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1.
J Clin Pharmacol ; 63(11): 1186-1196, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37293880

RESUMO

Human fibrinogen concentrate (Fibryga) received temporary approval for fibrinogen replacement therapy in France (2017), with subsequent full approval for congenital and acquired hypofibrinogenemia. We evaluated real-world use for on-demand treatment of bleeding and prophylaxis to enhance our knowledge on fibrinogen concentrate as an option for fibrinogen replacement. Data were retrospectively collected from adult and pediatric patients with fibrinogen deficiency. The primary end point was indication for fibrinogen concentrate use; the secondary end point was treatment success for on-demand treatment/perioperative prophylaxis. The study included 150 adult (median age, 62 years; range, 18-94 years) and 50 pediatric (median age, 3 years; range, 0.01-17 years) patients with acquired fibrinogen deficiency. Fibrinogen concentrate was administered to 47.3% for nonsurgical bleeding, 22.7% for surgical bleeding, and 30.0% for perioperative prophylaxis in adult patients, and to 4.0% for surgical bleeding and 96.0% for perioperative prophylaxis in pediatric patients. Cardiac surgeries accounted for 79.5%/75.0% perioperative prophylaxis and 82.4%/100.0% surgical bleeding cases in adult/pediatric patients, respectively. The mean ± standard deviation (SD, median) total fibrinogen doses were 3.06 ± 1.69 g (32.61 mg/kg), 2.09 ± 1.36 g (22.99 mg/kg), and 2.36 ± 1.25 g (29.67 mg/kg) for adult nonsurgical bleeding, surgical bleeding, and perioperative prophylaxis, respectively; doses of 0.75 ± 0.35 g (47.64 mg/kg) and 0.83 ± 0.62 g (55.56 mg/kg) were used for pediatric surgical bleeding and perioperative prophylaxis, respectively. Treatment success was 85.7%/97.1/93.3% in adults and 50.0%/87.5% in pediatrics for nonsurgical bleeding (adults only), surgical bleeding, and perioperative prophylaxis, respectively. Fibrinogen concentrate demonstrated favorable effectiveness and safety across the age groups. This study contributes to evidence supporting fibrinogen concentrate for bleeding control/prevention in real-world clinical practice, particularly for patients with acquired fibrinogen deficiency.

2.
Arch Cardiovasc Dis ; 114(11): 715-726, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34620574

RESUMO

BACKGROUND: The number of heart transplantations (HTs) has decreased in France since 2017 (-5%/year) despite a stable rate of patients referred on the waiting list. Ex vivo heart perfusion (EVHP) is an innovative approach for organ preservation, reducing graft ischaemic time and facilitating continuous organ monitoring before transplantation. AIM: To report our preliminary experience of seven donor hearts preserved with EVHP, including the first heart resuscitated after circulatory-determined death in France. METHODS: Seven hearts were procured from donation after brain death (DBD) for HT or donation after circulatory-determined death (DCD) for research purposes (Protocol PFS20-004, Agence de la Biomédecine, La Plaine Saint-Denis, France). All grafts were preserved using the Organ Care System® (TransMedics Inc., Andover, MA, USA) for normothermic EVHP. Perfusion parameters were adjusted to achieve stable or decreasing arterial lactate trend consistent with suitability for organ transplantation. RESULTS: Indications for EVHP were assessment of a marginal graft in four cases, prolonged preservation in two cases (anticipated duration for retrieval of recipient's heart>3hours) and resuscitation after circulatory-determined death in one case. Median duration of EVHP was 270 (interquartile range 216-343) minutes. five were transplanted, with a median ex situ preservation time (ischaemic time+EVHP time) of 334 (interquartile range 326-444) minutes. The two other grafts were discarded for HT. Three recipients had extracorporeal life support after HT, and presented complete cardiac recovery within a week after HT. One patient died at day 11 because of septic shock. The 3-month survival rate was 75% among recipients. Three months after HT, the left ventricular ejection fraction was>60% in all cases. CONCLUSIONS: EVHP enabled safe prolonged preservation and assessment of marginal grafts. This approach provides an opportunity to expand the donor pool by resuscitating grafts from donors with extended criteria, including controlled DCD.


