Céline Eiden

Toxicity and death following recreational use of 2-pyrrolidino valerophenone.

Abstract Background. Consumption of substituted cathinones, frequently called ‘legal highs’ or ‘designer drugs’, is increasing in the European Union. In July 2012, the French Medicine Agency listed the substituted cathinones chemical family as narcotic and psychotropic substances, to restrict their use and distribution. We present, here, the first documented cases of recreational use of 2-pyrrolidino valerophenone (PVP) associated with death for one patient, with post-mortem toxicological analysis. Case reports. Two men purchased the legal high Energy-3 (NRG-3). It can be sold as laboratory reagent and is available from Internet. The oldest died of sudden cardiac arrest. The other experienced visual hallucinations and psychotic symptoms for 24 h. He also presented bilateral mydriasis, sinus tachycardia and rhabdomyolysis. He reported an occasional intranasal use of NRG-3. Analysis of the powder and blood and urine from both men revealed the presence of PVP. Discussion and conclusion. PVP belongs to the substituted cathinones chemical family. These cases highlight the need for emergency physicians, toxicologists and networks of toxicovigilance to control the use of these substances and their dangers, quickly identify cases of severe poisoning associated with the use of new drugs and to develop detection methods.

Posaconazole-increased vincristine neurotoxicity in a child: a case report.

A 9-year-old girl was managed according to the COPRALL 04 protocol for treatment of a relapse of acute lymphoblastic leukemia. Owing to a previous case of disseminated fusariosis, posaconazole was started 5 days before initiation of chemotherapy. Six days after the last dose of vincristine, the child reported symptoms of severe peripheral neuropathy, abdominal cramps, and constipation. After this, she developed fluctuations in her level of consciousness and seizures. After cessation of therapy with posaconazole, a complete resolution of the above occurred within 7 days. This case illustrates the possibility of vincristine toxicity exacerbated by coadministration of posaconazole. As posaconazole is an inhibitor of the isoenzyme CYP3A4, interactions with drugs that are metabolized via this pathway, such as vincristine, can be anticipated. Another possibility is that, like itraconazole, posaconazole may also inhibit P-glycoprotein–mediated vincristine efflux. Although case reports of neurotoxicity owing to possible interaction between itraconazole and vincristine exist in the literature, only 1 case report relating to the possible interaction between posaconazole and vincristine exists. Clinicians should be made aware of this possible drug-drug interaction.

Slow-Release Oral Morphine Sulfate Abuse: Results of the Postmarketing Surveillance Systems for Psychoactive Prescription Drug Abuse in France

Background: Few data are available concerning the diversion and abuse of morphine sulfate. In France, morphine sulfate abuse is currently investigated by the health authorities. The aim of our study was to provide data on morphine sulfate abuse in France, collected during the period 1996–2011. Methods: The French monitoring system for psychoactive medication abuse collected data from several sources: spontaneous reporting of cases of abuse or dependence (NotS; ‘Notifications Spontanées’), specific periodic surveys from specialized care centers (OPPIDUM; ‘Observation des Produits Psychotropes Illicites ou Détournés de leur Utilisation Médicamenteuse’), and community pharmacists (OSIAP; ‘Ordonnances Suspectes Indicateur d’Abus Possible’). Results: A total of 649 cases (75% men, median age: 34 years) were spontaneously reported: 578 cases of abuse and 71 cases of use as opiate maintenance treatment. The medication formulation was Skenan® (614 cases), and Moscontin® (35 cases). All surveys (NotS, OPPIDUM, and OSIAP) showed an overrepresentation of Skenan® (87.9–94.6% of cases) that was intravenously injected in 60.4–61.2% of the cases. Data analysis showed that patients abusing morphine sulfate have a long history of drug abuse and a history of polydrug use. Conclusion: All the data presented in this study highlight the level of morphine sulfate abuse, specify the modalities of use (intravenous route), and show the risks associated with abuse (infectious diseases). This study outlines the usefulness of our epidemiological tools, and provides evidence supporting intensive surveillance.

Pharmacokinetic variability of voriconazole and N-oxide voriconazole measured as therapeutic drug monitoring.

Voriconazole (VRC), a triazole agent is extensively metabolized by CYP2C19, CYP2C9, and to a lesser extent, by CYP3A4. Few data are available regarding disposition of the main VRC metabolite (MVRC; UK121,265). The aim of this study was to investigate the pharmacokinetic variability of VRC and MVRC plasma concentrations on the basis of 115 drug monitoring samples from patients treated with VRC. Plasma concentrations of VRC and MVRC were determined by HPLC assay. During the study period, therapeutic drug monitoring (TDM) of 39 adult in- and out-patients were realized. The residual interquartile range (IQR) were 0.5–2.6 mg/l (median: 1.4 mg/l) for VRC plasma concentrations and 1.6–3.4 mg/l for MVRC (median: 2.5 mg/l). Median IQR metabolic ratio [VRC]/[MVRC] was 0.2–1.1 (median: 0.6 mg/l). VRC Cmin was <1 mg/l in 41% of cases and <0.5 mg/l in 25% of them. Patients with VRC Cmin <1 mg/l have a lower [VRC]/[MVRC] ratio than patients with VRC Cmin ≥1 mg/l (median ratio 0.1 vs. 1.0 p < 0.0001). VRC TDM is now recommended to optimize their benefit/risk ratio. In addition, measurement of MVRC in unstable patients could quickly detect patients with impaired metabolism, in cases of subtherapeutic (Cmin <1 mg/l) or toxic (Cmin >5 mg/l) VRC plasma levels.

