RESUMO
Cannabis may have therapeutic benefits to relieve symptoms of amyotrophic lateral sclerosis (ALS) thanks to its pleiotropic pharmacological activity. This study is the first to present a large questionnaire-based survey about the "real-life" situation regarding cannabis use in the medical context in ALS patients in France. There were 129 respondents and 28 reported the use of cannabis (21.7%) to relieve symptoms of ALS. Participants mostly reported the use of cannabidiol (CBD) oil and cannabis weed and declared benefits both on motor (rigidity, cramps, fasciculations) and non-motor (sleep quality, pain, emotional state, quality of life, depression) symptoms and only eight reported minor adverse reactions (drowsiness, euphoria and dry mouth). Even if cannabis is mostly used outside medical pathways and could expose patients to complications (street and uncontrolled drugs, drug-drug interactions, adverse effects ), most of the participants reported "rational" consumption (legal cannabinoids, with only few combustion and adverse reactions). Despite some limitations, this study highlights the need for further research on the potential benefits of cannabis use for the management of ALS motor and non-motor symptoms. Indeed, there is an urgent need and call for and from patients to know more about cannabis and secure its use in a medical context.
Assuntos
Esclerose Lateral Amiotrófica , Canabinoides , Cannabis , Humanos , Cannabis/efeitos adversos , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/complicações , Qualidade de Vida , Canabinoides/efeitos adversos , DorRESUMO
PURPOSE: Beta-lactams (BL), the most commonly prescribed class of antibiotics, are recommended as the first-line therapy for multiple indications in infectious disease guidelines. Meropenem (MERO) is frequently used in intensive care units (ICU) to treat bacterial infections with or without sepsis. The pharmacokinetics of MERO display a large variability in patients admitted to ICUs due to altered pathophysiology. The aim of this study was to perform an external evaluation of published population pharmacokinetic models of MERO in order to test their predictive performance in a cohort of ICU adult patients. METHODS: A literature search in PubMed/Medline database was made following the PRISMA statement. External evaluation was performed using NONMEM software, and the bias and inaccuracy values were calculated. RESULTS: An external validation dataset from the Timone Hospital in Marseille, France, included 84 concentration samples from 27 patients. Four models of MERO were identified according to the inclusion criteria of the study. None of the models presented acceptable values of bias and inaccuracy. CONCLUSION: While performing external evaluations on some populations may confirm a model's suitability to diverse groups of patients, there is still some variability that cannot be explained nor solved by the procedure. This brings to light the difficulty to develop only one model for ICU patients and the need to develop one specific model to each population of critically ill patients.
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Antibacterianos/farmacocinética , Unidades de Terapia Intensiva , Meropeném/farmacocinética , Modelos Biológicos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/administração & dosagem , Estado Terminal , Feminino , Humanos , Masculino , Meropeném/administração & dosagem , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto JovemRESUMO
Despite the lack of progress in the curative treatment of mental illness, especially schizophrenia, the accumulation of neuroscience data over the past decade suggests the re-conceptualization of schizophrenia. With the advent of new biomarkers and cognitive tools, new neuroscience technologies such as functional dynamic connectivity and the identification of subtle clinical features; it is now possible to detect early stages at risk or prodromes of a first psychotic episode. Current concepts reconceptualizes schizophrenia as a neurodevelopmental disorder at early onset, with polygenic risk and only symptomatic treatment for positive symptoms at this time. The use of such technologies in the future suggests new diagnostic and therapeutic options. Next steps include new pharmacological perspectives and potential contributions of new technologies such as quantitative system pharmacology brain computational modeling approach.