Assuntos
Transplante de Coração , Transplante de Coração/efeitos adversos , Humanos , Perfusão , Volume Sistólico , Doadores de Tecidos , Função Ventricular Esquerda
3.
Artigo em Inglês | MEDLINE | ID: mdl-34070124

RESUMO

Reducing fuel consumption and thus CO2 emissions is one of the most urgent tasks of current research in the field of internal combustion engines. Water Injection has proven its benefits to increase power or optimize fuel consumption of passenger cars. This technology enables knock mitigation to either increase the engine power output or raise the compression ratio and efficiency while enabling λ = 1 operation in the complete engine map to meet future emission targets. Current systems have limited container capacity. It is necessary to refill the water tank regularly. This also means that we cannot get the benefits of an engine with a higher compression ratio. For this reason, the self-contained system was investigated. This article is a methodology for finding the right design of a self-contained water injection system, but also a vehicle test that proves the function.


Assuntos
Gasolina , Emissões de Veículos , Automóveis , Gasolina/análise , Pesquisa , Emissões de Veículos/análise , Água
4.
Cardiovasc Res ; 117(5): 1391-1401, 2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32653925

RESUMO

AIMS: Although right ventricular (RV) function is an important determinant of morbidity and mortality in patients with pulmonary arterial hypertension (PAH), there is no treatment targeting directly the RV. We evaluate the efficacy of sacubitril/valsartan (LCZ 696) as add-on therapy to bosentan in rats with severe pulmonary hypertension (PH). METHODS AND RESULTS: Combination therapy of LCZ 696 and bosentan has additive vascular protective effects against the pulmonary vascular remodelling and PH in two preclinical models of severe PH. Compared with monotherapy, co-treatment of LCZ 696 (30 or 68 mg/kg/day for 2 weeks, per os) and bosentan (100 mg/kg/day for 2 weeks, per os) started 7 days after monocrotaline (MCT) injection substantially reduces pulmonary pressures, vascular remodelling, and RV hypertrophy and fibrosis in rats. Consistent with these observations, co-treatment of rats with established PH induced by sugen/hypoxia (SuHx) with LCZ 696 (30 mg/kg/day for 3 weeks, per os) and bosentan (100 mg/kg/day for 3 weeks, per os) started 5 weeks after Sugen injection partially attenuate total pulmonary vascular resistance and cardiovascular structures. We also obtained evidence showing that LCZ 696 has anti-proliferative effect on cultured human pulmonary artery smooth muscle cells derived from patients with idiopathic PAH, an effect that is more pronounced in presence of bosentan. Finally, we found that the plasma levels of atrial natriuretic peptide (ANP) and cyclic guanosine monophosphate (cGMP) are higher in rats co-treated with LCZ 696 (30 mg/kg/day) and bosentan (100 mg/kg/day) than in MCT and SuHx rats treated with vehicle. CONCLUSION: Dual therapy with LCZ 696 plus bosentan proved significantly superior beneficial effect to LCZ 696 or bosentan alone on vascular remodelling and severity of experimental PH.


Assuntos
Aminobutiratos/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Compostos de Bifenilo/farmacologia , Bosentana/farmacologia , Antagonistas dos Receptores de Endotelina/farmacologia , Inibidores de Proteases/farmacologia , Hipertensão Arterial Pulmonar/tratamento farmacológico , Artéria Pulmonar/efeitos dos fármacos , Valsartana/farmacologia , Remodelação Vascular/efeitos dos fármacos , Animais , Fator Natriurético Atrial/sangue , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , GMP Cíclico/sangue , Modelos Animais de Doenças , Progressão da Doença , Combinação de Medicamentos , Quimioterapia Combinada , Hipertensão Pulmonar Primária Familiar/tratamento farmacológico , Hipertensão Pulmonar Primária Familiar/metabolismo , Hipertensão Pulmonar Primária Familiar/fisiopatologia , Humanos , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Neprilisina/antagonistas & inibidores , Hipertensão Arterial Pulmonar/metabolismo , Hipertensão Arterial Pulmonar/fisiopatologia , Artéria Pulmonar/metabolismo , Artéria Pulmonar/fisiopatologia , Ratos Wistar
5.
Nutrients ; 12(7)2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664341

