Evolution of sexual functioning of men through treated and untreated depression.

OBJECTIVES: Depression as well as a treatment by antidepressant are factors that may interfere with sexuality. Due to this complex relationship between depression, antidepressant and sexuality, it is difficult to incontestably establish the exclusive accountability of a treatment or of a psychiatric disorder on sexual dysfunctions. The main purpose of the SADD (for Sexuality, Anti-Depressant and Depression) study is to evaluate sexual dysfunctions in depressed men treated with antidepressant or not. METHODS: Participants of this transversal, observational study were men aged over 18 years old, suffering from unipolar major depressive disorder and treated by a psychiatrist, with or without antidepressant. Assessment of sexual functioning through three times: euthymia (before depression), untreated depression and treated depression if applicable was performed based on the ASEX scale. RESULTS: Seventy patients were included. Eight percent of euthymic patients presented a sexual dysfunction (average score on the ASEX=12.4) whereas 56% of untreated patients presented a sexual dysfunction (average total score on the ASEX=17.7) and 62% (34/55) of patients treated with antidepressant (average total score on ASEX=18.5) (P<0.001). Sexual functioning of men receiving treatment is not significantly different to that among men not receiving any antidepressant, even if patients treated with antidepressant reported that they had a better mood than those untreated. CONCLUSIONS: Our results reveal a high prevalence of sexual dysfunction within the framework of major depressive disorder and its treatment and underlines the complex relationship between major depressive disorder, antidepressant and sexuality.

Fatal and life-threatening ADRs associated with paliperidone palmitate: an observational study in the French pharmacovigilance database.

INTRODUCTION: Paliperidone palmitate (PP), a long-acting intramuscular formulation of paliperidone, has been marketed in Europe within the last 10 years and provides an important treatment option for patients with schizophrenia.Our aim was to describe PP-related adverse drug reactions (ADRs) leading to death or life-threatening events, specifying their main clinical and pharmacological characteristics. METHODS: This observational study was a retrospective review of PP-related ADRs in the French pharmacovigilance database between January 1, 2013, and December 31, 2019. RESULTS: Out of 473 PP-related ADRs, we identified 13 deaths and 14 life-threatening events. ADRs were primarily cardiorespiratory (n = 17; 63%). Other symptoms observed were mainly metabolic (n = 4), digestive (n = 4), and neurological (n = 4). Cardiorespiratory symptoms were generally observed within first 6 months after initiation of treatment (11 out of 17 cases), unlike metabolic disorders (all 4 cases 12-21 months after initiation). Cardiac arrests and sudden unexpected deaths occurred 10-14 days after the last PP once-monthly injection (23 cases) or 11-24 days after the last PP three-monthly injection (remaining 4 cases). No PP blood concentration assays were performed for these patients. DISCUSSION: In this study, PP-related ADRs leading to death or life-threatening events mainly presented with cardiorespiratory symptoms and tended to occur in the first 6 months after the initiation of treatment and within postadministration periods aligned with peak plasma PP concentrations. The hypothesis of supratherapeutic drug concentrations following intramuscular PP injection must be raised. CONCLUSION: PP-related ADRs leading to death or life-threatening events mainly presented with cardiorespiratory symptoms. Cardiac arrests and sudden unexpected deaths following initiation of PP treatment could be due to supratherapeutic drug concentrations. This study highlights the need to monitor blood concentrations of PP.Key pointsAdverse reactions to paliperidone palmitate can lead to death or life-threatening events.It is hypothesized that cardiac arrests and sudden unexpected deaths following initiation of paliperidone palmitate treatment could be due to supratherapeutic drug concentrations.This paper proposes the need to monitor blood concentrations of paliperidone palmitate in future studies.

Benzodiazepine dependence in subjects with alcohol use disorders: what prevalence?