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Antipsicóticos , Intervenção Médica Precoce/métodos , Farmacologia Clínica/métodos , Esquizofrenia/tratamento farmacológico , Adolescente , Adulto , Fatores Etários , Idade de Início , Antipsicóticos/classificação , Antipsicóticos/uso terapêutico , Encéfalo , Criança , Pré-Escolar , Continuidade da Assistência ao Paciente , Diagnóstico Precoce , Feminino , Humanos , Lactente , Recém-Nascido , Pessoa de Meia-Idade , Gravidez , Esquizofrenia/diagnóstico , Esquizofrenia/epidemiologia , Esquizofrenia/patologia , Psicologia do Esquizofrênico , Integração de Sistemas , Adulto JovemRESUMO
PURPOSE: Little is known about the informativeness of initial patient reports before they are reviewed by a pharmacovigilance centre (PVC). We aim to describe the patterns of patient adverse drug reaction (ADR) reporting in France and estimate the contribution of a review by a PVC assessor on the informativeness of these reports. METHODS: A retrospective study was conducted on patient reports between July 2011 and July 2015. Informativeness of 16 key elements of information (including drug start and end date, duration of treatment, time to onset and duration of the ADR, outcome, medical history and concomitant medication) was assessed in initial reports before and after review by a pharmacovigilance assessor. RESULTS: Overall, 240 reports concerning 522 ADR and involving 278 drugs were reported over this 4-year period. Mean number of available key elements of information in initial reports was increased from 11/16 to 15/16 after review of reports by the PVC. Time to onset and duration of the ADR were respectively available in only 51 and 58% of the reports before review compared to 83 and 90% after review. Medical history and concomitant medication were missing in 75% of the initial reports compared to less than 30% of the reports after review. Contacting the reporter enabled an increase of informativeness of most elements of information for more than 90% of the reports. CONCLUSION: Patient reports often need to be completed on key elements of information that are required to assess reports. Both upstream education of patients and downstream intervention of a pharmacovigilance assessor to complete missing information could help to enhance the informativeness of such reports.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Autorrelato/normas , Adulto , Idoso , Feminino , França/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , FarmacovigilânciaRESUMO
BACKGROUND: In the field of Alzheimer's disease (AD), the validation of biomarkers for early AD diagnosis and for use as a surrogate outcome in AD clinical trials is of considerable research interest. OBJECTIVE: To characterize the clinical profile and genetic, neuroimaging and neurophysiological biomarkers of prodromal AD in amnestic mild cognitive impairment (aMCI) patients enrolled in the IMI WP5 PharmaCog (also referred to as the European ADNI study). METHODS: A total of 147 aMCI patients were enrolled in 13 European memory clinics. Patients underwent clinical and neuropsychological evaluation, magnetic resonance imaging (MRI), electroencephalography (EEG) and lumbar puncture to assess the levels of amyloid ß peptide 1-42 (Aß42), tau and p-tau, and blood samples were collected. Genetic (APOE), neuroimaging (3T morphometry and diffusion MRI) and EEG (with resting-state and auditory oddball event-related potential (AO-ERP) paradigm) biomarkers were evaluated. RESULTS: Prodromal AD was found in 55 aMCI patients defined by low Aß42 in the cerebrospinal fluid (Aß positive). Compared to the aMCI group with high Aß42 levels (Aß negative), Aß positive patients showed poorer visual (P = 0.001), spatial recognition (P < 0.0005) and working (P = 0.024) memory, as well as a higher frequency of APOE4 (P < 0.0005), lower hippocampal volume (P = 0.04), reduced thickness of the parietal cortex (P < 0.009) and structural connectivity of the corpus callosum (P < 0.05), higher amplitude of delta rhythms at rest (P = 0.03) and lower amplitude of posterior cingulate sources of AO-ERP (P = 0.03). CONCLUSION: These results suggest that, in aMCI patients, prodromal AD is characterized by a distinctive cognitive profile and genetic, neuroimaging and neurophysiological biomarkers. Longitudinal assessment will help to identify the role of these biomarkers in AD progression.
