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4.
Therapie ; 74(1): 103-117, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30745156

RESUMO

In a context of perpetual evolution of treatments, access to therapeutic innovation is a major challenge for patients and the various players involved in the procedures of access to medicines. The revolutions in genomic and personalized medicine, artificial intelligence and biotechnology will transform the medicine of tomorrow and the organization of our health system. It is therefore fundamental that France prepares for these changes and supports the development of its companies in these new areas. The recent "Conseil stratégique des industries de santé" launched by Matignon makes it possible to propose a regulatory arsenal conducive to the implementation and diffusion of therapeutic innovations. In this workshop, we present a number of proposals, our approach having remained pragmatic with a permanent concern to be effective in the short term for the patients and to simplify the procedures as much as possible. This was achieved thanks to the participation in this workshop of most of the players involved (industrial companies, "Agence nationale de sécurité du médicament et des produits de santé", "Haute Autorité de santé", "Institut national du cancer", "Les entreprises du médicament", hospitals, "Observatoire du médicament, des dispositifs médicaux et de l'innovation thérapeutique"…). The main proposals tend to favor the implementation of clinical trials on our territory, especially the early phases, a wider access to innovations by favoring early access programs and setting up a process called "autorisation temporaire d'utilisation d'extension" (ATUext) that make it possible to prescribe a medicinal product even if the latter has a marketing authorisation in another indication. In addition, we propose a conditional reimbursement that will be available based on preliminary data but will require re-evaluation based on consolidated data from clinical trials and/or real-life data. Finally, in order to better carry out these assessments, with a view to access or care, we propose the establishment of partnership agreements with health agencies/hospitals in order to encourage the emergence of field experts, in order to prioritize an ascending expertise closer to patients' needs and to real life.


Assuntos
Setor de Assistência à Saúde/legislação & jurisprudência , Ensaios Clínicos como Assunto/legislação & jurisprudência , Aprovação de Equipamentos , Difusão de Inovações , Aprovação de Drogas , França , Órgãos dos Sistemas de Saúde , Hospitais , Humanos
6.
Medicine (Baltimore) ; 97(30): e11413, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-30045263

RESUMO

The aim of this study was to determine the characteristics, treatment, and outcome according to each etiology of pachymeningitis.We conducted a retrospective multicenter French nationwide study between 2000 and 2016 to describe the characteristics, outcome, and treatment of pachymeningitis.We included 60 patients (median age 55.5 years; interquartile range [IQR] 30-80, female/male ratio 0.43). Neurologic signs were present in 59 patients (98%) and consisted of headache in 43 (72%), cranial nerve palsy in 33 (55%), confusion in 10 (17%), seizures in 7 (12%), and focal neurologic signs in 9 (15%). Fever and weight loss were present in 8 (13%) and 13 cases (22%), respectively. Cerebral venous thrombosis was present in 8 cases (13%). Analysis of cerebrospinal fluid showed moderate hyperproteinorachia (median 0.68 g/L; IQR 0.46-3.2) with or without pleiocytosis. Diagnosis included idiopathic pachymeningitis (n = 18; 30%); granulomatosis with polyangiitis (n = 13; 17%); Erdheim-Chester disease (n = 10; 17%); IgG4-related disease and tuberculosis (n = 3; 5% each); Rosai-Dofman disease, microscopic polyangiitis, and sarcoidosis (n = 2, 3% each); cryptococcal meningitis, Lyme disease, ear-nose-throat infection, postlumbar puncture, low spinal-fluid pressure syndrome, and lymphoma (n = 1 each). We found no difference in demographics and neurologic presentation among idiopathic pachymeningitis, Erdheim-Chester disease, and granulomatosis with polyangiitis. In contrast, frequencies were lower with idiopathic pachymeningitis than Erdheim-Chester disease for general signs (6% and 40%, respectively, P = .041) and complete neurologic response (0% vs 39%, P = .045).The detection of extraneurologic signs and routine screening are needed to classify the pachymeningitis origin. Prospective studies are warranted to determine the best treatment in each case.


