striatum. In addition, no correlation was seen between [(11)C]ABP688 binding in the striatum and the choice to self-administer cocaine. Overall, these results show that long-term cocaine use is associated with a decrease in mGluR5 availability compared with matched healthy control subjects and suggests that this receptor may serve as a viable target for treatment development for this disorder.

Xanthine Oxidase Contributes to Mitochondrial ROS Generation in an Experimental Model of Cocaine-Induced Diastolic Dysfunction

Recent studies have shown that long-term cocaine use induces diastolic impairment and a myocardial oxidative stress. Recently, we have reported that cocaine-induced cardiac dysfunction may be due to a mitochondrial reactive oxygen species (ROS) overproduction, which occurs at the same time as xanthine oxidase (XO) activation. In this work, we hypothesized that XO activation contributes to mitochondrial ROS overproduction, which in turn contributes to diastolic dysfunction. To test this, we used a well-established in vivo model of cocaine-induced diastolic dysfunction. In this experimental model treated with or without allopurinol, an inhibitor of XO, we measured mitochondrial ROS production and function. Mitochondrial alterations were characterized by an increase in oxygen consumption through complexes I and III, a reduction in ATP production, and an increased ROS production specifically in isolated interfibrillar mitochondria. Allopurinol treatment prevented the rise in mitochondrial ROS levels and the decrease in ATP production. In the same way, allopurinol treatment improved ventricular relaxation with a decrease in Tau, an index of left ventricle relaxation and of end-diastolic pressure volume relation. These results confirmed the critical role of XO in the sequence of events leading to cocaine-induced cardiac dysfunction.

Gene × Disease Interaction on Orbitofrontal Gray Matter in Cocaine Addiction

Long-term cocaine use has been associated with structural deficits in brain regions having dopamine-receptive neurons. However, the concomitant use of other drugs and common genetic variability in monoamine regulation present additional structural variability. To examine variations in gray matter volume (GMV) as a function of lifetime drug use and the genotype of the monoamine oxidase A gene, MAOA, in men with cocaine use disorders (CUD) and healthy male controls. Cross-sectional comparison. Clinical Research Center at Brookhaven National Laboratory. Forty individuals with CUD and 42 controls who underwent magnetic resonance imaging to assess GMV and were genotyped for the MAOA polymorphism (categorized as high- and low-repeat alleles). The impact of cocaine addiction on GMV, tested by (1) comparing the CUD group with controls, (2) testing diagnosis × MAOA interactions, and (3) correlating GMV with lifetime cocaine, alcohol, and cigarette smoking, and testing their unique contribution to GMV beyond other factors. (1) Individuals with CUD had reductions in GMV in the orbitofrontal, dorsolateral prefrontal, and temporal cortex and the hippocampus compared with controls. (2) The orbitofrontal cortex reductions were uniquely driven by CUD with low- MAOA genotype and by lifetime cocaine use. (3) The GMV in the dorsolateral prefrontal cortex and hippocampus was driven by lifetime alcohol use beyond the genotype and other pertinent variables. Long-term cocaine users with the low-repeat MAOA allele have enhanced sensitivity to gray matter loss, specifically in the orbitofrontal cortex, indicating that this genotype may exacerbate the deleterious effects of cocaine in the brain. In addition, long-term alcohol use is a major contributor to gray matter loss in the dorsolateral prefrontal cortex and hippocampus, and is likely to further impair executive function and learning in cocaine addiction.

Long-term cocaine use is associated with premature alterations in regional aortic strain and distensibility measured by magnetic resonance imaging

