Vanessa Bloch

Intentional overdose with insulin: prognostic factors and toxicokinetic/toxicodynamic profiles

IntroductionPrognostic factors in intentional insulin self-poisoning and the significance of plasma insulin levels are unclear. We therefore conducted this study to investigate prognostic factors in insulin poisoning, in relation to the value of plasma insulin concentration.MethodsWe conducted a prospective study, and used logistic regression to explore prognostic factors and modelling to investigate toxicokinetic/toxicodynamic relationships.ResultsTwenty-five patients (14 female and 11 male; median [25th to 75th percentiles] age 46 [36 to 58] years) were included. On presentation, the Glasgow Coma Scale score was 9 (4 to 14) and the capillary glucose concentration was 1.4 (1.1 to 2.3) mmol/l. The plasma insulin concentration was 197 (161 to 1,566) mIU/l and the cumulative amount of glucose infused was 301 (184 to 1,056) g. Four patients developed sequelae resulting in two deaths. Delay to therapy in excess of 6 hours (odds ratio 60.0, 95% confidence interval 2.9 to 1,236.7) and ventilation for longer than 48 hours (odds ratio 28.5, 95% confidence interval 1.9 to 420.6) were identified as independent prognostic factors. Toxicokinetic/toxicodynamic relationships between glucose infusion rates and insulin concentrations fit the maximum measured glucose infusion rate (Emax) model (Emax 29.5 [17.5 to 41.1] g/hour, concentration associated with the half-maximum glucose infusion rate [EC50] 46 [35 to 161] mIU/l, and R2 range 0.70 to 0.98; n = 6).ConclusionIntentional insulin overdose is rare. Assessment of prognosis relies on clinical findings. The observed plasma insulin EC50 is 46 mIU/l.

Could the inter-individual variability in cocaine-induced psychotic effects influence the development of cocaine addiction?: Towards a new pharmacogenetic approach to addictions

Cocaine addiction is a chronic disease marked by relapses, co-morbidities and the importance of psychosocial consequences. The etiology of cocaine addiction is complex and involves three types of factors: environmental factors, factors linked to the specific effects of cocaine and genetic factors. The latter could explain 40-60% of the risk for developing an addiction. Several studies have looked for a link between cocaine addiction and the genes of the dopaminergic system: the genes DRD2, COMT, SLC6A3 (coding for the dopamine transporter DAT) and DBH (coding for the dopamine beta hydroxylase) but unfortunately very few well established results. Pharmacogenetic approach could be an interesting opportunity for the future. The gene DBH has particularly been linked with the psychotic effects caused by cocaine. This so-called cocaine-induced psychosis (CIP) or cocaine-induced paranoia may influence the development of cocaine addiction. Indeed, these psychotic symptoms during cocaine exposure could cause an aversive effect limiting the development of an addiction. Several functional alterations caused by different mutations of the genes involved in dopaminergic transmission (principally-1021C>T of the gene DBH, but also Val158Met of the gene COMT, TaqI A of the gene DRD2 and VNTR 9 repeat of the DAT) could result in a cocaine-induced psychosis prone phenotype. We are hypothesising that the appearance of CIP during the first contact with cocaine is associated with a lower risk of developing cocaine addiction. This protective effect could be associated with the presence of one or more polymorphisms associated with CIP. A pharmacogenetic approach studying combination of polymorphism could isolate a sub-group of patients at risk for CIPs but more favorably protected from developing an addiction. This theory could enable a better understanding of the protective factors against cocaine addiction and offer new therapeutic or preventive targets in vulnerable sub-groups exposed to cocaine.

Anxiety and substance use disorders: co-occurrence and clinical issues.

The co-occurrence of substance use disorders (SUDs) and anxiety disorders has been now well established. This association is frequent and can be explained by three models: the shared vulnerability factors model, the self-medication model, and the substance-induced model. General population epidemiological studies provide strong evidence of the frequency of the association for the most used substances: tobacco, alcohol, cannabis, and to a lesser extent sedatives, opiates, and cocaine. For substances that are less commonly used in the general population, the frequency of the co-occurrence can more precisely be studied in clinical samples. We provide the most recent literature results on the association of SUDs and anxiety, and evidence for one explicative model or the other when available. For substances with sedative properties (alcohol, benzodiazepines, cannabis, opioids), both evidence for a self-medication and for a toxic effect exist. For substances with psychostimulant properties (tobacco, cocaine, and amphetamines), the literature favors the toxic hypothesis to explain the association with anxiety disorders. We give practical steps for the recognition of these dual diagnoses and present therapeutic issues, although the strategies are rarely evidence based.