Assuntos
Granulomatose com Poliangiite , Meningite , Proteínas do Líquido Cefalorraquidiano/análise , Diagnóstico Diferencial , Gerenciamento Clínico , Feminino , França/epidemiologia , Granulomatose com Poliangiite/diagnóstico , Granulomatose com Poliangiite/epidemiologia , Humanos , Masculino , Meningite/diagnóstico , Meningite/epidemiologia , Meningite/fisiopatologia , Meningite/terapia , Pessoa de Meia-Idade , Exame Neurológico/métodos , Estudos Retrospectivos , Avaliação de Sintomas
7.
Presse Med ; 47(2): e15-e23, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29478794

RESUMO

OBJECTIVES: Guidelines recommend routine universal HIV testing in adults to reduce the pool of infected patients unaware of their status, without specific recommendations concerning the method. We compared acceptability and feasibility of HIV testing by ELISA tests or rapid tests from finger-stick whole blood. METHODS: Prospective randomized multi-center study comparing acceptability and feasibility of routine universal HIV testing by ELISA tests, with a charge, subsequently reimbursed by Social Security for affiliated patients, or rapid tests from finger-stick whole blood, without any charge from the patients or the general practitioner for the study. A single investigator performed all interventions. After consent, all adults (18-70 years old) consulting their general practitioner in Paris, France, unaware of their status, were enrolled. Testing was performed immediately for the patients in the rapid test arm; a prescription was given for testing in a lab for the patients in the ELISA arm. The primary endpoint was acceptability of each method. The secondary endpoint was feasibility of each method, assessed one month after the consultation. RESULTS: Two hundred and seventy patients were enrolled: 133 patients in the ELISA arm, 137 in the rapid test arm. Acceptability of the rapid test (92%) was higher than that of the ELISA (63.9%), P<0.0001. Feasibility of the rapid test (100%) was higher than that of the ELISA (50.5%), P<0.0001. A center effect was shown concerning feasibility of ELISA but not concerning feasibility of rapid tests. CONCLUSION: Rapid testing from finger-stick whole blood is more acceptable and feasible than ELISA for routine universal HIV testing. A larger use of rapid tests, ideally free of charge, by general practitioners could reduce the pool of infected patients unaware of their status.


Assuntos
Coleta de Amostras Sanguíneas , Testes Diagnósticos de Rotina , Medicina Geral , Infecções por HIV/diagnóstico , Programas de Rastreamento , Aceitação pelo Paciente de Cuidados de Saúde , Adulto , Coleta de Amostras Sanguíneas/métodos , Coleta de Amostras Sanguíneas/psicologia , Testes Diagnósticos de Rotina/métodos , Testes Diagnósticos de Rotina/psicologia , Teste em Amostras de Sangue Seco/métodos , Ensaio de Imunoadsorção Enzimática , Estudos de Viabilidade , Feminino , Dedos , Medicina Geral/métodos , HIV/isolamento & purificação , Infecções por HIV/sangue , Humanos , Masculino , Programas de Rastreamento/métodos , Programas de Rastreamento/psicologia , Pessoa de Meia-Idade , Testes Sorológicos/métodos , Testes Sorológicos/psicologia
8.
Therapie ; 73(3): 185-191, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29395300

