Hélène Peyrière

Adverse Drug Events Associated with Hospital Admission

OBJECTIVE To increase the knowledge base on the frequency, causality, and avoidability of adverse drug events (ADEs) as a cause for admission in internal medicine or when occurring during hospitalization. METHODS A prospective study was performed for 6 periods of 8 days each. Epidemiologic data (e.g., age, gender, medical history), drug utilization, and adverse drug reactions on patients hospitalized during these periods were collected by a pharmacy student. RESULTS A total of 156 patients (70 men and 86 women) were included in the study. The patients’ mean age ± SD was 66.5 ± 18.1 years and mean length of stay was 13.2 ± 9 days. Renal and hepatic insufficiency and previous history of drug intolerance were observed in 17.9%, 10.2%, and 2% of the hospitalized patients, respectively. Thirty-eight ADEs occurred in 32 patients; in 15 cases, ADEs were identified as the reason for admission, 10 cases occurred during hospitalization, and 13 cases were present at admission, but were not the cause of admission. The most frequent ADEs involved the neurologic (23.6%), renal (15.7%), and hematologic (13.1%) systems. Among these 38 ADEs, 22 were considered avoidable (57.9%); 20 of these were associated with therapeutic errors (inappropriate administration, drug–drug interactions, dosage error, drug not stopped despite the onset of ADEs). Patients with ADEs stayed longer in the hospital and took more drugs both before and during their hospital stay (p < 0.05). CONCLUSIONS Most of the ADEs observed in this study were avoidable. The risk/benefit ratio of administered drugs could be improved with better knowledge of the patients’ medical history and the risk factors of ADEs.

Is the Recommended Dose of Efavirenz Optimal in Young West African Human Immunodeficiency Virus-Infected Children?

ABSTRACT We aimed in this study to describe efavirenz concentration-time courses in treatment-naïve children after once-daily administration to study the effects of age and body weight on efavirenz pharmacokinetics and to test relationships between doses, plasma concentrations, and efficacy. For this purpose, efavirenz concentrations in 48 children were measured after 2 weeks of didanosine-lamivudine-efavirenz treatment, and samples were available for 9/48 children between months 2 and 5 of treatment. Efavirenz concentrations in 200 plasma specimens were measured using a validated high-performance liquid chromatography method. A population pharmacokinetic model was developed with NONMEM. The influence of individual characteristics was tested using a likelihood ratio test. The estimated minimal and maximal concentrations of efavirenz in plasma (Cmin and Cmax, respectively) and the area under the concentration-time curve (AUC) were correlated to the decrease in human immunodeficiency virus type 1 RNA levels after 3 months of treatment. The threshold Cmin (and AUC) that improved efficacy was determined. The target minimal concentration of 4 mg/liter was considered for toxicity. An optimized dosing schedule that would place the highest percentage of children in the interval of effective and nontoxic concentrations was simulated. The pharmacokinetics of efavirenz was best described by a one-compartment model with first-order absorption and elimination. The mean apparent clearance and volume of distribution for efavirenz were 0.211 liter/h/kg and 4.48 liters/kg, respectively. Clearance decreased significantly with age. When the recommended doses were given to 46 of the 48 children, 19% (44% of children weighing less than 15 kg) had Cmins below 1 mg/liter. A significantly higher percentage of children with Cmins of >1.1 mg/liter or AUCs of >51 mg/liter·h than of children with lower values had viral load decreases greater than 2 log10 copies/ml after 3 months of treatment. Therefore, to optimize the percentage of children with Cmins between 1.1 and 4 mg/liter, children should receive the following once-daily efavirenz doses: 25 mg/kg of body weight from 2 to 6 years, 15 mg/kg from 6 to 10 years, and 10 mg/kg from 10 to 15 years. These assumptions should be prospectively confirmed.

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.

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

[Psychiatric disorders associated with high-dose methadone (>100 mg/d): a retrospective analysis of treated patients].

BACKGROUND Recent studies show that high-dose methadone (>100 mg/d) allow a better control of the consumptions of illicit opiates by treated patients. OBJECTIVE The aim of this retrospective study was to analyze data of patients requiring high-dose methadone (>100 mg/d) as well as associated factors. METHODS We retrospectively reviewed charts of treated patients with high-dose methadone followed in the maintenance methadone treatment center between 01/01/07 and 01/07/10. The following variables (medical history, psychiatric comorbidities, associated drugs, and polyaddictions), were assessed with high-dose methadone, using an univariate and then a multavariate analysis. The threshold value of 130 mg/day (median of maximal daily dose) was used to perform analysis. RESULTS During the study period, 78 patients, mainly men (75.6%), with a median age of 34 years [22-57] were included. The both groups with posology of methadone ≤ 130 mg/d (n=44) versus posology of methadone >130 mg/d (n=34) were close in term of demographic characteristics, consumption of drugs and associated treatments. Plasma methadone concentrations were higher in patients with the daily doses of methadone superior than 130 mg/d (NS), as well as the methadone metabolite (EDDP, p=0.048). Among studied factors, the presence of psychiatric comorbidities was significantly associated with high-dose methadone (threshold 130 mg/d) [OR 4,6 IC 95% (1.412;14.925)]. Seven patients presented with complications related to methadone: cardiac disorder (3), libido troubles (3) and hypofertility (1). CONCLUSION Patients requiring high-dose methadone are polydrug addicts. In our study, patients with psychiatric comorbidities needed daily dose of methadone significantly more raised.

Once-a-day pediatric HAART with DDI+3TC+EFV in Burkina Faso. A phase II trial (ANRS 12103 trial)

chronic viral infections transmitted to infants: from mechanisms to prevention and care Meeting

Doxycycline in the management of sexually transmitted infections

Doxycycline is a second-generation tetracycline, available worldwide for half a century. It is an inexpensive broad-spectrum antimicrobial agent largely used in the management of several bacterial infections, particularly involving intracellular pathogens, as well as in the treatment of acne or for the prophylaxis of malaria. Physicochemical characteristics of doxycycline (liposolubility) allow a high diffusion in the tissues and organs. It has high bioavailability and a long elimination half-life allowing oral administration of one or two daily doses. Over the last decade, the prevalence of bacterial sexually transmitted infections (STIs) (syphilis, chlamydiosis, gonorrhoea and Mycoplasma genitalium infections) has increased in most countries, mainly in MSM, many of whom are infected with HIV. In light of increasing prevalence of resistance towards first-line regimens of some STI agents and recently updated recommendations for STI management, doxycycline appears to be an attractive option compared with other available antibiotics for the treatment of some STIs due to its efficacy, good tolerability and oral administration. More recently, indications for doxycycline in STI prophylaxis have been evaluated. Considering the renewed interest of doxycycline in STI management, this review aims to update the pharmacology of, efficacy of, safety of and resistance to doxycycline in this context of use.

Are recommended doses of efavirenz optimal in young children? (ANRS 12103)

Address: 1Universite paris-descartes, Paris, France, 2Hopital Tarnier, Paris, France, 3Hopital Cochin-Saint Vincent de Paul, Paris, France, 4Hopital Lapeyronie, Montpellier, France, 5CHU Souro Sanou, Bobo Dioulasso, Burkina Faso, 6Centre Muraz, Bobo Dioulasso, Burkina Faso, 7Universite Paul Cezanne, Aix en Provence, France, 8Hopital Arnaud de Villeneuve, Montpellier, France and 9Universite Montpellier 1, Montpellier, France * Corresponding author