Assuntos
Doença de Alzheimer/diagnóstico , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Apolipoproteínas E/genética , Biomarcadores/líquido cefalorraquidiano , Encéfalo/diagnóstico por imagem , Eletroencefalografia , Feminino , Genótipo , Humanos , Imageamento por Ressonância Magnética , Masculino , Testes Neuropsicológicos , Fragmentos de Peptídeos/líquido cefalorraquidiano , Punção Espinal , Proteínas tau/líquido cefalorraquidianoRESUMO
After reminding the various phases of the development of molecules, this article will state the stages of commercialisation of treatments, underlining the FDA (Food and Drug Administration) and the EMA (European Medicine Agency) requirements. Like all the other treatments available in Europe and in the United States, the long acting injectable antipsychotics (LAI) have to prove their efficacy compared to placebo and their non-inferiority compared to a treatment of reference, usually the same molecule in the oral form. These criteria of efficacy have evolved over time. If initially classical criteria of symptomatic intensity (score on scale PANSS) were considered, criteria more adequate from a clinical perspective, such as relapse, but also related to functioning, quality of life and, more recently, costs-effectiveness have appeared. This evolution is probably due to several factors: vision on mental illness, progress in patient's rights and aspirations, but also the pregnant place of health costs recently taken in the evaluation of treatments. These modifications are also based on the indications of L.A.I., i.e. stabilized patients for whom the challenge is rehabilitation care more than the control of symptoms.
Assuntos
Antipsicóticos/administração & dosagem , Ensaios Clínicos como Assunto/métodos , Esquizofrenia/tratamento farmacológico , Antipsicóticos/economia , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/economia , Desenho de Fármacos , Descoberta de Drogas , Humanos , Injeções Intramusculares , Resultado do TratamentoRESUMO
As in the usual care of patients, paraclinical investigations have today only a very modest role in clinical trials in psychiatry, mainly to complete the pre-therapeutical assessments prior to inclusion of subjects or to monitor treatment tolerance. Yet, the accumulation of data in neurosciences suggests the next emergence of biomarkers, whose interest is that they are closely associated to the biological disturbances underlying psychiatric illnesses, and that they are accessible by means of technological tools such as imaging devices. These tools allow to explore the effects on brain of psychotropic medications, such as antidepressants, antipsychotics, or mood stabilizers, in relation to their therapeutic action. The obtained results allow to consider the use of such biomarkers in clinical trials in addition to more conventional approaches. In particular, they could be used as targets to measure brain response to treatment in association with clinical response, to predict a therapeutic response from the neurofunctional characteristics of patients, or to establish the safety profile of drugs on the nervous system. The use of such biomarkers in clinical trials would help to better define the explored populations and their characteristics, as well as the variables to assess, and to better measure the impact of the treatments and their potential harmful effects on the nervous system.
Assuntos
Biomarcadores Farmacológicos/análise , Ensaios Clínicos como Assunto/métodos , Monitorização Fisiológica/métodos , Neurociências/métodos , Psiquiatria/métodos , Antidepressivos/farmacocinética , Antidepressivos/uso terapêutico , Antipsicóticos/farmacocinética , Antipsicóticos/uso terapêutico , Humanos , Transtornos Mentais/diagnóstico , Transtornos Mentais/terapia , Psicotrópicos/farmacocinética , Psicotrópicos/uso terapêuticoRESUMO
To correctly interpret the results of a randomised controlled trial (RCT), practitioners have to spot bias and other potential problems present in the trial. Internal as well as external validity of the trial are linked to the presence of such bias. The internal validity is ensured by a clear definition of the objectives of the trial. The number of patients to be included in the trial is calculated on the basis of the main objective of the trial and more precisely on the basis of the primary endpoint selected to assess the efficacy of treatment. This is the best way to ensure that the statistical significance of the result may have a clinical relevance. Internal validity depends also on the process of patients selection, the methods used to ensure comparability of groups and treatments, the criteria employed to assess efficacy, and the methods for the analysis of data. External validity refers to subjects that have been excluded from the trial, limitations of RCTs, as well as the coherence and clinical relevance of the trial. Internal validity has to be fueled by external validity.