RESUMO

Functional constipation (FC) is a chronic constipation for which no physiological, anatomical or iatrogenic origin can be evidenced. This condition has a high impact on a patient's quality of life and healthcare costs. Since FC is frequently associated with low physical activity and a diet low in fiber and/or water, first-line recommendations focus on sufficient activity, and sufficient fiber and water intake. In case of inefficacy of these measures, numerous drug treatments are available, either over the counter or on prescription. Magnesium sulfate has a long history in the treatment of FC, and magnesium sulfate-rich mineral waters have been used for centuries for their laxative properties. The laxative effect of magnesium and sulfate has since been widely demonstrated. Nevertheless, it appears that no clinical studies aiming at demonstrating their efficacy in FC had been conducted before the 21st century. In this paper, we reviewed the clinical data reporting the efficacy of magnesium sulfate-rich natural mineral waters. In view of their reported efficacy and safety, magnesium sulfate-rich natural mineral waters may represent a natural treatment for FC.


Assuntos
Constipação Intestinal/terapia , Laxantes/administração & dosagem , Sulfato de Magnésio/administração & dosagem , Águas Minerais/administração & dosagem , Defecação , Fibras na Dieta/administração & dosagem , Feminino , Humanos , Óxido de Magnésio/administração & dosagem , Masculino , Probióticos/administração & dosagem , Qualidade de Vida
6.
Nutrition ; 65: 167-172, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31170680

RESUMO

OBJECTIVES: First-line recommendations for the management of functional constipation include nutritional-hygienic measures. We previously showed that a natural mineral water rich in sulphates and magnesium (Hépar) is efficient in the treatment of functional constipation. The aim of this study was to consolidate those first results and determine a precise time to respond to Hépar. METHODS: This multicenter, randomized, double-blind, controlled study of the effect of Hépar on stool consistency and frequency in functional constipation included 226 outpatients. After washout, patients used 1.5 L of water daily, including 1 L of Hépar or of low-mineral water, during 14 d. In addition to a daily reporting of stool consistency by the patient, an expert investigator blindly analyzed stool consistency (Bristol stool scale) based on photographs taken by the patient. RESULTS: The primary endpoint was met. Treatment response was more frequent in the Hépar arm than in the control group at day 14 (50% versus 29%, respectively; P = 0.001). Mean time to treatment response was shorter in the Hépar group (6.4 d) than in the control arm (7.3 d; P = 0.013). Concomitant stool scoring was available for 60% of the patients. Scores given to 79% of the stools were similar between the patient and the expert (differences ≤1). Safety analyses showed excellent results. CONCLUSION: This study confirms the efficacy and safety of Hépar in the treatment of functional constipation and shows that it is associated with a response within 7 d. Hépar could be a safe response to the current absence of first-line medication in the treatment of functional constipation.


Assuntos
Constipação Intestinal/terapia , Magnésio/uso terapêutico , Águas Minerais/uso terapêutico , Minerais/uso terapêutico , Sulfatos/uso terapêutico , Adulto , Método Duplo-Cego , Fezes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Tempo para o Tratamento , Resultado do Tratamento
7.
Bull Cancer ; 105(3): 245-255, 2018 Mar.
Artigo em Francês | MEDLINE | ID: mdl-29486920

RESUMO

PURPOSES: Analyze the relationship and expectations of cancer patients towards the community pharmacist in a pharmaceutical care coordination project. METHODS: In November 2014, a questionnaire was distributed to ambulatory patients of a university hospital specialized in oncology. Thirteen questions explored the consumption habits and the usage of the pharmacy (typology of consumers, use of goods and benefits consumed), and collected their expectations for pharmaceutical benefits in the context of the management of their cancer. RESULTS: One thousand two hundred and seventy two patients were included for a final response rate of 78%. Characteristics of the respondents: 64% were women, 63% lived in Île-de-France and 49% took cancer-related treatments (anticancer drugs, supportive care medications). More than 84% of respondents went to pharmacies at least once a month and 95% reported resorting to a single pharmacy. 36% to be ready to share their hospital discharge report with their pharmacist and 61% to have their hospitalization order sent to their "referral" pharmacy to anticipate treatments. Discussion Community pharmacists were perceived positively by the respondents. Patients were willing to share information and be accompanied by this health professional in their cancer care. Their expectations were first and foremost the management of drug-related iatrogenic effects with a report of adverse effects to the hospital, and validated solutions for their management.


