Development of original analytical methods for the therapeutic drug monitoring of CNS druges: Antipsychotics, Antidepressants and Anxiolytics-hypnotics

Great strides have been made in the last few years in the pharmacological treatment of neuropsychiatric disorders, with the introduction into the therapy of several new and more efficient agents, which have improved the quality of life of many patients. Despite these advances, a large percentage of patients is still considered “non-responder” to the therapy, not drawing any benefits from it. Moreover, these patients have a peculiar therapeutic profile, due to the very frequent application of polypharmacy, attempting to obtain satisfactory remission of the multiple aspects of psychiatric syndromes. Therapy is heavily individualised and switching from one therapeutic agent to another is quite frequent. One of the main problems of this situation is the possibility of unwanted or unexpected pharmacological interactions, which can occur both during polypharmacy and during switching. Simultaneous administration of psychiatric drugs can easily lead to interactions if one of the administered compounds influences the metabolism of the others. Impaired CYP450 function due to inhibition of the enzyme is frequent. Other metabolic pathways, such as glucuronidation, can also be influenced. The Therapeutic Drug Monitoring (TDM) of psychotropic drugs is an important tool for treatment personalisation and optimisation. It deals with the determination of parent drugs and metabolites plasma levels, in order to monitor them over time and to compare these findings with clinical data. This allows establishing chemical-clinical correlations (such as those between administered dose and therapeutic and side effects), which are essential to obtain the maximum therapeutic efficacy, while minimising side and toxic effects. It is evident the importance of developing sensitive and selective analytical methods for the determination of the administered drugs and their main metabolites, in order to obtain reliable data that can correctly support clinical decisions. During the three years of Ph.D. program, some analytical methods based on HPLC have been developed, validated and successfully applied to the TDM of psychiatric patients undergoing treatment with drugs belonging to following classes: antipsychotics, antidepressants and anxiolytic-hypnotics. The biological matrices which have been processed were: blood, plasma, serum, saliva, urine, hair and rat brain. Among antipsychotics, both atypical and classical agents have been considered, such as haloperidol, chlorpromazine, clotiapine, loxapine, risperidone (and 9-hydroxyrisperidone), clozapine (as well as N-desmethylclozapine and clozapine N-oxide) and quetiapine. While the need for an accurate TDM of schizophrenic patients is being increasingly recognized by psychiatrists, only in the last few years the same attention is being paid to the TDM of depressed patients. This is leading to the acknowledgment that depression pharmacotherapy can greatly benefit from the accurate application of TDM. For this reason, the research activity has also been focused on first and second-generation antidepressant agents, like triciclic antidepressants, trazodone and m-chlorophenylpiperazine (m-cpp), paroxetine and its three main metabolites, venlafaxine and its active metabolite, and the most recent antidepressant introduced into the market, duloxetine. Among anxiolytics-hypnotics, benzodiazepines are very often involved in the pharmacotherapy of depression for the relief of anxious components; for this reason, it is useful to monitor these drugs, especially in cases of polypharmacy. The results obtained during these three years of Ph.D. program are reliable and the developed HPLC methods are suitable for the qualitative and quantitative determination of CNS drugs in biological fluids for TDM purposes.

Calcium channel blockers are independently associated with short sleep duration in hypertensive patients with obstructive sleep apnea