Assuntos
Interpretação Estatística de Dados , Médicos , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Viés , Humanos , Controle Interno-Externo , Papel do Médico , Ensaios Clínicos Controlados Aleatórios como Assunto/normas , Reprodutibilidade dos TestesRESUMO
Clinical trials in psychiatry allow to build the regulatory dossiers for market authorization but also to document the mechanism of action of new drugs, to build pharmacodynamics models, evaluate the treatment effects, propose prognosis, efficacy or tolerability biomarkers and altogether to assess the impact of drugs for patient, caregiver and society. However, clinical trials have shown some limitations. Number of recent dossiers failed to convince the regulators. The clinical and biological heterogeneity of psychiatric disorders, the pharmacokinetic and pharmacodynamics properties of the compounds, the lack of translatable biomarkers possibly explain these difficulties. Several breakthrough options are now available: quantitative system pharmacology analysis of drug effects variability, pharmacometry and pharmacoepidemiology, Big Data analysis, brain modelling. In addition to more classical approaches, these opportunities lead to a paradigm change for clinical trials in psychiatry.
Assuntos
Ensaios Clínicos como Assunto , Transtornos Mentais/terapia , Psiquiatria/métodos , Psiquiatria/tendências , Encéfalo/patologia , Ensaios Clínicos como Assunto/métodos , Ensaios Clínicos como Assunto/organização & administração , Ensaios Clínicos como Assunto/normas , Simulação por Computador , Humanos , Transtornos Mentais/epidemiologia , Farmacoepidemiologia , Testes Farmacogenômicos/métodos , Testes Farmacogenômicos/tendências , Projetos de Pesquisa/normas , Interface Usuário-ComputadorRESUMO
The benefits of neuromodulatory procedures as a possible therapeutic application for cognitive rehabilitation have increased with the progress made in non-invasive modes of brain stimulation in aged-related disorders. Transcranial magnetic stimulation (TMS) is a non-invasive method used to examine multiple facets of the human brain and to ameliorate the impairment in cognition caused by Alzheimer's disease (AD). The present study was designed to evaluate how a chronic TMS treatment could improve learning and memory functions after sleep deprivation (SD) in old Octodon degus. SD was executed by gently handling to keep the animals awake throughout the night. Thirty young and twenty-four old O. degus females were divided in six groups (control, acute and chronic TMS treatment). Behavioral tests included; Radial Arm Maze (RAM), Barnes Maze (BM) and Novel Object Recognition (NOR). Although learning and memory functions improved in young animals with only one session of TMS treatment, a significant improvement in cognitive performance was seen in old animals after 4 and 7days of TMS, depending on the task that was performed. No side effects were observed following, which showed therapeutic potential for improving age-related cognitive performance.
Assuntos
Envelhecimento/fisiologia , Encéfalo/fisiopatologia , Cognição/fisiologia , Memória/fisiologia , Privação do Sono/fisiopatologia , Aprendizagem Espacial/fisiologia , Animais , Comportamento Animal/fisiologia , Feminino , Octodon , Estimulação Magnética TranscranianaRESUMO
OBJECTIVE: Psychosocial trauma during childhood is associated with schizophrenia vulnerability. The pattern of grey matter decrease is similar to brain alterations seen in schizophrenia. Our objective was to explore the links between childhood trauma, brain morphology and schizophrenia symptoms. METHOD: Twenty-one patients with schizophrenia stabilized with atypical antipsychotic monotherapy and 30 healthy control subjects completed the study. Anatomical MRI images were analysed using optimized voxel-based morphometry (VBM). Childhood trauma was assessed with the Childhood Trauma Questionnaire, and symptoms were rated on the Scale for the Assessment of Negative Symptoms (SANS) and Scale for the Assessment of Positive Symptoms (SAPS) (disorganization, positive and negative symptoms). In the schizophrenia group, we used structural equation modelling in a path analysis. RESULTS: Total grey matter volume was negatively associated with emotional neglect (EN) in patients with schizophrenia. Whole-brain VBM analyses of grey matter in the schizophrenia group revealed a specific inversed association between EN and the right dorsolateral prefrontal cortex (DLPFC). Path analyses identified a well-fitted model in which EN predicted grey matter density in DLPFC, which in turn predicted the disorganization score. CONCLUSION: Our findings suggest that EN during childhood could have an impact on psychopathology in schizophrenia, which would be mediated by developmental effects on brain regions such as the DLPFC.