OBJECTIVE: To our knowledge, no studies have been conducted in France on benzodiazepine (BZD) dependence among outpatients with alcohol use disorders (AUD). Some international studies have been conducted on the consumption of BZD in this specific population, but the comparisons among them are difficult. We aimed to assess the current prevalence of probable benzodiazepine and BZD-like hypnotics (Z-drugs) dependence among outpatients seeking treatment for AUD. METHODS: Participants were patients seeking treatment for AUD for the first time or repeating treatment after more than twelve months. Recruitment took place in seven addiction centres between January and December 2013 in the Nantes region (France). BZD/Z-drug dependence was assessed according to the DSM-IV diagnostic criteria for dependence. This information was gathered through a self-report questionnaire. RESULTS: Among the 1005 patients included in this study, 413 were BZD/Z-drug users (41.1%). Among the 413 patients, 217 were probably dependent on at least one substance, which represents 21.6% of the total population and 52.5% of BZD/Z-drug users. CONCLUSION: BZD/Z-drug dependence represents a public health concern. Prescribers should take the risks into account and keep treatment courses to a minimum.

Simultaneous determination of ceftaroline, daptomycin, linezolid and rifampicin concentrations in human plasma by on-line solid phase extraction coupled to high-performance liquid chromatography-tandem mass spectrometry.

Methicillin-resistant Staphylococcus aureus infection is a serious clinical problem worldwide. Ceftaroline, daptomycin, linezolid in combination with rifampicin are particularly used in this indication. To allow monitoring of these antibiotics, an on-line solid phase extraction coupled to high-performance liquid chromatography-tandem mass spectrometry assay requiring a 100 µL aliquot of human plasma has been developed. Besides, significance of 25-O-desacetylrifampicin concentrations was evaluated. Sample pre-treatment is limited to protein precipitation with methanol. After centrifugation 10 µL of supernatant are injected into the chromatographic system, which consists of an on-line solid phase extraction followed by a separation on a phenyl-hexyl column and detected by a tandem mass spectrometer. Plasma drug concentrations were determined by multiple reaction monitoring in positive ion mode, and assay performance was evaluated. 25-O-Desacetylrifampicin activity, was compared to rifampicin using a microbiological method. Sample preparation using methanol precipitation followed by solid-phase extraction yielded good recovery and ionization efficiency, with chromatographic separation achieved within 3 min per sample. Within-run and between-run precisions ranged respectively from 1.22% to 9.35% and from 1.61% to 9.36%. Lower limits of quantification were 0.04 mg/L for linezolid, 0.1mg/L for rifampicin, 0.2mg/L for ceftaroline and 0.5mg/L for daptomycin. It appears that 25-O-desacetylrifampicin displays a substantial intrinsic bactericidal activity against S. aureus. This assay provides simple, rapid, sensitive and accurate quantification of the four antibiotic drugs and one metabolite and can be routinely used to monitor drug concentration in methicillin-resistant S. aureus infected patients.

A liquid chromatography-tandem mass spectrometry assay for quantification of rilpivirine and dolutegravir in human plasma.

A liquid chromatography-tandem mass spectrometry assay requiring a 100µL aliquot of human plasma for simultaneous determination of rilpivirine, a second generation non-nucleoside reverse transcriptase inhibitors of HIV and dolutegravir, a novel integrase stand transfer inhibitors of HIV concentrations has been developed. Sample pre-treatment is limited to protein precipitation with a mixture of methanol and zinc sulfate. After centrifugation the supernatant is injected in the chromatographic system, which consists of on-line solid phase extraction followed by separation on a phenyl-hexyl column. This 2.5min method, with its simple sample preparation provides sensitive (the limit of quantitation is 25ng/mL for each compound), accurate and precise (the intra-day and inter-day imprecision and inaccuracy are lower than 15%) quantification of the plasma concentration of these drugs and can be used for therapeutic drug monitoring in patients infected with HIV.

[Prescription of methylphenidate for children: importance of recommendations to limit misuse]. / Prescription de méthylphénidate chez l'enfant : importance des recommandations pour limiter la consommation problématique.