Objective Obstructive sleep apnea (OSA) and hypertension (HYP) frequently coexist and have additive harmful effects on the cardiovascular system. There is also growing evidence that short sleep duration may contribute independently to poor cardiovascular outcome. The aim of this study was to evaluate the potential influence of antihypertensive medication on sleep parameters objectively measured by standard polysomnography in hypertensive patients with OSA. Methods We evaluated consecutive patients with a recent diagnosis of OSA by full polysomnography (apnea hypopnea index >= 5 events/h) and HYP. Smokers, patients with diabetes mellitus, heart failure, or using hypnotics and benzodiazepines were excluded. Results We evaluated 186 hypertensive patients with OSA, 64% men. All patients were on at least one antihypertensive medication, including angiotensin-converting enzyme inhibitors (37%), beta-blockers (35%), angiotensin receptor blockers (32%), diuretics (29%) and calcium channel blockers (21%). Backward multiple regression analysis showed that age (P <= 0.001) and the use of calcium channel blockers (P=0.037) were the only factors inversely associated with lower total sleep time. Sleep efficiency was inversely associated only with age (P <= 0.001), whereas the use of calcium channel blockers had a nonsignificant trend (P=0.092). Use of calcium channel blockers was associated with significant reduction in total sleep time (-41 min, P=0.005) and 8% lower sleep efficiency (P=0.004). No other antihypertensive medication, including diuretics and beta-blockers, was associated with sleep impairment. Conclusion Calcium channel blockers may impact negatively on sleep duration in hypertensive patients with OSA. The mechanisms and significance of this novel finding warrants further investigation. J Hypertens 29: 1236-1241 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

Use of psychoactive drugs and related falls among older people living in a community in Brazil

INTRODUCTION: Population aging in Brazil has increased the prevalence of neurodegenerative diseases (Parkinson's and Alzheimer's disease) and affective disorders (anxiety, depression), all common in old age. A retrospective study was carried out with the purpose of ascertaining if there is an association between falls and psychoactive medication use among older residents of a community in Brazil. METHODS: All residents aged 65+ (n=161) of one neighborhood of Campo Belo, Brazil (population of 48,000) were evaluated regarding the use of psychoactive drugs and the occurrence of falls in the 12 months preceding the study. Vision and hearing screenings were also performed. RESULTS: From the study population, 9.3% were taking prolonged half-life benzodiazepines, 4.4% anticonvulsants (mostly barbiturates), 2.5% antidepressants (all cyclics) and 8.1% alpha-methyldopa. No subject reported use of hypnotics, neuroleptics or drugs to treat Alzheimer's or Parkinson's diseases (except biperiden). As a whole, drugs that increase the risk of falls were used by 1/5 of this population. In the 12-month period preceding the study, 27 residents (16.8%) experienced falls and, of those, 4 (14.8%) had fracture(s). There was an independent association between psychoactive drug use and falls when variables such as age, gender, vision and hearing were controlled (p=0.02). CONCLUSIONS: Although the population of this neighborhood must be considered young (only 4% are 65 years old or more), there are already problems related to the use of psychoactive drugs among people. Prescribed anxiolytics, anticonvulsants, antidepressants and antihypertensives are not appropriate for this age group and their use is associated with falls.

The burden of chronic low back pain in the adult Portuguese population : an epidemiological population-based study under the scope of Epireumapt