Antihypertensive Drugs in Patients Treated with Antiretrovirals

Objective: To review the literature for information regarding pharmacokinetic interactions between antiretrovirals and antihypertensive agents, evaluate the clinical significance of these interactions, and analyze the effect of antihypertensive drugs on the metabolic complications frequently observed in HIV-infected patients to emphasize the advantages and inconveniences of every class of antihypertensive drugs in association with antiretrovirals. Data Sources: A literature search was conducted via PubMed and MEDLINE (1950-November 2011) using the search terms drug interactions, cytochrome P450, names of antiretrovirals, names of commonly prescribed antihypertensive drugs, pharmacokinetics, and metabolic complications. Reference citations from relevant publications, manufacturers’ product information, and www.HIV-druginteracttons.org were also reviewed. Study Selection And Data Extractions: All articles with an English abstract identified through the data search were examined. Of these, pharmacologic reviews, studies, and case reports were evaluated. Data Synthesis: Antihypertensive drugs interact with several antiretroviral drugs, non nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (Pls) in particular. Pharmacokinetic interactions are less expected with diuretics, jî-blockers excreted by the kidney, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs) other than losartan and irbesartan. Calcium channel blockers (CCBs) are metabolized by CYP3A4, with the potential for interaction with NNRTIs and Pls. Because CCBs do not adversely affect glucose or lipid metabolism or renal function, they may be preferred in patients with such complications. ACE inhibitors and ARBs may exert favorable effects on glucose homeostasis. In addition, they may significantly reduce protein excretion and further slow the progression of renal disease. Conclusions: The choice of antihypertensive drugs in HIV-infected patients is complex and must take into account the metabolic pathways of antiretroviral drugs and antihypertensive drugs with the potential of pharmacokinetic interactions, as well as the effect of antihypertensive drugs on some biological parameters.

Prevalence of levamisole and aminorex in patients tested positive for cocaine in a French University Hospital

Abstract Context. The prevalence of levamisole in urine samples of subjects positive for cocaine in the US was estimated at 78% (95%confidence interval or CI: 73%–83%). However, levamisole was not quantified, and at the time of this report, aminorex was not known to be a possible metabolite of levamisole in human. Moreover no data are available in Europe. Objective. The aim of this study was to determine the prevalence and concentration of levamisole and aminorex in positive cocaine urine toxicology tests, and in serum samples of cocaine-positive subjects driving under the influence of drugs or forensic autopsies. Materials and methods. Consecutive urine toxicology samples tested positive for cocaine by immunoassay (EMIT, Siemens) from April to May 2014 at the toxicology laboratory of a French University Hospital, and blood samples of cocaine-positive subjects driving under the influence of drugs or forensic autopsies from April to December 2014 were analyzed by liquid chromatography–tandem mass spectrometry or LC–MS/MS (3200 QTrap, AB Sciex) to detect and quantify the presence of levamisole and aminorex. Results. Forty-two urine samples tested positive for cocaine in 39 patients (79.5% males) with a median age of 43 [range: 20–51] years. Toxicological analyses were mainly required by addictions care centers (n = 17; 40%) in the context of the routine management of addict patients. Cocaine concentrations were above the limit of quantification for 33 patients, with a median value of 228 [0–645,000] ng/ml. Levamisole was detected in 32 urine samples (76%) (median concentration: 1,430 ng/ml, range: 30–258,000). Aminorex was never detected. During the study period, levamisole was detected in 87.5% of cocaine-positive blood samples of the subjects driving under the influence of drugs or forensic autopsies. Discussion. In this prospective study, the prevalence of levamisole in cocaine-positive samples was 76%. Over this period, although clinical complications related to cocaine use were reported (agitation, road accident, and cardiac arrest), no complication specifically related to levamisole or aminorex was reported. Conclusion. Our results show a high prevalence of levamisole in samples of subjects positive for cocaine, close to the prevalence found in the US. This high prevalence raises issues with respect to well-identified health risks associated with regular consumption of levamisole.

Evidence of slow-release morphine sulfate abuse and diversion: epidemiological approaches in a French administrative area.