Assuntos
Atitude , Neoplasias/tratamento farmacológico , Neoplasias/psicologia , Assistência Farmacêutica/estatística & dados numéricos , Farmácias/estatística & dados numéricos , Farmacêuticos , Relações Profissional-Paciente , Adulto , Idoso , Idoso de 80 Anos ou mais , Assistência Ambulatorial , Antineoplásicos/efeitos adversos , Feminino , França , Hospitais Universitários , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários
8.
Int J Clin Pharm ; 40(2): 376-385, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29446003

RESUMO

Background Adverse drug events (ADEs) occur frequently in oncology and justify continuous assessment and monitoring. There are several methods for detecting them, but the trigger tool method seems the most appropriate. Although a generic tool exists, its use for ADEs in oncology has not been convincing. The development of a focused version is therefore necessary. Objective To provide an oncology-focused trigger tool that evaluates the prevalence, harm, and preventability in a standardised method for pragmatic use in ADE surveillance. Setting Hospitals with cancer care in France. Method The tool has been constructed in two steps: (1) constitution of an oncology-centred list of ADEs; 30 pharmacists/practitioners in cancer care from nine hospitals selected a list of ADEs using a method of agreement adapted from the RAND/UCLA Appropriateness Method; and (2) construction of three standardised dimensions for the characterisation of each ADE (including causality, severity, and preventability). Main outcome measure The main outcome measure was validation of the tool, including preventability criteria. Results The tool is composed of a final list of 15 ADEs. For each ADE, a 'reviewer form' has been designed and validated by the panel. It comprises (1) the trigger(s), (2) flowcharts to guide the reviewer, (3) criteria for grading harm, and (4) a standardised assessment of preventability with 6-14 closed sentences for each ADE in terms of therapeutic management and/or prevention of side-effects. Conclusion A complete 'ready-to-use' tool for ADE monitoring in oncology has been developed that allows the assessment of three standardised dimensions.


Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos/tendências , Antineoplásicos/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Farmacêuticos , Serviço de Farmácia Hospitalar/tendências , Médicos , Antineoplásicos/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , França/epidemiologia , Humanos , Erros de Medicação/prevenção & controle , Erros de Medicação/tendências , Neoplasias/tratamento farmacológico , Neoplasias/epidemiologia , Serviço de Farmácia Hospitalar/métodos , Inquéritos e Questionários
9.
Eur J Cancer ; 51(4): 551-557, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25661828

RESUMO

BACKGROUND: The uses of internet-based technologies (e.g. patient portals, websites and applications) by cancer patients could be strong drive for change in cancer care coordination practices. The goal of this study was to assess the current utilisation of internet-based technologies (IBT) among cancer patients, and their willingness to use them for their health, as well as analyse the influence of socio-demographics on both aspects. METHODS: A questionnaire-based survey was conducted in June 2013, over seven non-consecutive days within seven outpatient departments of Gustave Roussy, a comprehensive cancer centre (≈160,000 consultations yearly), located just outside Paris. We computed descriptive statistics and performed correlation analysis to investigate patients' usage and attitudes in correspondence with age, gender, socioeconomic status, social isolation, and place of living. We then conducted multinomial logistic regressions using R. RESULTS: The participation level was 85% (n=1371). The median age was 53.4. 71% used a mobile phone everyday and 93% had access to Internet from home. Age and socioeconomic status were negatively associated with the use of IBT (p<0.001). Regarding patients' expected benefits, a wide majority valued its use in health care, and especially, the possibility to enhance communication with providers. 84% of patients reported feeling comfortable with the use of such technologies but age and socioeconomic status had a significant influence. CONCLUSION: Most patients used IBTs every day. Overall, patients advocated for an extended use of IBT in oncology. Differences in perceived ease of use corresponding to age and socioeconomic status have to be addressed.