RESUMO: Nos países desenvolvidos a lombalgia é a condição músculo-­‐esquelética mais prevalente. Quando evolui para um quadro crónico é responsável por um encargo económico bastante considerável, não só em relação aos indivíduos, mas também para a sociedade. A lombalgia crónica é por isso uma das principais causas de perda de produtividade e de perda de independência económica, nomeadamente através do absenteísmo (ausência do trabalho), do presenteísmo (perda de produtividade no trabalho, devido à capacidade diminuída provocada pela lombalgia) e da incapacidade para trabalhar (invalidez permanente, total ou parcial). Até à data, em Portugal, a prevalência e carga social da lombalgia crónica eram desconhecidas. Até agora não existiam estudos populacionais de grande dimensão sobre este tema. O objetivo principal desta tese foi determinar a prevalência de lombalgia crónica, e também avaliar a carga social que esta tem na população adulta Portuguesa. O trabalho de investigação foi desenvolvido no âmbito do Estudo Epidemiológico de Doenças Reumáticas em Portugal (EpiReumaPt). Este foi o primeiro estudo de larga escala e de base populacional, que determinou a prevalência de doenças reumáticas e músculo-­‐ esqueléticas na população adulta portuguesa. Foi realizado numa amostra aleatória e representativa, de 10.661 indivíduos do Continente, da Região Autónoma dos Açores e da Região Autónoma da Madeira, entre Setembro de 2011 e Dezembro de 2013. Esta tese foi dividida em duas secções. A primeira secção incluiu o detalhe das questões relativas ao desenvolvimento e gestão do EpiReumaPt, constituindo-­‐se como um guia prático sobre como realizar um estudo de base populacional de larga escala, em Portugal. A metodologia detalhada do EpiReumaPt foi também descrita nesta secção e incluiu os objectivos, o desenho do estudo, as características de recrutamento e a preparação de dados para análise. Nesta secção foram ainda descritos os principais resultados do EpiReumaPt. Estes evidenciaram que a lombalgia foi a condição músculo-­‐esquelética com maior prevalência na população adulta portuguesa.A segunda secção desta tese estimou a prevalência da lombalgia crónica ativa na população adulta Portuguesa, e avaliou a carga social esta condição. A lombalgia ativa foi definida com base na dor auto-­‐relatada no dia da entrevista e que persistia há pelo menos 90 dias (independentemente da causa). A lombalgia foi definida como dor na área definida entre a margem inferior das décimas segundas costelas até às pregas glúteas inferiores, com ou sem dor nos membros inferiores. A carga social foi medida tendo em conta os seguintes parâmetros: qualidade de vida, função, consumo de recursos de saúde, consumo de analgésicos e outros fármacos usados no alívio da dor, sintomas de ansiedade e sintomas de depressão. Os resultados mostraram que o consumo de recursos em saúde e a carga social da lombalgia crónica na população adulta Português é significativa. Também a incapacidade causada pela lombalgia crónica,nos indivíduos com idade ativa, é responsável por elevadas taxas de absenteísmo e má qualidade de vida, aos quais acresce o consequente ónus socioeconómico. Esta tese também concluiu que o consumo de analgésicos e outros medicamentos para alívio da dor, na população adulta portuguesa com lombalgia crónica ativa, é relativamente baixa. A maioria destes indivíduos não tomava nenhum medicamento analgésico, independentemente da intensidade da dor. Mesmo os indivíduos que reportaram dor intensa, apenas 4.0% estavam no primeiro degrau da escada analgésica da Organização Mundial de Saúde; 2.3% usavam opióides fracos e 0.03% usavam opióides fortes para controlar a dor (segundo e terceiro degrau da escada analgésica da Organização Mundial da Saúde). O trabalho de investigação também confirmou que a prevalência de sintomas de ansiedade e depressão entre os indivíduos adultos portugueses com lombalgia crónica ativa é elevada. Nestes indivíduos, registou-­‐se um consumo mais elevado de analgésicos e outros medicamentos para alívio da dor, quando comparados com os indivíduos com lombalgia crónica activa sem esses sintomas psicológicos. Os grupos terapêuticos mais utilizados foram os ansiolíticos, sedativos e hipnóticos, os antidepressivos e os anti-­‐inflamatórios não esteróides. A intensidade média da dor reportada foi também maior entre os indivíduos com lombalgia ativa e sintomas de ansiedade e/ou depressão. Também nestes, foi reportada pior função e pior estado de saúde. Em relação ao consumo de recursos de saúde foram encontradas diferenças significativas entre as duas populações: os indivíduos com lombalgia ativa e sintomas psicológicos concomitantes registaram maior número de consultas de psiquiatria de outras especialidades médicas, assim como precisaram de mais apoio domiciliário nos 12 meses prévios à entrevista do EpiReumaPt. Foram também identificados os fatores associados a sintomas isolados de ansiedade, a sintomas isolados de depressão e a sintomas de ansiedade e depressão. Resumindo,esta tese permitiu concluir que a lombalgia crónica é um problema de saúde comum na população adulta portuguesa, contribuindo para um elevado grau de incapacidade e que consequentemente afeta o desempenho laboral e o bem-­‐estar dos indivíduos. A lombalgia crónica é também responsável por um consumo considerável de recursos de saúde. Acresce ainda que os sintomas de ansiedade e depressão são comuns, entre os indivíduos com lombalgia crónica, contribuindo com uma carga social adicional.