RESUMO

BACKGROUND: To compare the steady state plasma concentrations (Css) of three antiretroviral drugs in both normal and overweight patients, and to determine the relationship between Css and fat mass (FM) or lean body mass. METHODS: Patients treated for more than 6 months once daily with one of the antiretroviral drugs: efavirenz (EFV) 600mg, atazanavir boosted with ritonavir (ATV-r) 300mg/100mg, or darunavir boosted with ritonavir (DRV-r) 800mg/100mg, combined with two nucleoside analogues, were enrolled prospectively. One at steady state, plasma samples for the assessment of drug concentration were taken and body composition was assessed by bioelectrical impedance. RESULTS: One hundred and thirty-nine patients were enrolled (46, 45 and 48 in the groups EFV, ATV-r and DRV-r respectively). Their mean age was 46.2±10.4 years, 58% were male, 55.4% were from Sub Sahara African (SSA); body mass index (BMI) was 25.4±4.4kg/m2. Mean drug plasma Css of the three drugs did not differ according to BMI group. DRV-r Css tended to be higher in patients with BMI≥25kg/m2 (2896.7±1689 versus 2091.9±1038, P=0.09) and was significantly correlated with FM (r=0.3, P=0.02). In subgroup analysis, the effect of FM on DRV-r Css was significant in patients from SSA (r=0.4, P=0.04). CONCLUSIONS: Css result from many factors and body composition has been shown to only weakly influence interindividual variability but should be investigated in morbidly obese patients treated with DRV-r.


Assuntos
Fármacos Anti-HIV/farmacocinética , Sulfato de Atazanavir/farmacocinética , Benzoxazinas/farmacocinética , Composição Corporal/fisiologia , Peso Corporal/fisiologia , Darunavir/farmacocinética , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sobrepeso/metabolismo
9.
Am J Med ; 131(3): 319-322, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29061498

RESUMO

BACKGROUND: Blood test results required for the evaluation of anemia are considered difficult to interpret after red blood cell transfusion. However, this hypothesis is neither supported by a strong physiological rationale nor is it evidence based. METHODS: We conducted a prospective multicenter study to compare the values of key assays prior to and after a course of red blood cell transfusion in the emergency or internal medicine units in 4 university hospitals. The following parameters were measured prior to and within 48 to 72 hours after transfusion: complete blood count with reticulocyte count, direct Coombs' test, ferritin, transferrin saturation, soluble transferrin receptor, serum and erythrocyte folate, cobalamin, lactate dehydrogenase, bilirubin, haptoglobin, and C-reactive protein. We investigated the impact of transfusion on these parameters and assessed whether abnormal values prior to the transfusion became normal after transfusion (or conversely). RESULTS: There were 77 patients included in the study. Changes in mean values of mean corpuscular volume, soluble transferrin receptor, erythrocyte folate, cobalamin, haptoglobin, lactate dehydrogenase, C-reactive protein, and direct Coombs' test were not statistically significant. Changes in reticulocyte count, ferritin, transferrin saturation, serum folate, and total bilirubin concentrations were statistically significant, but they remained in the same diagnostic category (normal or abnormal) in 79% to 98% of the cases; 97% of patients with iron deficiency still had low ferritin or transferrin saturation after a transfusion. CONCLUSION: Blood tests performed after a one-time red blood cell transfusion can be used to establish the cause of anemia when they have not been performed before.


Assuntos
Anemia/sangue , Anemia/etiologia , Biomarcadores/sangue , Transfusão de Eritrócitos , Proteínas da Fase Aguda/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/terapia , Bilirrubina/sangue , Contagem de Células Sanguíneas , Feminino , Ácido Fólico/sangue , Humanos , Proteínas de Ligação ao Ferro/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Vitamina B 12/sangue
10.
Liver Int ; 38(4): 611-618, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28834623

RESUMO

BACKGROUND & AIMS: Hepatitis B Virus (HBV) DNA during chronic infection can reach levels at which mother-to-child (MTC) transmission frequently occurs despite passive-active immunization of newborns. Hepatitis D Virus (HDV) RNA can reach high levels, we assessed HBV/HDV MTC co-transmission. METHODS: Monocentric retrospective study (registered in ClinicalTrials.gov (NCT02044055)), after informed consent in HBV/HDV co-infected women pregnant between 01/01/2004 and 01/01/2015 in Paris, France. The children were tested when 24 months of age or older. RESULTS: Twenty-two (3%) of 742 HBV infected women, HDV co-infected, gave birth to 54 children during the study period. HBV DNA was above 5 Log10 I.U/mL in 10 pregnancies previous any treatment, with HDV RNA of less than 2.3 Log10 I.U/mL. HDV RNA was above 5 Log10 I.U/mL in eight pregnancies previous any treatment, with HBV DNA of less than 1.5 Log10 I.U/mL. Inverse patterns of HBV DNA and HDV RNA were observed in 17 of 35 (49%) pregnancies: 13 (76%) received no HBV treatment; four (24%) were treated. HBV DNA was under 5 Log10 I.U/mL in 46 of the 50 assessed women (92%) at birth. Of the 36 assessed children, given passive-active immunization, 24 (66%) were protected, 10 (28%) were neither infected nor protected, one was chronically HBV infected, and one had a past HBV infection. HDV Ab was negative in the 36 children. CONCLUSIONS: These results suggest that HBV/HDV MTC co-transmission is exceptional. Studies are needed, mainly in developing countries.