Methods We enrolled 46 consecutive subjects from an addiction clinic: 33 long term cocaine users (13 men, 20 women, mean age: 46 ± 7 yrs, mean years of cocaine use: 15 ± 8) and 13 non-cocaine users (6 men, 7 women, mean age: 43 ± 9 yrs). Aortic stiffness of the ascending and descending aorta was determined by MRI from aortic strain (AS: relative difference in cross-sectional area) and distensibility (AD: aortic strain normalized by pulse pressure) using an automated contours detection method applied to modulus images of a phase-contrast acquisition perpendicular to the ascending aorta (Art-Fun, INSERM). Blood pressure was measured by a brachial cuff during aortic MRI. Drug and smoking habitus was determined by a standardized questionnaire. Results SBP was slightly higher in the cocaine group vs. non-users (130 ± 18 vs. 123 ± 37 mmHg) but pulse pressure was comparable (47 ± 12 vs. 46 ± 10 mmHg respectively) and hypertension was similarly distributed (30% vs. 38%). Total cholesterol was also slightly higher (174 ± 36 vs. 168 ± 35 mg) and current cigarette smoking more prevalent in the cocaine group (88% vs. 30%). Only 3 subjects of the cocaine group were diabetics and no diabetes in nonusers. Aortic strain and distensibility were lower in the cocaine group vs. non-users as summarized in Table 1. Univariate analysis showed a negative correlation between aortic strain and distensibility and duration of cocaine use. After further adjustment for age, gender, cholesterol, smoking and diabetes the duration of cocaine use was an independent predictor of descending aortic function with a significant average decrease in strain of 2.5% (p = 0.02) and a trend for a decrease in distensibility of 4.5 × 10-3.kPa-1 (p = 0.14) for 1 year of cocaine use.

C013 Cocaine-induced LV diastolic impairment is associated with cardiac mitochondrial dysfunction and ROS production: role of nadph and xanthine oxidase

Recent studies show that long-term cocaine use induces diastolic impairment. This functional effect may be linked to cocainetriggered biochemical responses such as oxidative stress. Indeed, previously we have demonstrated that myocardial NADPH and xanthine oxidase (XO) contribute to ROS generation in cocainetreated rats. In the current study, we hypothesized that cocaineinduced ROS production could induce mitochondrial damage that in turn might participate in ventricular diastolic dysfunction. Wistar rats were treated with cocaine alone (2×7.5 mg/kg/day, IP) or with a NOX inhibitor (apocynin, 50 mg/kg/day, po) or a XO inhibitor (allopurinol, 50 mg/kg/day, po). These groups were compared to control rats (saline solution, IP). After 7 days, LV pressure-volume signals were acquired. Oxygen consumption was measured in situ on permeabilized cardiac fibers isolated from the LV. ROS production was measured using electron paramagnetic resonance in both subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria. Our results show that cocaine-induced cardiac dysfunction is characterized by a diastolic impairment. Indeed cocaine induces an increase of Tau, an index of LV relaxation and of end-diastolic pressure volume relation (+80 % and +171 % respectively, p<0.05). Both apocynin and allopurinol were able to improve ventricular relaxation. Further, we found that cocaine increased oxygen consumption in mitochondria specifically through complex I (+34 %, p<0.05) and complex III (+120 %, p<0.05) whereas ATP production was decreased. Moreover, ROS level increased only in IFM from cocaine rats (+74 %, p<0.05). In contrast, apocynin or allopurinol treatments prevented the rise in ROS levels and prevented the mitochondrial respiratory chain alterations. In conclusion, this work shows that cocaine-induced LV diastolic impairment is associated with a specific mitochondrial dysfunction. An increase in ROS production via NADPH and XO induces a mitochondrial dysfunction which in turn contributes to the development of oxidative stress and ventricular diastolic dysfunction.

Chronic drug use confirmed by hair analysis: Its role in understanding both the medical cause of death and the circumstances surrounding the death

Analysis of hair for drugs is now a well established technique. It is being used increasingly in crime investigation but seldom in routine Coroner’s toxicology. Hair analysis is the only method of obtaining a reliable drug history for the weeks or months prior to death. Between 2004 and 2006 from the cases reported to HM Coroner, hair was submitted for analysis in addition to the routine specimens for 286 selected cases. These were all cases where drug use was thought to be involved in the death. The usefulness of the data from hair analysis was evaluated along with the data from the conventional samples. The types of cases were identified where hair analysis provided valuable supporting evidence. It was found that reliable information concerning long-term drug use was important in a wide range of cases including: – demonstrating a history of drug use or lack of it, demonstrating tolerance or lack of it, compliance with medication, death due to long-term cocaine use and its role in depression/suicide, sudden unexplained death, and excited delirium. The cases types are illustrated by reference to individual cases and the implications of the findings discussed. The study demonstrated that hair analysis can provide vital evidence in a wide range of cases reported to HM Coroner. This evidence can be invaluable to the pathologist, Coroner, and the family of the deceased in understanding both the medical cause of death and the circumstances surrounding the death.