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder appearing during childhood. Multimodal strategies have been developed to treat this disorder, some of them including medication. To this day in France, prescriptions are mainly based on methylphenidate. Ever since this drug was marketed in France in 1995, it has been subject to enhanced monitoring, mainly because of the risk of dependence, abuse, and misuse. The present study aims at assessing (1) whether the recommendations on methylphenidate use for children are being respected, (2) the extent of problematic use of methylphenidate, and (3) the impact of said recommendations being respected on the development of problematic consumption. We studied patients who were treated with methylphenidate in an academic child psychiatry department. We specifically developed a semistructured interview grid for this study. Both parents and children were interviewed. In almost three out of four cases, at least one recommendation had not been followed (52% of patients did not follow the recommendation of stopping use during weekends and holidays). We found an average of 1.6 (range, 0-5) recommendations that were not respected. In almost two out of three cases, the consumption of methylphenidate was problematic; for 40% of children, this meant the search for at least one effect other than the expected therapeutic effects, such as an intellectual, creative, or athletic boosting effect. Approximately one-third of parents also sought an effect other than therapeutic for their child. Conversely, if all of the prescription recommendations were followed, less problematic consumption was observed. Methylphenidate-based treatments must therefore be implemented after a specialist has evaluated the patient and be prescribed following the recommendations. In this context, the treatment's benefits are undeniable.

Ibuprofen dependence: a case report.

Ibuprofen is currently widely prescribed and has not been reported to produce dependence. We report the case of a 17-year old patient who presented many positive psychic symptoms related to a pharmacological dependence. During the treatment, she adjusted herself posology as she developed withdrawal symptoms. Pharmacological evidences (effect on COX-1 and COX-2, FAAH and PPARs) allow us to formulate hypotheses explaining this effect.

Melanoma and rituximab: an incidental association?

Rituximab is an anti-CD20 monoclonal antibody increasingly used in haematology and rheumatology, but also in internal medicine and dermatology. It has a good tolerance profile without known increased risk of cancer. We report a case of nodular melanoma with a 4.8 mm Breslow thickness that appeared after 2 years of rituximab in a 45-year-old patient with non-Hodgkin lymphoma. Fifteen additional rituximab-associated melanoma cases in 13 patients have been identified in the literature and in the EudraVigilance database. These patients were treated for various indications and had melanomas, often aggressive, initially diagnosed at a metastatic stage in 31% of cases. Our work raises the question of rituximab accountability in melanoma onset in these immunosuppressed patients. A dermatological monitoring seems necessary in patients treated with rituximab, especially in case of risk factors for melanoma. In case of individual melanoma history, the benefit/risk ratio of initiating rituximab therapy should be carefully assessed.

Pharmacoepidemiological characterisation of zolpidem and zopiclone usage.

PURPOSE: Zolpidem and zopiclone are two widely used non-benzodiazepine hypnotics whose usage seems to be associated to pharmacodependence. However, to our knowledge, there has as yet been no published epidemiological study which has compared their abuse or dependence potential. We used a pharmacoepidemiological approach to identify and characterise zolpidem and zopiclone users in real life situations. METHODS: Regular users of zolpidem or zopiclone were identified in the database of a French regional health insurance organisation. A latent class analysis (LCA) was used to identify different subgroups of users of these two hypnotics. RESULTS: The study cohort comprised 25,168 patients who regularly used zolpidem and 21,860 who regularly used zopiclone. The results of the latent class analysis, which enables subgroups with similar patterns of response to be identified, revealed four clinical subtypes of users of zolpidem: non-problematic users, users with associations with hypnotics/anxiolytics or with associated mental disorders, and problematic users. Only three subgroups were identified for zopiclone, and LCA did not discriminate a special class of problematic users for this drug. CONCLUSION: Our analysis indicates that there is a subclass of zolpidem user suggestive of abuse; this was not the case for zopiclone. This methodology is very interesting because it allows analysis of databases and determination of a specific signature of drugs potentially leading to abuse or dependence.

Pharmacokinetics of ertapenem in burns patients.