---------------------------------- ABSTRACT:Low Back Pain(LBP) is the most prevalent of musculoskeletal condition in developed countries.When it becomes chronic, LBP causesan enormous economic burden on individuals and society -­‐ it is one of the leading causes of loss of productivity and economic independence through absenteeism (time off work), presenteeism (lost productivity because of diminished capacity while at work) and work disability (permanent, partial or complete disablement for work purposes). In Portugal the prevalence and burden of LBP and chronic LBP (CLBP) were poorly defined. Until now no large population-­‐based studies have focused on this. The main aim of this thesis was to determine the prevalence of LBP and CLBP, and also to assess the burden of CLBP in the adult rtuguese population. The research work was developed under the scope of EpiReumaPt (the Portuguese Epidemiologic Study of Rheumatic Diseases). EpiReumaPt was the first national large population-­‐based and prevalence study of rheumatic and musculoskeletal diseases (RMD). It was performed among a randomized and representative sample of 10,661 adult Portuguese subjects recruited in Mainland, Azores and Madeira Islands, from September 2011 to December 2013. The first section of this thesis included detailed issues regarding the development and management of EpiReumaPt, and provided a practical guide on how to set-­‐up a large population-­‐based study in Portugal. The detailed methodology of EpiReumaPt, including its objectives,study design,recruitment features,and data preparation for analyses were also described. The main results from EpiReumaPt study were provided in this section and showed that LBP was the musculoskeletal condition with highest prevalence among Portuguese population. The second section of this thesis estimated the prevalence of active CLBP among adult Portuguese population, and assessed the social burden of this condition. Active CLBP was defined based on self-­‐reported pain on the day of the interview, and for most of the time for at least 90 days (independently from cause). LBP was defined as pain in the back area from the lower margin of the twelfth ribs to he lower gluteal folds, with or without pain referred to the lower limbs. Social burden was measured taking into account the following outcomes: quality of life, function, healthcare resources consumption, analgesic and other pain relief drugs intake, anxiety and depression symptoms. Results showed that the healthcare consumption and social burden of CLBP among adult Portuguese population were enormous, and the disability caused by CLBP among subjects in a working age provides high rates of absenteeism (work loss) and poor quality of life, with a consequent socioeconomic burden. This thesis also concluded that analgesic and other pain relief drugs untake among adult Portuguese population with active CLBP was very low. Most of the subjects with active CLBP did not take any analgesic drug regardless pain severity. Even when subjects self-­‐reported severe pain, only 24.0% were in the 1st step of the analgesic ladder,2.3% used weak analgesic opioids and 0.03% used strong opioids (2nd and 3rd step of WHO analgesic ladder, respectively) to control pain . The research work also confirmed that the prevalence of anxiety and depression symptoms among adult Portuguese subjects with active CLBP was high. Regarding pharmacological therapy, the intake of analgesic and other pain relief drugs was higher among subjects with anxiety and/or depression symptoms, when compared with subjects without these psychological symptoms. Anxiolytics, sedatives and hypnotics, antidepressants and NSAIDs intake had higher usage rates among these subjects. The pain severity mean was also higher among this subjects and function and health status was worse. Regarding healthcare resources consumption,significant differences between the two populations were found. Subjects with ctive CLBP and concomitant psychological symptoms had a higher number of psychiatrist and other physician visits. They also needed more home care in the previous 12 months. Factors associated with isolated symptoms of anxiety, depression,and concomitant anxiety and depression symptoms were also identified. Summarizing, we concluded that CLBP is a common health problem among adult Portuguese population contributing to disability and affecting labor performance, and the well being of subjects. it is also responsible for considerable healthcare resource consumption. Anxiety and depression symptoms are common among subjects with CLBP and provided an additional burden among them.