Assuntos
Antivirais/uso terapêutico , Hepatite B Crônica/transmissão , Hepatite D/transmissão , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Transmissão Vertical de Doença Infecciosa/estatística & dados numéricos , Adulto , Criança , Pré-Escolar , Coinfecção/tratamento farmacológico , DNA Viral/sangue , Países Desenvolvidos , Feminino , Anticorpos Anti-Hepatite/sangue , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B , Hepatite B Crônica/tratamento farmacológico , Hepatite D/tratamento farmacológico , Vírus Delta da Hepatite , Humanos , Imunização Passiva/estatística & dados numéricos , Lactente , Masculino , Paris , Gravidez , Estudos Retrospectivos , Carga Viral , Adulto Jovem
12.
Therapie ; 72(1): 51-61, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28159197

RESUMO

Estimating net benefit makes possible to clarify the basis for therapeutic decisions on an individual and collective level. This clarification is a must in shared medical decision-making and evidence-based medicine. Numerous methods are available, although none outweigh the others. The complex specifications of net benefit estimation should be tailored to the expectations of the central stakeholder, patient or society, and the unlimited range of potential contexts. The challenges, limitations, constraints and skills to be acquired by all stakeholders were discussed by the participants of the round table. They are described in this article, enabling key messages and guidelines to be presented. The essential priority is to ensure that all stakeholders receive the required training.


Assuntos
Tomada de Decisões , Medição de Risco , Medicina Baseada em Evidências , Humanos
14.
BMC Geriatr ; 17(1): 34, 2017 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-28125958

RESUMO

BACKGROUND: Data are available on short- and intermediate-term mortality rates after discharge for acutely decompensated heart failure (ADHF). However, few studies specifically addressed ADHF outcomes in patients aged 75 years or over, who contribute more than half of all ADHF admissions. Our objectives here were to estimate the long-term mortality of patients aged 75 years or over who were discharged after admission for ADHF and to identify factors, especially geriatric findings, independently associated with 2-year mortality. METHODS: This prospective cohort study in five French hospitals included consecutive patients aged 75 years or older and discharged after emergency-department admission for ADHF meeting Framingham criteria (N = 478; median age, 85 years; 68% female). Kaplan-Meier 1-year and 2-year survival curves were plotted. Admission characteristics independently associated with overall 2-year mortality were identified using multivariable Cox proportional-hazards regression. RESULTS: Mortality was 41.7% (95% confidence interval [95% CI], 37.2%-53.5%) after 1 year and 56.0% (95% CI, 51.5%-60.7%) after 2 years. By multivariable analysis, independent predictors of 2-year mortality were male sex (hazard ratio [HR], 1.36; 95% CI, 1.00-1.82), age >85 years (HR, 1.57; 95% CI, 1.19-2.07), higher number of impaired activities of daily living (HR, 1.11 per impaired item; 95% CI, 1.05-1.17), recent weight loss (HR, 1.61; 95% CI, 1.14-2.28), and lower systolic blood pressure (HR, 0.86 per standard deviation increase; 95% CI, 0.74-0.99). Creatinine clearance ≤30 mL/min showed a trend toward an association with 2-year mortality (HR, 1.36; 95% CI, 0.97-2.00). CONCLUSION: Functional impairment before admission is associated with higher long-term mortality in patients ≥75 years admitted for ADHF. This study focused on geriatric markers not traditionally collected in heart-failure patients but did not analyse all cardiologic parameters associated with outcomes in other studies. Nevertheless, our findings may contribute to identify those patients admitted for ADHF who have the worst prognosis.