The aims of this study were to evaluate pharmacokinetic (PK) parameters of total and unbound ertapenem (ERT) in burns patients and to identify which covariates influence these PK parameters. ERT plasma concentrations were measured in burns patients (n = 8) who received a 0.5-h infusion of ERT (1000 mg) every 24 h. PK parameters were estimated by a non-compartmental approach and the influence of covariates was estimated by multivariate analysis using a population approach. Clearance (CL) and the volume of distribution (V) of total ERT were lower than the results for unbound ERT [CL, 22.2 ± 5.6 mL/min vs. 279.4 ± 208.2 mL/min; V, 9.7 ± 1.4L vs. 120.6 ± 130.6L (mean ± standard deviation)]. Creatinine clearance (CL(Cr)) and the burned surface area (BSA) were the covariates identified that significantly (P<0.01) affected the pharmacokinetics of total ERT [CL (L/h)=0.373 +{0.00666 x CL(Cr) (mL/min)}] and unbound ERT [peripheral volume of distribution (L) = 3.05 + {0.959 x BSA (% of the total body surface)}], respectively. The influences of albuminaemia, glomerular filtration and burn wound on ERT pharmacokinetics are proposed to explain these results. These first results support that the ERT plasma concentration should be closely monitored particularly for patients with high values of BSA and/or CL(Cr) to avoid suboptimal exposure.

[Description of medicosocial profiles of pharmacodependent subjects consulting addictology centres using a computerized database]. / Description de profils médicosociaux de sujets pharmacodépendants consultant en addictologie à partir d'une base de données informatique.

INTRODUCTION: Lots of similar vulnerabilities to substance use disorders are described in the literature: clinical, genetics, family, environment, etc. Although, when we follow up patients, we know perfectly well that there are also differences due to the substance mainly causing addiction. But we found very little research on the differences between various substance use disorders according to the substance mainly causing dependence. HYPOTHESIS: Our main hypothesis was that significant differences do not exist in medical and social data between patients with substance use disorders according to the substance mainly used. We expected to find significant differences between illegal substance use disorders (opiates, cocaine, cannabis) and legal substance use disorders (BZD, alcohol). OBJECTIVE: Our study aimed to identify differences between patients with substance related disorders in medical and social data according to the main addictive substance. MATERIAL AND METHOD: A specific software has been created by the CEIP and the Department of Addictology of Nantes University Hospital. Anonymous data were gathered and all patients gave their written consent. This database has been declared to CNIL (number 1350706). All data have been directly collected by the physician during medical consultation. The following data were recorded during the first medical examination: age, sex, illicit substance use, prior criminal record or psychiatric disorders, prior addictive behaviours among relatives and/or friends, family history (divorce, separation, abandonment). Other data were gathered prospectively: socioprofessional insertion, marital status, drug prescriptions (time and duration). RESULTS: We found significant differences in social (age, sex) and medical data (prior psychiatric disorders) between patients according to the substance causing dependence. We identified five profiles depending on the substance: cannabis, cocaine, heroin, alcohol and benzodiazepine. DISCUSSION: We clearly identified different types of patient's profiles according to substances mainly causing addiction. These differences can modify our strategies of prevention and treatment, so as to meet patients' needs better.

A statement on cefazolin immediate hypersensitivity: data from a large database, and focus on the cross-reactivities.

BACKGROUND: More perioperative cefazolin use has resulted in an increased risk of cefazolin-associated reactions. OBJECTIVE: The aim of this article is to study immediate reactions to cefazolin and attempt to determine possible allergic cross-reactivity with other ß-lactams using data from the Drug Allergy and Hypersensitivity Database (DAHD). METHODS: All 25 cefazolin-associated reactions in the DAHD were reviewed. The cases identified were then investigated according to the European Network for Drug Allergy (ENDA) recommendations by skin testing and challenges. RESULTS: A total of 10 individuals with proven IgE-mediated cefazolin hypersensitivity were identified between January 1999 and July 2009. All the index reactions were compatible with an acute IgE-mediated process, six with anaphylaxis, two with systemic allergic reactions without hypotension, and two with urticaria/angioedema. Cefazolin skin tests were positive in seven individuals and cefazolin challenges were positive in three more individuals. In the eight cefazolin allergic patients who had challenges with other ß-lactams, there was no positive reaction noted. CONCLUSION AND CLINICAL RELEVANCE: In this cohort of patients with IgE-mediated reactions to cefazolin, a majority tolerated amoxicillin and several patients tolerated other cephalosporins. This implies that the R1 side-chain may play an essential role in IgE-mediated reactions to cefazolin. No clear rule to predict cross-reactivity with other ß-lactams could be determined. More research on IgE-mediated hypersensitivity to cefazolin and other cephalosporins is needed.