Off-label utilization of antipsychotics

Résumé Ce travail s'inscrit dans un programme de recherche centré sur la pharmacovigilance en psychiatrie. Buts de l'étude Les nouveaux antipsychotiques atypiques sont prescrits avec beaucoup de succès, parce qu'ils présentent une sécurité dans leur emploi bien supérieure à celle des antipsychotiques classiques. Cette situation a conduit à une large prescription «off-label» (hors indication admise). Le but de ce travail a été d'étudier la pratique en matière de prescription des psychiatres hospitaliers en ce qui concerne les antipsychotiques en comparant des patients traités pour des psychoses ou d'autres indications officielles aux patients recevant un traitement antipsychotique «off-label». Méthode Dans le cadre d'un programme de pharmacovigilance - pharmacoépidemiologie, tous les médicaments prescrits à 5 jours de référence (entre 1999 et 2001) à l'hôpital psychiatrique universitaire de Lausanne (98 lits) ont été enregistrés, avec des données sur l'âge, le sexe et le diagnostic des patients. Les prescriptions de 202 patients ont été évaluées. Les patients ont été classés dans 3 groupes diagnostiques : (1) patient présentant des troubles psychotiques, (2) patient présentant des épisodes maniaques et des épisodes dépressifs avec des symptômes psychotiques, et (3) patient présentant d'autres troubles. Les groupes (1) et (2) forment une classe de patients recevant un antipsychotique pour une indication officielle, et les prescriptions dans le groupe (3) ont été considérées comme «off-label». Résultats principaux Moins de patients psychotiques ont reçu un antidépresseur (p<0.05) ou des hypnotiques non-benzodiazepine (p<0.001) comparés aux patients des deux autres groupes. Les patients présentant des troubles affectifs recevaient seulement exceptionnellement une combinaison d'un antipsychotique atypique et conventionnel, tandis qu'un nombre inférieur de patients avec des indications « off-label » ont reçu moins .souvent des antipsychotiques atypiques que ceux des deux groupes de comparaison (p<0.05). L'analyse statistique (stepwise logistic regression) a révélé que les patients présentant des troubles psychotiques avaient un risque plus élevé de recevoir un médicament antipsychotique d'une dose moyenne ou élevée, (p<0.001) en comparaison aux deux autres groupes. Conclusion Les nouveaux médicaments antipsychotiques semblent être prescrits avec moins d'hésitation principalement pour des indications admises. Les médecins prescrivent de nouveaux médicaments « off-label » seulement après avoir acquis une certaine expérience dans le domaine des indications approuvées, et ils étaient plus prudents en ce qui concerne la dose en traitant sur la base «off-label». Abstract Objective The new brands of atypical antipsychotics are very successfully prescribed because of their enhanced safety profiles and their larger pharmacological profile in comparison to the conventional antipsychotic. This has led to broad off-label utilisation. The aim of the present survey was to study the prescription practice of hospital psychiatrists with regard to antipsychotic drugs, comparing patients treated for psychoses or other registered indications to patients receiving an off-label antipsychotic treatment. Method As part of a pharmacovigilance/pharmacoepidemiology program, all drugs given on 5 reference days (1999 - 2001) in the 98-bed psychiatric hospital of the University of Lausanne, Switzerland, were recorded along with age, sex and diagnosis. The prescriptions of 202 patients were assessed. Patients were classified in 3 diagnostic groups: (1) patient with psychotic disorders, (2) patients with manic episodes and depressive episodes with psychotic symptoms, and (3) patients with other disorders. Group (1) and (2) formed the class of patients receiving an antipsychotic for a registered indication, and the prescriptions in group (3) were considered as off-label. Main results A lesser number of psychotic patients received antidepressant (p<0.05) and nonbenzodiazepine hypnotics (p<0.001) compared to the patients of the other two groups. The patients with affective disorders received only exceptionally a combination of an atypical and a conventional antipsychotic, whereas a lesser number of patients with off-label indications received less often atypical antipsychotics than those of the two comparison groups (p<0.05). Stepwise logistic regression revealed that patients with psychotic disorder were at higher risk of receiving an antipsychotic medication in medium or high dose (p<0.001), in comparison to the two other groups. Conclusions The new antipsychotic drugs seem to be prescribed with less hesitation mainly for approved indications. Physicians prescribe new drugs on off-label application only after having gained some experience in the field of the approved indications, and were more cautious with regard to dose when treating on an off-label basis.

