Enzalutamide and analytical interferences in digoxin assays.

Objective: We report two cases of elevated digoxin plasma levels in patients receiving enzalutamide. Cases reported: The first patient, an 84-year-old male treated with enzalutamide, was hospitalized due to deterioration in his general state. Atrial fibrillation was discovered and treatment with digoxin was initiated. Supratherapeutic digoxin concentrations (4 µg/L and 3.5 µg/L 3 days later) led to treatment being stopped despite the lack of clinical or biological signs of overdose. The second patient, an 84-year-old male treated with digoxin and enzalutamide, was hospitalized for the same reasons. Digoxin concentration upon admission was 2.8 µg/L. Despite stopping treatment, digoxin blood levels were observed to have increased on D3 and D7 following admission (3 and 3.6 µg/L, respectively). However, no clinical or biological findings indicated an overdose. Blood samples were sent to the Pharmacology and Toxicology Laboratory for analysis. Methods: The second patient's digoxin plasma level was determined using the chemiluminescent microparticle immunoassay (CMIA®, Abbott, Illinois) method. Enzalutamide levels were determined using HPLC-UV/DAD method. An interference study was performed using different assay methods by adding enzalutamide to control plasma at various concentrations from a Xtandi® (40mg) capsule. Results: Plasma concentration of digoxin at D7 for patient 2 was identical in both laboratories (3.5 vs. 3.6 µg/L). Enzalutamide was found in the patient's plasma (12,5 mg/L). Adding 4, 10, 20, and 40 mg/L of enzalutamide to the untreated plasma showed that the plasma concentration of digoxin was positive (from 0.35 to 3.69 µg/L) using the CMIA method. Conclusions: Our results highlight the analytical interferences of enzalutamide with digoxin assays using the CMIA method.

Baclofen and Alcohol-Dependent Patients: A Real Risk of Severe Self-Poisoning.

Baclofen is often prescribed in high doses to fight cravings experienced by alcohol-dependent patients. Such an increase in the availability of baclofen is concerning. This study aimed to determine the change in number and profile of self-poisoning with baclofen over time, as baclofen has become increasingly popular, in order to describe the severity of self-poisoning with baclofen and to focus on co-existing alcohol use disorders, and psychiatric illnesses determine predictors of severity. This was a retrospective study of self-poisoning with baclofen as reported by the western France Poison Control Center (PCC), which represents a population of more than 12 million people from January 2008 to March 2014. One hundred and eleven cases of self-poisoning with baclofen were reported to the western France PCC (62 males and 49 females; average age 39 ± 12). Poisoning severities were as follows: 'null' (nine cases), 'minor' (37 cases), 'moderate' (19 cases) and 'high' (46 cases, including four deaths). The most frequently reported symptoms were neurological (45%) and cardiovascular (27%). The severity was significantly associated with psychiatric disorders (OR = 2.9; p = 0.03). Baclofen, prescribed in high doses, may lead to severe poisoning, particularly in patients with psychiatric illnesses. Authorities should put forward a new policy for prescribing the drug as a treatment for alcohol dependence.

Parachuting: a dangerous trend in recreational psychoactive substance delivery.

INTRODUCTION: Medicine diversion for recreational use is a constant concern for health authorities. Parachuting, also refered to as bombing, is used in order to increase the expected effect, to accelerate time-to-onset and to create mixtures of medicines and substances. Aeras covered: Firstly, we analyzed all available scientific literature (PRISMA) and internet forums without any limiting timeframe. Secondly, we collected cases of parachuting reported in the west of France by the addictovigilance and poison control centres. Our study confirms the reality of this emerging issue associated with a higher medical risk (60% of intoxication cases were moderate-to-severe in our study). The substances involved in parachuting were primarily stimulants, with a majority of MDMA, although the use of diverted medication and psychotropes is also of concern. Expert opinion: Parachuting is a dangerous way of using substances and of diverting medicines. This type of administration gives users a certain pharmacokinetic latitude to 'play' with respect to substances and medicines. Medicine abuse deterrent formulations do not seem to be sufficient in preventing diversions. This dangerous method of using substances and of diverting medicines should drive pharmaceutical companies to innovate in the interest of public health and safety.

New evidence for oxetorone toxicity.