Pharmacokinetic/pharmacodynamic modelling of cardiac toxicity in venlafaxine overdose

Sir: We found the article by Isbister et al. [1], presenting the pharmacokinetic/pharmacodynamic (PK/PD) model-based guidelines for managing citalopram poisoninginduced QT prolongation very interesting. The Bayesian methodology used by these authors is a useful tool for a population approach of data arising from overdoses. However, at the individual level and especially for patients with life-threatening symptoms, only single PK/PD relationships allow the quantitative characterization of the time-course of the in vivo drug effect in relation to its concentrations [2]. Moreover, individual PK/PD approach is useful to assess any interindividual variability of the drug effects. Overdoses with serotonin reuptake inhibitors, including citalopram and venlafaxine, have become an increasing concern as patients demonstrate life-threatening coma, seizures, and cardiovascular failure [3, 4]. We present a case of severe venlafaxine overdose with a PK/PD modelling of the cardiovascular effects. A 52-yearold woman was found unconscious (Glasgow Coma Scale score 3) with seizures, 5 h after ingesting 5 g venlafaxine. Blood pressure was 60/45 mmHg, heart rate 74 beats/min, and respiratory rate 12 breaths/min. Her temperature was 36.6 °C. She was mechanically ventilated and referred to our intensive care unit. She received 1 mg clonazepam intravenously and 0.42 μg/kg/min epinephrine infusion. On admission, examination showed lower limb-predominating hypertonicity, hyperreflexia, myoclonus, and mydriasis. Patellar deep-tendon reflexes demonstrated sustained clonus. Routine tests were unremarkable, excepting the lactate concentration of 5.90 mmol/l. Electrocardiogram exhibited a right bundle-branch block with 144 ms QRS duration

Case report: quantification of methadone-induced respiratory depression using toxicokinetic/toxicodynamic relationships

IntroductionMethadone, the most widely delivered maintenance therapy for heroin addicts, may be responsible for life-threatening poisonings with respiratory depression. The toxicokinetics and the toxicokinetic/toxicodynamic (TK/TD) relationships of methadone enantiomers have been poorly investigated in acute poisonings. The aim of this study was to describe the relationships between methadone-related respiratory effects and their corresponding concentrations.MethodsWe report a 44-year-old methadone-maintained patient who ingested a 240-mg dose of methadone. He was found comatose with pinpoint pupils and respiratory depression. He was successfully treated with intravenous naloxone infusion over the course of 31 hours at a rate adapted to maintain normal consciousness and respiratory rate. We performed a TK/TD analysis of the naloxone infusion rate needed to maintain his respiratory rate at more than 12 breaths per minute (as toxicodynamics parameter) versus plasma R,S- and R-methadone concentrations (as toxicokinetics parameter), determined using an enantioselective high-performance liquid chromatography assay.ResultsInitial plasma R,S-methadone concentration was 1,204 ng/ml. Decrease in plasma R- and S-methadone concentrations was linear and demonstrated a first-order pharmacokinetics (maximal observed concentrations 566 and 637 ng/ml, half-lives 16.1 and 13.2 hours, respectively). TK/TD correlation between naloxone infusion rate and R,S- and R- methadone concentrations fitted well a sigmoidal Emaxmodel (concentration associated with a half-maximum effect [EC50] 334 and 173 ng/ml, Hill coefficient 10.0 and 7.8, respectively). In our chronically treated patient, EC50 values were in the range of previously reported values regarding methadone analgesic effects, suggesting that plasma methadone concentrations to prevent withdrawal are lower than those associated with methadone analgesic effects.ConclusionAfter the ingestion of a toxic dose of a racemic mixture, plasma R- and S-enantiomer concentrations decreased in parallel. Despite large inter-individual variability in methadone toxicokinetics and toxicodynamics, TK/TD relationships would be helpful for providing quantitative data regarding the respiratory response to methadone in poisonings. However, further confirmatory TK/TD data are needed.