Assuntos
Maus-Tratos Infantis/psicologia , Substância Cinzenta/patologia , Córtex Pré-Frontal/patologia , Esquizofrenia Infantil/patologia , Esquizofrenia Hebefrênica/patologia , Adulto , Mapeamento Encefálico , Estudos de Casos e Controles , Criança , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética/métodos , Masculino , Valor Preditivo dos Testes , Psicologia , Psicologia do EsquizofrênicoRESUMO
OBJECTIVE: The present study examined whole-brain structural abnormalities in schizophrenia, with a special focus on the anterior and posterior cingulate cortex (ACC, PCC) as this is an understudied issue in schizophrenia. METHOD: Whole-brain voxel-based morphometry analyses of gray matter (GM) and white matter (WM) were performed to detect volumetric differences between 14 patients with schizophrenia and 14 healthy controls matched for age, sex, educational level and parents' educational level. We examined within-group GM and WM correlations and completed the analysis with measurements of sulci in medial cortical areas. RESULTS: Compared with the healthy controls, the schizophrenic patients showed significant decreases in GM volumes in the ACC and PCC, and in neighboring WM regions such as the corpus callosum and the fimbriae of the fornix. Moreover, the patient group also displayed a negative correlation between volumes of GM and WM in the ACC. Finally, the patients showed significantly reduced volumes in the right cingulate sulci and left inferior frontal sulci. CONCLUSION: Our results replicate typical brain-structural abnormalities with new findings in the medial prefrontal cortex, suggested to be a key region in this disorder.
Assuntos
Substância Cinzenta/patologia , Giro do Cíngulo/patologia , Esquizofrenia/patologia , Substância Branca/patologia , Adulto , Atrofia/patologia , Encéfalo/patologia , Estudos de Casos e Controles , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroimagem , Adulto JovemRESUMO
In chronic diseases such as Alzheimer's disease (AD), the arsenal of biomarkers available to determine the effectiveness of symptomatic treatment is very limited. Interpretation of the results provided in literature is cumbersome and it becomes difficult to predict their standardization to a larger patient population. Indeed, cognitive assessment alone does not appear to have sufficient predictive value of drug efficacy in early clinical development of AD treatment. In recent years, research has contributed to the emergence of new tools to assess brain activity relying on innovative technologies of imaging and electrophysiology. However, the relevance of the use of these newer markers in treatment response assessment is waiting for validation. This review shows how the early clinical assessment of symptomatic drugs could benefit from the inclusion of suitable pharmacodynamic markers. This review also emphasizes the importance of re-evaluating a step-by-step strategy in drug development.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Animais , Biomarcadores Farmacológicos , Humanos , Resultado do TratamentoRESUMO
OBJECTIVE: Patients with schizophrenia often become non-adherent following negative treatment experiences as antipsychotics'side-effects. The objective of this study was to propose an alternative measure of patients'perception of atypical antipsychotics'side-effects on weight, as weight is a major concern reported by patients. METHOD: We used a computer-assisted method called Alceste, which is a pragmatic analysis of speech. We selected three groups of ten patients respectively treated by three different atypical antipsychotics: aripiprazole, olanzapine and risperidone. Participants were administered an interview. All speeches were retranscribed and structured in a set of texts, called a corpus. Regarding antipsychotic treatment, we constituted three corpuses of ten speeches. We analyzed separately the three corpuses with the software Alceste. RESULTS: Our findings revealed the presence of a specific class dealing with treatment and illness in the speech of patients, regardless of their treatment. We found weight-related words in all three-treatment groups. The examination of the context of use showed this notion was differently employed in each treatment group: if weight was statistically associated with the notion of loss in the aripiprazole group, the reverse was found (notion of gain) in the two other treatment groups. CONCLUSION: Our findings are valuable because they contribute to validate this speech analysis method. Actually our results, which are mathematically obtained through speech analysis, are convergent with those objectively observed by clinicians. Thus we hypothesize the Alceste-software is a relevant tool to evaluate the perceptions of antipsychotic side-effects.