Assuntos
Insuficiência Cardíaca , Efeitos Adversos de Longa Duração/mortalidade , Alta do Paciente/estatística & dados numéricos , Atividades Cotidianas , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , França/epidemiologia , Avaliação Geriátrica/métodos , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/terapia , Humanos , Masculino , Modelos de Riscos Proporcionais , Estudos Prospectivos , Exacerbação dos Sintomas
15.
Pharmacol Res ; 118: 64-70, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27609660

RESUMO

The purpose of the present work was to study the change in morphine metabolic ratio in obese subjects before and after Roux-en-Y Gastric Bypass (RYGB) and to identify clinical and/or biological factors associated with this change. The pharmacokinetics (PK) of oral morphine (30mg), morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) was performed in patients before (n=25; mean BMI=43.2 (35.4-61.9)kg/m2), 7-15days (n=16) and 6 months after RYGB (n=19; mean BMI=32.3 (25.4-46.0)kg/m2). Morphine Cmax and AUC0-inf were significantly increased and morphine Tmax significantly shortened at 6 months after RYGB compared with preoperative data, indicating an important increase in the rate and extent of morphine absorption. The morphine metabolic ratio 0-inf M3G+M6G/Morphine, decreased significantly from the preoperative to 6 months postoperative period with an average of -26% (range -74%; +21%; p=0.004), but not in the immediate post-operative period. The change in morphine metabolic ratio was associated with a change in BMI, fat mass in kg, and triglyceride levels (rho=0.5, p≤0.04). The degree of change in several markers of low-grade inflammation, or the level of liver steatosis and fibrosis before surgery, was not associated with the change in morphine metabolic ratios. Our findings indicate that RYGB-induced weight loss significantly decreases morphine metabolic ratio, arguing for an effect of morbid obesity on glucuronidation. With glucuronide exposure at 6 months similar to preoperative values, a higher morphine AUC0-inf should encourage reducing morphine dosage in patients undergoing RYGB and chronically receiving immediate-release oral morphine.


Assuntos
Derivados da Morfina/metabolismo , Morfina/metabolismo , Obesidade Mórbida/metabolismo , Feminino , Derivação Gástrica , Humanos , Masculino , Obesidade Mórbida/cirurgia
16.
Eur J Gastroenterol Hepatol ; 29(3): 259-263, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27879486

RESUMO

BACKGROUND: The risk of vertical transmission of hepatitis B virus (HBV) increases as maternal HBV DNA increase, despite serovaccination to newborns. METHODS: From 1 July 2012 to 1 January 2016, all pregnant women in Lariboisiere Hospital, Paris, France, with HBV DNA of 5 log10 IU/ml and above were administered tenofovir from week 28 of pregnancy until delivery. HBV DNA was measured at months 1, 2 of tenofovir and at delivery. The newborns were serovaccinated, tested for hepatitis B surface antigen, hepatitis B core antibody (HBcAb)±HBV DNA, and hepatitis B surface antibody (HBsAb) when aged 9 months, and then 24 months. This study was registered in http://www.ClinicalTrials.gov (NCT02039362). RESULTS: Thirty-one women gave birth to 37 newborns. Maternal HBV DNA at baseline was 8.23 log10 IU/ml and above in 12 pregnancies. The mean (median) HBV DNA were 4.4±1.2 (4.8), 3.3±1.7 (3.8), and 2.1±1.9 (2.0) log10 IU/ml at months 1, 2 of tenofovir and at delivery, respectively. Twenty-seven newborns were followed up: none of the 19 children aged 9 months or older was positive for hepatitis B surface antigen when aged 9 months; 14 children tested positive for HBcAb (probably transferred maternal antibodies, not found when aged 24 months) and for HBsAb without HBV DNA. Four of the 19 children showed HBsAb without HBcAb, the last being doubtful for HBcAb and HBsAb without HBV DNA. Eight newborns aged less than 9 months were not tested. CONCLUSION: Tenofovir from week 28 of pregnancy to highly viremic HBV women plus serovaccination to newborns could prevent chronic and past infection.