Blood concentrations are better predictors of chioroquine poisoning severity than plasma concentrations: a prospective study with modeling of the concentration/effect relationships

Introduction. Chloroquine causes rare but life-threatening toxicity. The prognostic value of plasma chloroquine concentrations in acute poisonings remains poorly investigated. We investigated the hypothesis that blood chloroquine concentrations better predicted chloroquine poisoning severity than plasma concentrations. Methods. A prospective study of consecutive chloroquine poisonings admitted to an intensive care unit from 2003 to 2007 was performed with simultaneous measurements of blood and plasma chloroquine (chloroquine and desethylchloroquine) concentrations. A population pharmacokinetic–pharmacodynamic model described epinephrine infusion rate, our surrogate marker of cardiovascular toxicity, as function of blood or plasma chloroquine concentrations. Results. Forty-four patients [29F/15M, 33 years (25–41), median (25–75th percentile), 34% with cardiac arrest] were included. Management included mechanical ventilation (80%), 8.4% sodium bicarbonate (66%), epinephrine [73%, maximal rate: 2.8 mg/h (0.8–5.0)], and extracorporeal life support (16%). Seven patients died. Blood [6.7 mg/L (4.0–13.0)] and plasma [1.5 mg/L (1.2–2.9)] chloroquine concentrations were weakly, although significantly correlated (r = 0.66, p < 0.0001, Spearman test). Admission chloroquine concentrations correlated with the reported ingested dose (r = 0.70 for blood vs. 0.48 for plasma), QRS duration (r = 0.82 vs. 0.64), lactate concentrations (r = 0.63 vs. 0.47), and epinephrine infusion rates (r = 0.70 vs. 0.62). Chloroquine concentrations differed significantly between patients with and without cardiac arrest (p = 0.0002 for blood vs. 0.02 for plasma). A one-compartment pharmacokinetic (PK) model adequately described blood chloroquine concentrations. An effect compartment linked to the blood compartment adequately described plasma chloroquine concentrations. Using a sigmoidal Emax pharmacodynamic (PD) model, epinephrine infusion rate was better predicted with blood than plasma concentrations (p < 0.01), suggesting that time-course of blood concentrations is a better prognostic value than plasma concentrations. Conclusion. Immediate and serial measurements of blood chloroquine concentrations are better than plasma for predicting cardiovascular severity of chloroquine poisonings.

Blood cocaine and metabolite pharmacokinetics after cardiac arrest in a body-packer case

Introduction: Cocaine body packing, the internal concealment of cocaine for transportation between countries, may expose to life-threatening intoxications. No data is currently available on the pharmacokinetics of cocaine and its metabolites when a packet rupture occurs in a body packer. Case report: We report the first pharmacokinetic data associated with a severe cocaine intoxication in a body packer, resulting in cardiac arrest. Massive concentrations of cocaine (observed maximal concentration: 1.66 mg/L, 1 hour after the cardiac arrest) were measured in plasma up to about 15 hours, suggesting a prolonged absorption due to a slow-release in the gastrointestinal tract despite surgical extraction of the packets. Apparent cocaine elimination half-life was 7.6 hours. Conclusion: A prolonged apparent cocaine elimination half-life has been observed. Further pharmacokinetic studies are needed to understand better the pathophysiology of acute cocaine intoxication in body packers.

Self-reported sleep disturbances during cannabis withdrawal in cannabis-dependent outpatients with and without opioid dependence.

A cannabis withdrawal syndrome (at least two symptoms) occurs in more than 50% of dependent smokers after cessation (1). The typical withdrawal pattern is composed of 6 symptoms: anger or aggression, decreased appetite or weight loss, irritability, nervousness/ anxiety, restlessness, and sleep difficulties (1). The rate of sleep disturbances during cannabis cessation was found to be 32% in non-treatment seeking dependent smokers (2). The two most frequent sleep symptoms are reduced sleep duration and strange or vivid dreams. These have been related to longer sleep onset latency, reduced slow wave sleep, and REM rebound (3).

Smoking ban in a psychiatry department: Are nonsmoking employees less exposed to environmental tobacco smoke?

Staff members of psychiatric facilities are at high risk of secondhand smoking. Smoking exposure was assessed in 41 nonsmoking employees of a psychiatry department before and after a ban. Subjective exposure measures decreased in 76% of the subjects. Salivary cotinine decreased in the subsample of seven subjects with high pre-ban levels (32+/-8 vs 40+/-17 ng/ml, p=.045).

Childhood trauma are not associated with the intensity of transient cocaine induced psychotic symptoms

A personal history of childhood trauma has been associated with the severity of psychotic symptoms in several disorders. We evaluated retrospectively cocaine-induced psychotic symptoms with the SAPS-CIP and childhood trauma with the CTQ in a clinical sample of 144 cocaine users. The SAPS-CIP score was not statistically associated with the presence or number or intensity of trauma, but was associated with rapid routes of administration (intravenous and smoked) and with frequent cocaine use.