Assuntos
Antipsicóticos/efeitos adversos , Satisfação do Paciente , Esquizofrenia/tratamento farmacológico , Psicologia do Esquizofrênico , Software , Comportamento Verbal , Adolescente , Adulto , Antipsicóticos/uso terapêutico , Peso Corporal/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto JovemRESUMO
RATIONALE: Donepezil is a potent, noncompetitive, reversible, clinically effective acetylcholinesterase inhibitor. The effects of this drug on healthy brains have seldom been investigated. OBJECTIVES: The primary objective of the present study was to identify possible functional connectivity markers of the effect of donepezil in healthy young adult volunteers. METHODS: The study had a double-blind, randomized, crossover design. 30 healthy adult volunteers underwent resting-state MRI scans during 15 days of donepezil or placebo treatment, in accordance with the design. RESULTS: Results showed significant differences in intrinsic functional connectivity between donepezil and placebo, mainly in the right executive control network (RECN). More specifically, we found a decrease in the connectivity of the right inferior parietal node with other RECN nodes. Analysis using the cingulate cortex and parahippocampal regions as seeds also revealed complex modulation of functional connectivity in the donepezil condition. CONCLUSIONS: In conclusion, donepezil treatment for 15 days may result in reorganization of resting-state networks, compared with placebo.
Assuntos
Acetilcolinesterase , Imageamento por Ressonância Magnética , Cognição , Donepezila/farmacologia , Método Duplo-Cego , Voluntários Saudáveis , Humanos , Adulto JovemRESUMO
Modifications of antibiotic pharmacokinetic parameters have been reported in critically ill patients, resulting in a risk of treatment failure. We aimed to determine optimised amikacin (AMK), gentamicin (GEN) and tobramycin (TOB) intravenous dosing regimens in this patient population. Patients admitted to the medical ICU and treated with AMK, GEN or TOB were included. Analyses were performed using a parametric population approach. Monte Carlo simulations were performed and the probability of target attainment (PTA) was calculated using Cmax/MIC ≥ 8 and trough concentrations as targets. A total of 117 critically ill hospitalised patients were studied. Median values (interindividual variability, É·2) of clearance were 3.51 (0.539), 3.53 (0.297), 2.70 (0.339) and 5.07 (0.339) L/h for AMK, GEN, TOB, and TOB in cystic fibrosis (CF), respectively. Median values (É·2) of central volume of distribution were 30.2 (0.215), 20.0 (0.109) and 25.6 (0.177) L for AMK, GEN and TOB, respectively. Simulations showed that doses should be adjusted to actual body weight and creatinine clearance (CLCR) for AMK and GEN, and according to CLCR and presence of CF for TOB. In conclusion, our recommendations for treating Pseudomonas aeruginosa infections in this population include using initial doses of 35 mg/kg for AMK or 10 mg/kg for TOB (CF and non-CF patients). GEN demonstrated the best rates of target attainment against Staphylococcus aureus infections with a dose of 5 mg/kg. As high aminoglycoside doses are required in this population, efficacy and safety targets are conflicting and therapeutic drug monitoring remains an important tool to manage this issue.