An evaluation of the inappropriate prescribing in older residents in long term care facilities in the greater Cork and Northern Ireland regions using the STOPP and Beers' criteria.

This work has highlighted a number of areas of prescribing concern, for example, the long term use of both benzodiazepines and hypnotics, in older residents residing in long term care facilities. Each of these individual areas should be further investigated to determine the underlying reason(s) for the prescribing concerns in these areas and strategic methods of addressing and preventing further issues should be developed on a national level.This resource was contributed by The National Documentation Centre on Drug Use.

Sédation par propofol administrée par un non-anesthésiste pour l'endoscopie digestive [Administration of propofol by non-anesthesiologists for digestive endoscopy].

Propofol is progressively replacing benzodiazepines for sedation during endoscopy, even when the sedation is administered by non-anesthesiologists. Propofol ensures a more rapid induction of sedation and recovery and, in certain conditions, higher patient satisfaction and improved quality of endoscopic examination. Specific training is required to use this drug. Patients at risk of complications should be identified before the endoscopy to optimize patient management with an anesthesiologist. After sedation, psychomotor recovery is faster with propofol compared to traditional sedation agents but tasks requiring particular attention (eg, driving) should be avoided. It is important to advise patients of these restrictions in advance.

Non-medical prescription drug and illicit street drug use among young Swiss men and associated mental health issues.

Non-medical use of prescription drugs (NMUPD) is increasing among the general population, particularly among teenagers and young adults. Although prescription drugs are considered safer than illicit street drugs, NMUPD can lead to detrimental consequences. The aim of the present study was to investigate the relationship between drug use (NMUPD on the one side, illicit street drugs on the other side) with mental health issues and then compare these associations. A representative sample of 5719 young Swiss men aged around 20 years filled in a questionnaire as part of the ongoing baseline Cohort Study on Substance Use Risk Factors (C-SURF). Drug use (16 illicit street drugs and 5 NMUPDs, including sleeping pills, sedatives, pain killers, antidepressants, stimulants) and mental health issues (depression, SF12) were assessed. Simple and multiple linear regressions were employed. In simple regressions, all illicit and prescription drugs were associated with poorer mental health. In multiple regressions, most of the NMUPDs, except for stimulants, were significantly associated with poorer mental health and with depression. On the contrary, the only associations that remained significant between illicit street drugs and mental health involved cannabis. NMUPD is of growing concern not only because of its increasing occurrence, but also because of its association with depression and mental health problems, which is stronger than the association observed between these problems and illicit street drug use, excepted for cannabis. Therefore, NMUPD must be considered in screening for substance use prevention purposes.

Predictors of awakening from postanoxic status epilepticus after therapeutic hypothermia.