Assuntos
Antivirais/administração & dosagem , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B/tratamento farmacológico , Hepatite B/transmissão , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Complicações Infecciosas na Gravidez/tratamento farmacológico , Tenofovir/administração & dosagem , Viremia/tratamento farmacológico , Viremia/transmissão , Antivirais/efeitos adversos , Biomarcadores/sangue , Pré-Escolar , DNA Viral/sangue , Esquema de Medicação , Feminino , Hepatite B/diagnóstico , Anticorpos Anti-Hepatite B/sangue , Antígenos do Núcleo do Vírus da Hepatite B/imunologia , Antígenos de Superfície da Hepatite B/sangue , Vacinas contra Hepatite B/administração & dosagem , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Vírus da Hepatite B/patogenicidade , Humanos , Lactente , Recém-Nascido , Paris , Gravidez , Complicações Infecciosas na Gravidez/diagnóstico , Complicações Infecciosas na Gravidez/virologia , Segundo Trimestre da Gravidez , Terceiro Trimestre da Gravidez , Estudos Prospectivos , Tenofovir/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Carga Viral , Viremia/diagnóstico
17.
Pain Physician ; 19(5): E729-41, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27389116

RESUMO

BACKGROUND: The frequency of chronic postsurgical pain (CPSP) after knee replacement remains high, but might be decreased by improvements to prevention. OBJECTIVES: To identify pre- and postsurgical factors predictive of CPSP 6 months after knee replacement. STUDY DESIGN: Single-center prospective observational study. SETTING: An orthopedic unit in a French hospital. METHODS: Consecutive patients referred for total or unicompartmental knee arthroplasty from March to July 2013 were prospectively invited to participate in this study. For each patient, we recorded preoperative pain intensity, anxiety and depression levels, and sensitivity and pain thresholds in response to an electrical stimulus. We analyzed OPRM1 and COMT single-nucleotide polymorphisms. Acute postoperative pain (APOP) in the first 5 days after surgery was modeled by a pain trajectory. Changes in the characteristics and consequences of the pain were monitored 3 and 6 months after surgery. Bivariate analysis and multivariate logistic regression were conducted to identify predictors of CPSP. RESULTS: We prospectively evaluated 104 patients in this study, 74 (28.8%) of whom reported CPSP at 6 months. Three preoperative factors were found to be associated with the presence of CPSP in multivariate logistic regression analysis: high school diploma level (OR = 3.83 [1.20 - 12.20]), consequences of pain in terms of walking ability, as assessed with the Brief Pain Inventory short form "walk" item (OR = 4.06 [1.18 - 13.94]), and a lack of physical activity in adulthood (OR = 4.01 [1.33 - 12.10]). One postoperative factor was associated with the presence of CPSP: a high-intensity APOP trajectory. An association of borderline statistical significance was found with the A allele of the COMT gene (OR = 3.4 [0.93 - 12.51]). Two groups of patients were identified on the basis of their APOP trajectory: high (n = 28, 26%) or low (n = 80, 74%) intensity. Patients with high-intensity APOP trajectory had higher anxiety levels and were less able to walk before surgery (P < 0.05). LIMITATIONS: This was a single-center study and the sample may have been too small for the detection of some factors predictive of CPSP or to highlight the role of genetic factors. CONCLUSION: Our findings suggest that several preoperative and postoperative characteristics could be used to facilitate the identification of patients at high risk of CPSP after knee surgery. All therapeutic strategies decreasing APOP, such as anxiety management or performing knee replacement before the pain has a serious effect on ability to walk, may help to decrease the risk of CPSP. Further prospective studies testing specific management practices, including a training program before surgery, are required.