Assuntos
Aminoglicosídeos/uso terapêutico , Antibacterianos/uso terapêutico , Infecções por Pseudomonas/tratamento farmacológico , Sepse/tratamento farmacológico , Infecções Estafilocócicas/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Amicacina/administração & dosagem , Amicacina/uso terapêutico , Aminoglicosídeos/administração & dosagem , Antibacterianos/administração & dosagem , Estado Terminal , Feminino , Gentamicinas/administração & dosagem , Gentamicinas/uso terapêutico , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Estudos Prospectivos , Pseudomonas aeruginosa/efeitos dos fármacos , Sepse/microbiologia , Staphylococcus aureus/efeitos dos fármacos , Tobramicina/administração & dosagem , Tobramicina/uso terapêutico , Adulto JovemRESUMO
RATIONALE: Studies on emotional processing report that schizophrenic patients present a specific pattern of emotional responding that usually includes deficits in emotional expressiveness, increased feelings of unpleasant emotion but decreased feelings of pleasant emotion, and increased physiological reactivity. However, studies have rarely controlled the nature of antipsychotic medication. Yet, the influence of these drugs on emotional response is uncertain and could vary depending on their pharmacological profile. OBJECTIVE: This prospective and randomized study aimed to compare the effects of an atypical antipsychotic, risperidone, to a typical one, haloperidol, on patients' emotional responding during an emotional induction task. MATERIALS AND METHODS: Twenty-five schizophrenic patients underwent two emotional and clinical evaluations: one before treatment initiation and a second 4 weeks after. Emotional states of fear, sadness, anger, joy, and disgust were induced, as well as a neutral baseline state. Video recordings of patients during the induction task allowed for assessment of emotional expressiveness. Self-reports and measures of skin conductance and heart rate were performed to determine both subjective and physiological reactions to emotional experience. RESULTS: Compared to haloperidol, risperidone did not reduce patients' facial expressiveness, decreased physiological reactivity, and decreased experience of unpleasant emotion but maintained experience of pleasant emotion. Emotional expressiveness was negatively correlated to parkisonism. CONCLUSIONS: Our preliminary results suggest that atypical antipsychotics allow for better-adapted patterns of emotional responding than typical ones do. We suggest that this effect is due to reduced striatal D2 blockade, therefore, attenuating akinesia, coupled with increased 5HT and DA levels in prefrontal cortex, which improves emotional regulation.
Assuntos
Antipsicóticos/farmacologia , Emoções/efeitos dos fármacos , Haloperidol/farmacologia , Risperidona/farmacologia , Esquizofrenia/tratamento farmacológico , Adolescente , Adulto , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Dopamina/metabolismo , Antagonistas dos Receptores de Dopamina D2 , Expressão Facial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Psicologia do Esquizofrênico , Serotonina/metabolismo , Gravação em Vídeo , Adulto JovemRESUMO
BACKGROUND: The application of population pharmacokinetic models and Bayesian methods offers the potential to develop individualized therapeutic approaches. OBJECTIVES: The current study presents an external evaluation of a vancomycin pharmacokinetic model in a pediatric cancer population and proposes an easy-to-use chart for clinicians for a priori vancomycin schedule adaptation to achieve target concentration. METHODS: External evaluation of a population pharmacokinetic model of vancomycin administered via continuous infusion was realized in a new retrospective dataset of pediatric patients with cancer. The published population pharmacokinetic model was implemented in NONMEM 7.3 with the structural and variance parameter values set equal to estimates previously reported. Predictive performance was assessed by quantifying bias and accuracy of model prediction. Normalized prediction distribution errors were also evaluated. Dosage simulations were performed according to the target concentration. RESULTS: A total of 77 patients were included in this study, representing 146 vancomycin courses and 289 concentrations. The model adequately predicted vancomycin concentrations (median prediction error % of - 9.4%, median |PE|% of 24.1%). Based on simulation results, vancomycin dosage (mg/kg) should be adapted for each child on the basis of body weight and cyclosporine coadministration. CONCLUSION: The model previously proposed by Guilhaumou et al. in pediatric patients with solid or hematological malignant disease was externally validated. Simulations have enabled the description of new dosage schedules and creation of a chart to help clinicians adapt vancomycin dosage.