CONTEXT: Oxetorone is a serotonin antagonist antimigraine drug but literature relating to its toxic properties is poor. The aim of this study is to describe the toxicological profile of oxetorone and to highlight any relationship between clinical and analytical findings. MATERIALS AND METHODS: This is a retrospective and observational study of cases exposure to oxetorone, reported to the Angers Poison and Toxicovigilance Centre between January 2002 and May 2016. Severity was assessed using the Poisoning Severity Score (PSS). Cases where data were incomplete, where oxetorone was deemed not accountable, where clinical signs were linked mainly to a co-ingested drug or where the plasma concentration of oxetorone was negative were all excluded. RESULTS: We included 43 cases of exposure, 31 of whom were suicide attempts. The assumed ingested dose (60-3600 mg) was correlated to severity (rs = 0.45, p = 0.01). Symptoms of moderate severity (PSS2 = drowsiness, hypertonia, myosis, convulsions, arterial hypotension, QRS widening, QTc prolongation) were observed following ingestion of more than 600 mg of oxetorone (median dose =1200 mg) and severe symptoms (PSS 3 = coma, convulsions, QTc prolongation, QRS widening, ventricular tachycardia, arterial hypotension, cardiogenic shock) were observed starting from 1800 mg (median dose =2700 mg). In four cases, a secondary worsening of symptoms 10-48 h following ingestion was observed. Plasma oxetorone was measured in four patients. Severe symptoms were observed in the event of a concentration over 0.3 mg/L and the highest measured serum oxetorone level was delayed by 20-48 h following the ingestion for two cases. CONCLUSIONS: Several clinical and paraclinical parameters strongly point towards membrane-stabilising properties of the molecule and the risk of a delayed occurrence of symptoms or a secondary worsening.

Recreational phenethylamine poisonings reported to a French poison control center.

OBJECTIVES: Over the last decade, use of phenethylamines has become increasingly prevalent. This study aimed to describe typical aspects of phenethylamine poisoning in order to better inform patient care. METHODS: Phenethylamine poisoning cases reported to the Poison Control Center of Angers, France, from January, 2007 to December, 2013 were examined. Clinical findings were examined in 105 patients, including phenethylamine used, symptoms and final outcome. Patients were predominantly male (80%), with mean age 26±8 years. RESULTS: MDMA (38%), amphetamine (18%) and methamphetamine (14%) were the most commonly reported. Synthetic cathinones (10%) and the 2C series (7%) were also found. Substances most commonly associated with phenethylamine poisoning were cannabis (27%), ethanol (20%) and cocaine (9%). The most frequently reported symptoms included anxiety and hallucinations (49%), mydriasis and headache (41%), tachycardia (40%) and hypertension (15%). Complications such as seizures (7%), cardiac arrest (5%), toxic myocarditis (1%) and hemorrhagic stroke (1%) were also observed. Of the cases, the Poison Severity Score was: null or low, 66%, moderate, 21%, severe or fatal, 13%. Of the patients, 77% received hospital care and 12.4% were admitted to an intensive care unit. Analytical confirmations were obtained for all severe cases. While 93% of patients recovered, there were 5 deaths and 2 patients presented with neurological sequelae. CONCLUSIONS: Phenethylamine poisonings may be severe in young and healthy individuals. Physicians, toxicologists and analysts should be aware of new phenethylamine consumption trends in order to inform management of patient care and to contribute to a more responsive drug policy.

Biotransformation and detectability of the designer drug 2,5-dimethoxy-4-propylphenethylamine (2C-P) studied in urine by GC-MS, LC-MS(n), and LC-high-resolution-MS(n).

2,5-Dimethoxy-4-propylphenethylamine (2C-P) is a hallucinogenic designer drug of the phenethylamine class, the so-called 2Cs, named according to the ethyl spacer between the nitrogen and the aromatic ring. The aims of the present work were to identify the phases I and II metabolites of 2C-P. In addition, the detectability of 2C-P and its metabolites in urine as proof of an intake in clinical or forensic cases was tested. According to the identified metabolites, the following pathways were proposed: N-acetylation; deamination followed by reduction to the corresponding alcohol and oxidation to carbonic acid; mono- and bis-hydroxylation at different positions; mono- and bis-O-demethylation, followed by glucuronidation, sulfation, or both; and combination of these steps. Proof of an intake of a common user's dose of 2C-P was possible by both standard urine screening approaches, the GC-MS as well as the LC-MS(n) approach.