Assuntos
Artroplastia do Joelho/efeitos adversos , Dor Crônica , Dor Pós-Operatória , Idoso , Dor Crônica/diagnóstico , Dor Crônica/etiologia , Dor Crônica/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dor Pós-Operatória/diagnóstico , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/genética , Estudos Prospectivos , Fatores de Risco
18.
Mol Pharm ; 13(8): 2631-40, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27347605

RESUMO

Protein expression levels of drug-metabolizing enzymes and transporters in human jejunal tissues excised from morbidly obese subjects during gastric bypass surgery were evaluated using quantitative targeted absolute proteomics. Protein expression levels of 15 cytochrome P450 (CYP) enzymes, 10 UDP-glucuronosyltransferase (UGT) enzymes, and NADPH-P450 reductase (P450R) in microsomal fractions from 28 subjects and 49 transporters in plasma membrane fractions from 24 of the same subjects were determined using liquid chromatography-tandem mass spectrometry. Based on average values, UGT1A1, UGT2B15, UGT2B17, SGLT1, and GLUT2 exhibited high expression levels (over 10 fmol/µg protein), though UGT2B15 expression was detected at a high level in only one subject. CYP2C9, CYP2D6, CYP3A5, UGT1A6, P450R, ABCG2, GLUT5, PEPT1, MCT1, 4F2 cell-surface antigen heavy chain (4F2hc), LAT2, OSTα, and OSTß showed intermediate levels (1-10 fmol/µg protein), and CYP1A1, CYP1A2, CYP1B1, CYP2C18, CYP2C19, CYP2J2, CYP3A7, CYP4A11, CYP51A1, UGT1A3, UGT1A4, UGT1A8, UGT2B4, ABCC1, ABCC4, ABCC5, ABCC6, ABCG8, TAUT, OATP2A1, OATP2B1, OATP3A1, OATP4A1, OCTN1, CNT2, PCFT, MCT4, GLUT4, and SLC22A18 showed low levels (less than 1 fmol/µg protein). The greatest interindividual difference (364-fold) was detected for UGT2B17. However, differences in expression levels of other quantified UGTs (except UGT2B15 and UGT2B17), CYPs (except CYP1A1 and CYP3A5), and P450R, and all quantified transporters, were within 10-fold. Expression levels of CYP1A2 and GLUT4 were significantly correlated with body-mass index. The levels of 4F2hc showed significant gender differences. Smokers showed increased levels of UGT1A1 and UGT1A3. These findings provide a basis for understanding the changes in molecular mechanisms of jejunal metabolism and transport, as well as their interindividual variability, in morbidly obese patients.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Glucuronosiltransferase/metabolismo , Jejuno/metabolismo , Obesidade Mórbida/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/metabolismo , Feminino , Transportador de Glucose Tipo 2/metabolismo , Transportador de Glucose Tipo 5/metabolismo , Humanos , Técnicas In Vitro , Intestino Delgado/metabolismo , Masculino , Antígenos de Histocompatibilidade Menor/metabolismo , Proteínas de Neoplasias/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Transportador 1 de Peptídeos , Transportador 1 de Glucose-Sódio/metabolismo , Simportadores
19.
Mol Pharm ; 13(3): 766-73, 2016 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-26751618