Slow‐release oral morphine sulfate (SM) is one of the most abused prescription opioids in France. However, the regional feature of the abuse of morphine is poorly documented. To investigate the abuse of SM in a French administrative region, a multisource approach was applied. The first approach was based on SM exposition at national and regional level using the OPPIDUM survey. In a second approach, we analyzed a drug reimbursement database to assess the magnitude of SM abuse in Languedoc‐Roussillon (LR) region. A clustering method was applied to classify patients and to describe the profile of deviant patients. The third approach was based on a self‐administered anonymous questionnaire, proposed to patients seen in addiction care centers in the LR region and consuming oral SM. The OPPIDUM study showed that in most regions, where the prevalence of heroin use is higher than the national average of 9.1%, SM consumers were fewer. With the clustering method, three subgroups were identified. One of them gathered 35 users (3.2%) with a deviant behavior characterized by significantly more dispensations, dispensing pharmacies, and prescribers. These subjects were mainly men, younger, and more consumers of benzodiazepines and opioid maintenance therapy than the others. The third study allowed specifying that SM was mainly injected (93.7%), bought in the street (80%), and used because of unavailability and the poor quality of heroin (33.9%). The three proposed approaches are complementary and help to clarify the abuse of oral SM, while assessing the motivations of this abuse.

Illicit drugs or medicines taken by parachuting

Parachuting (also called bombing) is a method of drug delivery where illicit drugs or medicines are ingested after wrapping the substance. There are little data describing parachuting in the literature. To provide a description of this practice, all cases of parachuting reported to the national addictovigilance network up to 31 December 2014 were identified from spontaneous reports and specific surveillance programs. Cases were described according to the type of substance used, patient age and gender, type of complications, context of use and year of the event. Forty‐five cases of parachute use were identified and most (n = 43) occurred after 2011. Patients were mostly men (60%), and mean age was 28.9 years. The context of use, known in 19 cases, was mostly recreational. Complications were present in 24 cases, of which eight were serious. The substance was supposed to be 3,4‐methylenedioxymethamphetamine (MDMA) in the majority of cases (64.4%); research chemicals were more involved in the most recent years. The physical form was mainly granular (51.6%). The wrappers were a cigarette paper (nine cases) and in one case plastic package; in the other cases, the term of parachute was used without further details. The reason for use was not explained in the majority of cases; two patients indicated using a parachute for faster effect than with a methadone capsule. Clinicians should be aware of this delivery form as the results suggest that it is common and can involve a great variability of drugs.

Withdrawal syndrome after co-medication of opioid maintenance therapy with nalmefene: unrecognized interaction

To the editor: We read with interest the recently published paper reporting two cases of severe opioid withdrawal syndrome due to the drug interaction between the recently approved opioid antagonist nalmefene and opioids [1]. Since the end of 2014, the French network of the addictovigilance centers received several notifications of withdrawal syndrome after prescription of nalmefene in patients receiving opioid maintenance therapy (OMT) [2]. Up to March 2015, 7 cases of withdrawal syndromewere identified (5 men and 2 women, mean age 40 years [range 31–49]). Methadone was mentioned in 3 cases, buprenorphine in 3 cases, and buprenorphine/ naloxone in 1 case. When documented, the delay of onset of withdrawal syndrome was between 1 and 2 h. The withdrawal syndrome was sometimes severe (hallucinations, convulsions, and cardiac disorders), leading to hospitalization in 71 % of cases (not specified in 2 cases). The outcome was favorable in the majority of cases (1 case unknown), but with symptoms that lasted until 10–12 h with buprenorphine and buprenorphine/naloxone. At the time of the events, this pharmacologically expected interaction was not clearly mentioned in the nalmefene summary of product characteristics (SPC) [3]. It was stated that the use of nalmefene was contraindicated in patients taking opioid analgesics, in those with a recent history of opioid dependence and in those for whom a recent opioid consumption is suspected [3]. The specific interaction with methadone and buprenorphine was not mentioned. Accordingly, in the report of its March 2015 meeting, the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency recommended clarifying the contraindication [4]. However, cases of withdrawal syndrome were also reported with the association between OMT and naltrexone, another opioid antagonist used in alcohol dependence despite a clear mention in SPC [5,6]. This association was observed in 1.8 % of patients treated with OMT [7]. Another explanation could be close consonance between nalmefene and baclofen, another drug authorized for the treatment of alcohol dependence but with different pharmacological properties (RTU Baclofène; http://ansm. sante.fr/var/ansm_site/storage/original/application/ 5478accaf69e1a0f97987c9eeb9b9347.pdf). Prescribers should be aware of this interaction, as the alcoholic comorbidity is common in patients under OMT. Vigilance is also needed for nalmefene in combination with other opioid analgesics or antitussives. * Hélène Peyrière h-peyriere@chu-montpellier.fr

A case of drug-facilitated sexual assault involving 3,4-methylenedioxy-methylamphetamine.

Abstract Typical scenarios of drug-facilitated sexual assaults usually involve victims having ingested a drink after which they had little, partial or no recollection of events for a period of time. We were surprised by the case of a woman who was sexually assaulted and described a state of amazement, leading to an incapacity to resist physically or verbally to her aggressor, and who remembered everything. Alcohol was first suspected but toxicological analysis revealed the presence of 3,4-methylene-dioxy-methylamphetamine (MDMA, Ecstasy). In the literature review, a few cases of sexual assault involving involuntarily MDMA intake are described.