BACKGROUND: Postanoxic status epilepticus (PSE) is considered a predictor of fatal outcome and therefore not intensively treated; however, some patients have had favorable outcomes. The aim of this study was to identify favorable predictors for awakening beyond vegetative state in PSE. METHODS: We studied six subjects treated with hypothermia improving beyond vegetative state after cerebral anoxia, despite PSE. They were among a cohort of patients treated for anoxic encephalopathy with therapeutic hypothermia in our institution between October 1999 and May 2006 (retrospectively, 3/107 patients) and June 2006 and May 2008 (prospectively, 3/74 patients). PSE was defined by clinical and EEG criteria. Outcome was assessed according to the Glasgow-Pittsburgh Cerebral Performance Categories (CPC). RESULTS: All improving patients had preserved brainstem reflexes, cortical somatosensory evoked potentials, and reactive EEG background during PSE. Half of them had myoclonic PSE, while three had nonconvulsive PSE. In the prospective arm, 3/28 patients with PSE showed this clinical-electrophysiologic profile; all awoke. Treatments consisted of benzodiazepines, various antiepileptic drugs, and propofol. One subject died of pneumonia in a minimally conscious state, one patient returned to baseline (CPC1), three had moderate impairment (CPC2), and one remained dependent (CPC3). Patients with nonconvulsive PSE showed a better prognosis than subjects with myoclonic PSE (p = 0.042). CONCLUSION: Patients with postanoxic status epilepticus and preserved brainstem reactions, somatosensory evoked potentials, and EEG reactivity may have a favorable outcome if their condition is treated as status epilepticus.

Home and hospital treatment of acute seizures in children with nasal midazolam.

Rectal diazepam is widely used in the treatment of acute seizures in children but has some disadvantages. Nasal/sublingual midazolam administration has been recently investigated for this purpose but never at home or in a general paediatric hospital. The aim of this open study was to determine the efficacy, the tolerance and the applicability of nasal midazolam during acute seizures in children both in hospital and at home. We included known epileptic children for treatment at home and all children with acute seizures in the hospital. In all, 26 children were enrolled, 11 at home and 17 in the hospital (including two treated in both locations); only one had simple febrile seizure. They had a total of 125 seizures; 122 seizures (98%) stopped within 10 minutes (average 3.6 minutes). Two patients in the hospital did not respond and in three, seizures recurred within 3 hours. None had serious adverse effects. Parents had no difficulties administering the drug at home. Most of those who were using rectal diazepam found that nasal midazolam was easier to use and that postictal recovery was faster. Among 15 children who received the drug under electroencephalogram monitoring (six without clinical seizures), the paroxysmal activity disappeared in ten and decreased in three. Nasal midazolam is efficient in the treatment of acute seizures. It appears to be safe and most useful outside the hospital in severe epilepsies, particularly in older children because it is easy for parents to use. These data should be confirmed in a larger sample of children. Its usefulness in febrile convulsions also remains to be evaluated.

Complex suicide with homemade nicotine patches.

Suicide by self-poisoning is rather common around the world. This paper presents an exceptional complex suicide in which nicotine was applied in the form of self-made patches soaked with an extraction from fine-cut tobacco. In addition, the 51-year-old suicide victim took a lethal dose of diphenhydramine. Toxicological analysis also revealed the presence of tetrazepam in subtherapeutic concentrations. The scene of death suggested an autoerotic accident at first, as the body was tied with tapes, cables and handcuffs. As a result of the entire investigations, the fatality had to be classified as a suicidal intoxication by nicotine and diphenhydramine.

Sedation palliative: aspects cliniques pratiques [Clinical and practical aspects of palliative sedation]

Un certain nombre de patients palliatifs en fin de vie présentent des symptômes qui ne peuvent pas être soulagés malgré la mise en oeuvre de tous les moyens traditionnels à disposition. Pour ces patients, lorsque des symptômes réfractaires induisent une souffrance intolérable, la sédation palliative est un moyen de dernier recours qui peut leur offrir un soulagement transitoire ou même définitif. Tout en présentant les enjeux éthiques, cet article explore les dimensions cliniques d'ordre pratique qui peuvent se présenter lors d'une sédation palliative chez un patient en fin de vie. Patients at the end-of-life may present with refractory symptoms which cannot be adequately relieved despite the use of all traditional means. When refractory symptoms lead to intolerable suffering, palliative sedation is a last recourse temporary or definitive treatment. While discussing ethical issues, clinical practice dimensions of palliative sedation are explored in this article