Elucidation of the metabolites of the novel psychoactive substance 4-methyl-N-ethyl-cathinone (4-MEC) in human urine and pooled liver microsomes by GC-MS and LC-HR-MS/MS techniques and of its detectability by GC-MS or LC-MS(n) standard screening approaches.

4-methyl-N-ethcathinone (4-MEC), the N-ethyl homologue of mephedrone, is a novel psychoactive substance of the beta-keto amphetamine (cathinone) group. The aim of the present work was to study the phase I and phase II metabolism of 4-MEC in human urine as well as in pooled human liver microsome (pHLM) incubations. The urine samples were worked up with and without enzymatic cleavage, the pHLM incubations by simple deproteinization. The metabolites were separated and identified by gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-high resolution-tandem mass spectrometry (LC-HR-MS/MS). Based on the metabolites identified in urine and/or pHLM, the following metabolic pathways could be proposed: reduction of the keto group, N-deethylation, hydroxylation of the 4-methyl group followed by further oxidation to the corresponding 4-carboxy metabolite, and combinations of these steps. Glucuronidation could only be observed for the hydroxy metabolite. These pathways were similar to those described for the N-methyl homologue mephedrone and other related drugs. In pHLM, all phase I metabolites with the exception of the N-deethyl-dihydro isomers and the 4-carboxy-dihydro metabolite could be confirmed. Glucuronides could not be formed under the applied conditions. Although the taken dose was not clear, an intake of 4-MEC should be detectable in urine by the GC-MS and LC-MS(n) standard urine screening approaches at least after overdose.

Ketamine-derived designer drug methoxetamine: metabolism including isoenzyme kinetics and toxicological detectability using GC-MS and LC-(HR-)MSn.

Methoxetamine (MXE; 2-(3-methoxyphenyl)-2-(N-ethylamino)-cyclohexanone), a ketamine analog, is a new designer drug and synthesized for its longer lasting and favorable pharmacological effects over ketamine. The aims of the presented study were to identify the phases I and II metabolites of MXE in rat and human urine by GC-MS and LC-high-resolution (HR)-MS(n) and to evaluate their detectability by GC-MS and LC-MS(n) using authors' standard urine screening approaches (SUSAs). Furthermore, human cytochrome P450 (CYP) enzymes were identified to be involved in the initial metabolic steps of MXE in vitro, and respective enzyme kinetic studies using the metabolite formation and substrate depletion approach were conducted. Finally, human urine samples from forensic cases, where the ingestion of MXE was suspected, were analyzed. Eight metabolites were identified in rat and different human urines allowing postulation of the following metabolic pathways: N-deethylation, O-demethylation, hydroxylation, and combinations as well as glucuronidation or sulfation. The enzyme kinetic studies showed that the initial metabolic step in humans, the N-deethylation, was catalyzed by CYP2B6 and CYP3A4. Both SUSAs using GC-MS or LC-MS(n) allowed monitoring an MXE intake in urine.

[Peganum harmala L. poisoning in Morocco: about 200 cases]. / L'intoxication au Peganum harmala L. au Maroc : à propos de 200 cas.

AIM OF THE STUDY: Peganum harmala L. is commonly used in traditional medicine in Morocco for its sedative and emmenagogue properties but expose to the risk of overdose and poisoning. The aim of our study was to analyze a series of 200 cases of poisoning collected in poison control and pharmacovigilance center of Morocco in order to describe the epidemiological, clinical, therapeutic features and outcome of patients and indicate the toxicity of this plant used primarily for therapeutic purposes. METHODS: This retrospective study performed over a period of twenty four years from January 1984 to December 2008. RESULTS: The mean age of patients was 24.4±16.8 years with a female predominance (167 women against 33 men). Therapeutic circumstance was found in 32.5%, followed by suicide (28.5%) and abortion (13.5%). The symptomatology was dominated by neurological, gastrointestinal and cardiovascular signs respectively 34.4%, 31.9 % and 15.8%. The evolution has been specified in 114 cases, 7 deaths have been deplored with a fatality rate of 6.2%.

Hypoglycaemia: a little known effect of Venlafaxine overdose.