[Early neurorehabilitation in an acute university hospital: from dream to reality]. / Neurorééducation précoce au Centre hospitalier universitaire vaudois: du rêve à la réalité.

The need for an early neurorehabilitation pathway was identified in an acute university hospital. A team was formed to draw up and implement it. A neuro-sensorial, interdisciplinary and coordinated therapy program was developed, focused on tracheostomised patients as soon as they were admitted to the intermediate care in neurology and neurosurgery. The impact of this care plan was evaluated by comparing the results obtained with that pertaining to patients treated previously in the same services. The comparison showed a reduction of 48% of the mean duration of tracheostomy, of 39% in the time to inscription in a neurorehabilitation centre and of 20% in the length of stay in the intermediate care. An early neurorehabilitation care program, with an interdisciplinary and coordinated team, reduces complications and lengths of stay.

A liquid chromatography assay for a quantification of doripenem, ertapenem, imipenem, meropenem concentrations in human plasma: application to a clinical pharmacokinetic study.

A simple chromatographic assay based on ultra high performance liquid chromatography with ultraviolet detection at 295 nm is proposed to determinate simultaneously human plasma concentrations of imipenem, doripenem, meropenem and ertapenem. After deproteinization by acetonitrile, carbapenems are separated on a PentaFluoroPhenyl column with a binary gradient elution. This method is specific, accurate, precise (the intra-day and inter-day imprecision and inaccuracy are lower than 15%), sensitive (the limit of quantitation is equal to 0.50 mg/L for imipenem, doripenem, ertapenem, meropenem) and not time consuming (run time=7 min). An application of this method to measure ertapenem plasma concentrations in burn patients is presented.

A liquid chromatography-tandem mass spectrometry assay for quantification of nevirapine, indinavir, atazanavir, amprenavir, saquinavir, ritonavir, lopinavir, efavirenz, tipranavir, darunavir and maraviroc in the plasma of patients infected with HIV.

A liquid chromatography-tandem mass spectrometry assay for simultaneous determination of the plasma concentration of 11 antiretroviral agents (nevirapine, indinavir, atazanavir, amprenavir, saquinavir, ritonavir, lopinavir, efavirenz, tipranavir, darunavir and maraviroc) has been developed. Sample pre-treatment is limited to protein precipitation with a mixture of methanol and zinc sulfate. After centrifugation the supernatant is injected in the chromatographic system, which consists of on-line solid phase extraction followed by separation on a phenyl-hexyl column. This method, with its simple sample preparation provides sensitive, accurate and precise quantification of the plasma concentration of antiretroviral drugs and can be used for therapeutic drug monitoring in patients infected with HIV.

Immobilization and the risk of venous thromboembolism. A meta-analysis on epidemiological studies.

BACKGROUND: The thrombogenic burden of immobilization remains unknown especially in the medical setting. Most of epidemiological studies estimating the link between risk factors and venous thromboembolism (VTE) have not been designed to evaluate immobilization. The aim of this work was to estimate the risk of VTE in medical bedridden patients by a systematic review and a meta-analysis. METHODS: A research on PUBMED and EMBASE was carried out to retrieve case-control and cohort studies showing the proportion of bedridden patients with or without VTE. Included studies were assigned in six groups according to the following criteria: 1) their design (cohort or case-control), 2) the targeted population (with or without suspicion of VTE) and 3) the medical setting (ambulatory or hospital). Odd-Ratios and Relative Risk for case-control and cohort studies were calculated using a random effect method. Heterogeneity and publication bias were statistically assessed by the I(2) statistics and funnel plots with Egger's tests. RESULTS: 43 studies were included (24181 patients). The pooled RR ranged from 1.46 to 2.77 in the subgroups of cohort studies (n=36) with an overall RR of 1.86 (1.61-2.14; P<0.001). The pooled OR were 2.79 and 2.47 in the two subgroups of case-control studies (n=7), both statistically significant (overall OR: 2.52; 1.70-3.74; P<0.001). Heterogeneity through studies was demonstrated in four subgroups. Publication bias was only observed in one subgroup. CONCLUSIONS: Among medical patients, immobilization increases the risk of VTE. Nevertheless, a specific role of underlying conditions can not be excluded.