Assuntos
Antibacterianos/farmacocinética , Cálculos da Dosagem de Medicamento , Neoplasias Hematológicas/sangue , Modelos Biológicos , Vancomicina/farmacocinética , Antibacterianos/administração & dosagem , Teorema de Bayes , Criança , Pré-Escolar , Monitoramento de Medicamentos , Emolientes , Feminino , Humanos , Masculino , Neoplasias/sangue , Estudos Retrospectivos , Vancomicina/administração & dosagemRESUMO
Schizophrenia is characterized by cognitive, social, and emotional impairments and by psychotic symptoms. Neuroimaging studies have reported abnormalities within the prefrontal cortex and it has been hypothesized that schizophrenia results from poor or miswired anatomical/functional connections. We have compared the functional connectivity within the frontal cortex in control and schizophrenic subjects during the realization of a Continuous Performance Task. The connectivity pattern within the frontal cortex was uncovered by the analysis of the correlation matrix computed from the fMRI time series in frontal areas for 14 schizophrenic patients and 14 control subjects. In control subjects, the right dorsolateral prefrontal cortex (DLFCr) activity correlated i) positively with the left dorsolateral prefrontal cortex and the posterior part of the supplementary motor area, ii) negatively with the medial and anterior/inferior part of the frontal cortex. In the schizophrenic group, these relations were abolished or strongly lowered. The negative relation between the DLFCr and the medial frontal cortex has been proposed to play a key role in setting a harmonious balance between the direction of attention to the external world and the expression of the individual believes and self-referential activities, and therefore, the impaired relation of right DLFCr with other frontal areas could explain a distorted perception of external world in relation with internal motivations.
Assuntos
Lobo Frontal/fisiopatologia , Esquizofrenia/fisiopatologia , Adulto , Atenção/fisiologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Rede Nervosa/fisiopatologia , Córtex Pré-Frontal/fisiopatologiaRESUMO
OBJECTIVES: The objective of this study is to evaluate the validity of a new self questionnaire: the "ESQ" (Emotional State Questionnaire). BACKGROUND: This novel instrument possesses a number of original attributes: first of all, it is designed to assess a general emotional profile, in opposition to other similar scales which can only be applied to the emotional reactions provoked by specific stimuli. Secondly, this scale is composed of several emotional dimensions. The ESQ has been constructed according to four components: recognition, expression, internal emotional experience and social context. The first three dimensions were selected because of their wide use through behavioral experiments. Indeed, contrary to most scales used in this field, which only assess the emotional experience, we wanted to propose an instrument also able to assess the subject's impression of his own capacities to encode and decode emotions. We hypothesized that these three dimensions could not be dissociated from a fourth dimension, the social context, which therefore also figures in this scale. The emotions explored were the five fundamental emotions indicated by Izard (fear, happiness, sadness, disgust and surprise) to which we added a neutral feeling that we considered as a basic emotion. STUDY DESIGN: To establish this instrument, a first conceptual phase was conducted by a group of experts. These experts all worked in the psychological field. They proposed the scale on the base of their clinical experience and after study of the literature. The scale was then validated in a population of 218 healthy volunteers, aged between 15 and 88 years. Subjects were not included if they presented depression (score above 16 in the Beck Depression Scale) or pathological anxiety (score above 5 in the Spieberger State Anxiety Inventory). The psychometric characteristics tested were: the item analysis, the item-dimension correlation, the factor analysis and the internal consistency reliability. RESULTS: The population studied was equally distributed according to gender (sex ratio: 0.97), the mean age was of 36.2 2 +/- 16.1 years. Acceptability was good with less than 5% of data missing. The analysis of items revealed no floor or ceiling effect and a low correlation between items. Item-dimension correlation ranged from 0.23 to 0.62, with most scores above 0.4. The items were always better correlated to their dimension than to other dimensions, except for one item. The 4 dimensions (recognition, expression, internal emotional experience and social context of emotions) explained 42% of the total variance. Finally, the scale showed good internal consistency with Cronbach coefficients, equal or above 0.84 for the total score, the recognition and the expression dimensions. This coefficient reached 0.77 for the feeling dimension but only 0.58 for the social context dimension. CONCLUSION: All together, results showed satisfactory characteristics in regard of the complexity of the notion measured. However, an important drawback is the lack of an external instrument to assess convergent validity. This instrument can be of great interest in the emotional characterization of healthy volunteers. More-over, if validated in psychiatric populations, this scale could be most useful in psychopathological assessment and also in comparison with behavioral evaluations of emotion.