We report the case of a 39-year-old woman who presented with serotonin syndrome and hypoglycaemia likely due to intoxication with a very high dose of venlafaxine. This case of venlafaxine-associated hypoglycaemia was treated first by glucose perfusion, but despite large doses, hypoglycaemia recurred. Blood glucose normalized after injection of octreotide, eliminating the need for hypertonic glucose. Octreotide has been shown to decrease glucose requirements and the number of hypoglycaemic episodes in patients with sulfonylurea-induced hypoglycaemia but, to our knowledge, its ability to resolve hypoglycaemic episodes due to massive venlafaxine overdose has not yet been described.

Suicide by skull stab wounds: a case of drug-induced psychosis.

Suicide by stabbing to the head and/or driving sharp objects into the skull is of extreme rarity. This article reports the case of a 27-year-old man, who committed suicide by multiple knife stabs and cuts to the head, the torso, one shoulder and the forearms. Autopsy showed a perforating wound of the skull and the 10-cm long broken blade of the knife being still embedded in the right temporal lobe of the brain. The deceased had no history of psychiatric illness but was currently treated by mefloquine, a quinine derivative associated with a high rate of psychiatric adverse effects. Toxicological examination confirmed a recent intake of mefloquine together with chloroquine, another antimalarial drug. To our knowledge, this is the first report of a completed suicide with very strong evidence of mefloquine implication. Discussion focuses upon mefloquine-induced psychiatric disorders and highlights the importance of performing toxicological investigations in cases of unusual suicides.

Cost-effectiveness analysis of individualized mycophenolate mofetil dosing in kidney transplant patients in the APOMYGRE trial.

BACKGROUND: In the prospective, randomized, multicenter APOMYGRE trial conducted in France, concentration-controlled mycophenolate mofetil (MMF) dosing based on mycophenolic acid (MPA) exposure significantly reduced the treatment failure and acute rejection during the first posttransplantation year compared with fixed-dose MMF. This analysis investigated the cost effectiveness of dose individualization. METHOD: The study included 65 patients per group (intent-to-treat population). Treatment failure (primary efficacy endpoint) was defined as death, graft loss, acute rejection, or MMF discontinuation because of adverse effects. Data on hospitalizations, drugs prescribed, physicians' fees, laboratory expenses, ambulatory visits, and transportation were retrieved. Costs were calculated from the French National Health System perspective. RESULTS: The mean (95% confidence interval) total yearly cost per patient was Euro 47,477 (Euro 43,933; Euro 51,020) in the concentration-controlled group and Euro 46,783 ( Euro 44,152; Euro 49,414) in the fixed-dose group (P=0.7). The observed incremental cost-effectiveness ratio was Euro 3757 per treatment failure (Purchasing Power Parities United States/France: $4129). Hospitalization and drug costs accounted for approximately 50% and 25% of total costs, respectively. The cost for MPA area under the concentration-time curve and dose calculation was Euro 452 per patient, less than 1% of the total cost. CONCLUSION: In the APOMYGRE trial, therapeutic MPA monitoring using a limited sampling strategy reduced the risk of treatment failure and acute rejection in renal allograft recipients during the first 12 months posttransplantation, at neutral cost.

Tacrolimus population pharmacokinetic-pharmacogenetic analysis and Bayesian estimation in renal transplant recipients.

OBJECTIVES: The aims of this study were (i) to investigate the population pharmacokinetics of tacrolimus in renal transplant recipients, including the influence of biological and pharmacogenetic covariates; and (ii) to develop a Bayesian estimator able to reliably estimate the individual pharmacokinetic parameters and inter-dose area under the blood concentration-time curve (AUC) from 0 to 12 hours (AUC(12)) in renal transplant patients. METHODS: Full pharmacokinetic profiles were obtained from 32 renal transplant patients at weeks 1 and 2, and at months 1, 3 and 6 post-transplantation. The population pharmacokinetic analysis was performed using the nonlinear mixed-effect modelling software NONMEM version VI. Patients' genotypes were characterized by allelic discrimination for PXR -25385C>T genes. RESULTS: Tacrolimus pharmacokinetics were well described by a two-compartment model combined with an Erlang distribution to describe the absorption phase, with low additive and proportional residual errors of 1.6 ng/mL and 9%, respectively. Both the haematocrit and PXR -25385C>T single nucleotide polymorphism (SNP) were identified as significant covariates for apparent oral clearance (CL/F) of tacrolimus, which allowed improvement of prediction accuracy. Specifically, CL/F decreased gradually with the number of mutated alleles for the PXR -25385C>T SNP and was inversely proportional to the haematocrit value. However, clinical criteria of relevance, mainly the decrease in interindividual variability and residual error, led us to retain only the haematocrit in the final model. Maximum a posteriori Bayesian forecasting allowed accurate prediction of the tacrolimus AUC(12) using only three sampling times (at 0 hour [predose] and at 1 and 3 hours postdose) in addition to the haematocrit value, with a nonsignificant mean AUC bias of 2% and good precision (relative mean square error = 11%). CONCLUSION: Population pharmacokinetic analysis of tacrolimus in renal transplant recipients showed a significant influence of the haematocrit on its CL/F and led to the development of a Bayesian estimator compatible with clinical practice and able to accurately predict tacrolimus individual pharmacokinetic parameters and the AUC(12).