RESUMO

The objective of our work was to study the association between the jejunal expression levels of P-gp, MRP2, MRP3, UGT2B7, CYP3A4, the ABCB1 c.3435C > T polymorphism, and several obesity-associated biomarkers, as well as oral morphine and glucuronides pharmacokinetics in a population of morbidly obese subjects. The pharmacokinetics of oral morphine (30 mg) and its glucuronides was performed in obese patients candidate to bariatric surgery. A fragment of jejunal mucosa was preserved during surgery. Subjects were genotyped for the ABCB1 single nucleotide polymorphism (SNP) c.3435C > T. The subjects were 6 males and 23 females, with a mean body mass index of 44.8 (35.4-61.9) kg/m(2). The metabolic ratios AUC0-inf M3G/morphine and AUC0-inf M6G/morphine were highly correlated (rs = 0.8, p < 0.0001) and were 73.2 ± 24.6 (34.7-137.7) and 10.9 ± 4.1 (3.8-20.6). The pharmacokinetic parameters of morphine and its glucuronides were not associated with the jejunal contents of P-gp, CYP3A4, MRP2, and MRP3. The jejunal content of UGT2B7 was positively associated with morphine AUC0-inf (rs = 0.4, p = 0.03). Adiponectin was inversely correlated with morphine Cmax (rs = -0.44, p = 0.03). None of the factors studied was associated with morphine metabolic ratios. The interindividual variability in the jejunal content of drug transporters and metabolizing enzymes, the ABCB1 gene polymorphism, and the low-grade inflammation did not explain the variability in morphine and glucuronide exposure. High morphine metabolic ratio argued for an increased morphine glucuronidation in morbidly obese patients.


Assuntos
Analgésicos Opioides/farmacocinética , Biomarcadores/análise , Glucuronídeos/farmacocinética , Jejuno/metabolismo , Morfina/farmacocinética , Obesidade Mórbida/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Administração Oral , Adolescente , Adulto , Analgésicos Opioides/administração & dosagem , Índice de Massa Corporal , Citocromo P-450 CYP3A , Feminino , Glucuronídeos/administração & dosagem , Glucuronosiltransferase/metabolismo , Humanos , Jejuno/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Morfina/administração & dosagem , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Obesidade Mórbida/tratamento farmacológico , Polimorfismo de Nucleotídeo Único/genética , Distribuição Tecidual , Adulto Jovem
20.
Medicine (Baltimore) ; 95(2): e2372, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26765411

RESUMO

Several studies have focused on the clinical and biological characteristics of meningitis in order to distinguish between bacterial and viral meningitis in the emergency setting. However, little is known about the etiologies and outcomes of aseptic meningitis in patients admitted to Internal Medicine.The aim of the study is to describe the etiologies, characteristics, and outcomes of aseptic meningitis with or without encephalitis in adults admitted to an Internal Medicine Department.A retrospective cohort study was conducted in the Internal Medicine Department of the Lariboisière Hospital in Paris, France, from January 2009 to December 2011. Clinical and biological characteristics of aseptic meningitis were recorded. These included cerebrospinal fluid analysis, results of polymerase chain reaction testing, final diagnoses, and therapeutic management.The cohort included 180 patients fulfilling the criteria for aseptic meningitis with (n = 56) or without (n = 124) encephalitis. A definitive etiological diagnosis was established in 83 of the 180 cases. Of the cases with a definitive diagnosis, 73 were due to infectious agents, mainly enteroviruses, Herpes Simplex Virus 2, and Varicella Zoster Virus (43.4%, 16.8%, and 14.5% respectively). Inflammatory diseases were diagnosed in 7 cases. Among the 97 cases without definitive diagnoses, 26 (26.8%) remained free of treatment throughout their management whereas antiviral or antibiotic therapy was initiated in the emergency department for the remaining 71 patients. The treatment was discontinued in only 10 patients deemed to have viral meningitis upon admission to Internal Medicine.The prevalence of inflammatory diseases among patients admitted to internal medicine for aseptic meningitis is not rare (4% of overall aseptic meningitis). The PCR upon admission to the emergency department is obviously of major importance for the prompt optimization of therapy and management. However, meningitis due to viral agents or inflammatory diseases could also be distinguished according to several clinical and biological characteristics highlighted in this retrospective study. As recommendations are now available concerning the prescriptions of antiviral agents in viral meningitis, better therapeutic management is expected in the future.


Assuntos
Meningite Asséptica/virologia , Adulto , Encefalite/virologia , Enterovirus/isolamento & purificação , Feminino , Herpesvirus Humano 2/isolamento & purificação , Herpesvirus Humano 3/isolamento & purificação , Departamentos Hospitalares , Humanos , Medicina Interna/estatística & dados numéricos , Masculino , Meningite Asséptica/terapia , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
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