High-performance liquid chromatography coupled with electrospray tandem mass spectrometry (LC/MS/MS) method for the simultaneous determination of diazepam, atropine and pralidoxime in human plasma.

A high-performance liquid chromatography coupled with electrospray tandem mass spectrometry (LC/MS/MS) procedure for the simultaneous determination of diazepam from avizafone, atropine and pralidoxime in human plasma is described. Sample pretreatment consisted of protein precipitation from 100microl of plasma using acetonitrile containing the internal standard (diazepam D5). Chromatographic separation was performed on a X-Terra MS C8 column (100mmx2.1mm, i.d. 3.5microm), with a quick stepwise gradient using a formate buffer (pH 3, 2mM) and acetonitrile at a flow rate of 0.2ml/min. The triple quadrupole mass spectrometer was operated in positive ion mode and multiple reaction monitoring was used for drug quantification. The method was validated over the concentration ranges of 1-500ng/ml for diazepam, 0.25-50ng/ml for atropine and 5-1000ng/ml for pralidoxime. The coefficients of variation were always <15% for both intra-day and inter-day precision for each analyte. Mean accuracies were also within +/-15%. This method has been successfully applied to a pharmacokinetic study of the three compounds after intramuscular injection of an avizafone-atropine-pralidoxime combination, in healthy subjects.

Cardiogenic shock and status epilepticus after massive bupropion overdose.

BACKGROUND: To describe a profound cardiac dysfunction and a status epilepticus after a massive bupropion overdose. CASE REPORT: A 35-year-old man was admitted in coma following the deliberate ingestion of 12 g of bupropion. The course was marked by the rapid onset of severe and prolonged status epilepticus and cardiogenic shock. Plasma bupropion level determined four hours after the estimated time of ingestion was 1.4 mg/L. All clinical features resolved completely in response to symptomatic treatment. CONCLUSION: Several cases of bupropion overdose, with sinus tachycardia and seizures rapidly corrected by symptomatic treatment, have been reported in the literature. To our knowledge, this case of overdose with bupropion alone, at very high doses, is the first to describe clinical features comprising severe and prolonged status epilepticus and direct cardiotoxicity with the development of cardiogenic shock documented by echocardiogram.

[Spectacular suicide associated with mefloquine]. / Suicide spectaculaire lié à une prise de méfloquine.

INTRODUCTION: We present a case in which suicide was a severe neuropsychiatric reaction to treatment with mefloquine. Physicians must be aware of these serious psychiatric complications and bear them in mind when faced with atypical behavior or suspected suicide. CASE REPORT: The body of a 27-year-old man was discovered at his home, covered with multiple knife wounds. The autopsy report concluded that death was due to a craniocerebral wound from a violent blow. Homicide was initially suspected. Suicide during acute psychosis associated with mefloquine was suggested, and toxicologic analyses confirmed this hypothesis. DISCUSSION: Serious neurologic and psychiatric adverse events associated with mefloquine (Lariam) have been reported since its introduction in 1985. Mefloquine prophylaxis is recommended for travelers to high-risk areas of chloroquine-resistant plasmodium falciparum. The risk of malarial infection and the proven efficacy of mefloquine to prevent malaria should be weighed against the risk of drug-associated adverse events. Physicians must nonetheless be aware of these serious psychiatric complications, especially when faced with atypical behavior and atypical suicides. The patient's' family and friends should be asked about a possible trips abroad that might have entailed antimalaria treatment, even several months earlier. Testing for mefloquine during toxicological examinations is then essential. The World Health Organization recommendations and contraindications must be followed in prescribing mefloquine.