Assuntos
Internet , Neoplasias/terapia , Telemedicina , Atitude , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Classe Social , Inquéritos e Questionários
10.
Eur J Cancer ; 51(3): 427-35, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25549531

RESUMO

BACKGROUND: Drug-related iatrogenic effects are common in oncology because chemotherapy is toxic. The evaluation of the application of the guidelines may be a way to understand the occurrence of adverse drug-related event (ADE). There is no specific method for identifying ADEs and measuring harm to patients in oncology. OBJECTIVE: Our objective was to develop and test an Oncology Trigger Tool (OTT) for ADEs and to describe ADE characteristics and incidence. METHODS: A clinical advisory panel identified situations at high risk of ADE occurrence and built 22 triggers with, in each case, an analysis flowchart to confirm or refute occurrence. The OTT was used to review 288 random admissions (Oct. 2010-Sept. 2011) and measure ADE incidence and severity (CTCAE 4.03 - Common Terminology Criteria for Adverse Events). Tool feasibility (time required), inter-rater (IR) reproducibility and positive predictive value (PPV) were measured. RESULTS: Overall, 884 triggers were detected and 122 ADEs, with 42.4 ADEs/100 admissions or 46.0 ADEs/1000 patient-days, and a 31.1% rate of severe ADEs. The most common ADEs were hyperglycaemia (14.5%), unplanned drug-related admission within 30 days (13.7%) and opiate-induced constipation (12.1%). Unplanned drug-related admission was the most serious (82.4% incidence of severe harm). Mean time for OTT implementation was 21.8 min; IR reproducibility was high (κ=0.965 (trigger); κ=0.935 (ADE); κ=0.853 (harm)); PPV 22-trigger version was 20.7%. CONCLUSIONS: ADE analysis flowcharts coupled with standardised grading of harm considerably reduced IR variability, thus providing a robust oncology-focused trigger tool for use in ADE audits and hospital comparisons. The involvement of a clinical advisory panel in tool development should help drive changes for improving practice. Further research on the OTT is warranted.


Assuntos
Antineoplásicos/efeitos adversos , Monitoramento de Medicamentos/métodos , Prescrições de Medicamentos/estatística & dados numéricos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Doença Iatrogênica/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Fidelidade a Diretrizes/estatística & dados numéricos , Humanos , Incidência , Lactente , Recém-Nascido , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
12.
Expert Opin Drug Metab Toxicol ; 6(8): 919-38, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20446865

RESUMO

IMPORTANCE OF THE FIELD: The oxazaphosphorines (cyclophosphamide, ifosfamide and trofosfamide) are widely used in clinical practice for their antitumor and immunomodulatory activities. However, their use is associated with toxicities. The metabolism of oxazaphosphorines involves cytochrome P450 biotransformations, leading to highly reactive metabolites such as acrolein and chloroacetaldehyde responsible for urotoxicity, neurotoxicity and nephrotoxicity. While the mechanisms behind these toxicities remain under investigation, some advances have been made, as exemplified by the use of mesna to limit acrolein related urotoxicity. AREAS COVERED IN THIS REVIEW: This review highlights potential strategies for limiting side effects commonly associated with the oxazaphosphorine drugs, through pharmacological or medicinal chemistry-based approaches. WHAT THE READER WILL GAIN: The readers will gain a comprehensive review of these approaches to treatment in terms of: i) pharmacology: use of antidotes and modification of metabolism through inhibition/induction of CYP enzymes or use of gene therapy; and ii) medicinal chemistry: the design of new drugs to target cancer cells and avoid CYP biotransformation with pre-activated prodrugs or with side-chain substituted analogues. TAKE HOME MESSAGE: An increased knowledge of oxazaphosphorines' metabolism and toxicity may allow the development of new anticancer drugs combined with drug delivery systems to circumvent drug toxicity, providing increased tumoral specificity and greater anticancer activity.


Assuntos
Ciclofosfamida/farmacologia , Desenho de Fármacos , Ifosfamida/farmacologia , Animais , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/metabolismo , Antineoplásicos Alquilantes/farmacologia , Ciclofosfamida/efeitos adversos , Ciclofosfamida/análogos & derivados , Ciclofosfamida/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Sistemas de Liberação de Medicamentos , Terapia Genética/métodos , Humanos , Ifosfamida/efeitos adversos , Ifosfamida/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/fisiopatologia
13.
Pharmacoepidemiol Drug Saf ; 16(11): 1227-33, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17879355

RESUMO

PURPOSE: We describe drug-drug interactions (DDIs) encountered with antifungals in clinical practice. METHODS: Retrospective observational study of hospitalized adults receiving systemic antifungal treatment in the intensive care unit (ICU) and in the infectious diseases unit (IDU) of the University Hospital of Bordeaux, France between 1996 and 2001. All treatment episodes with antifungal agent were examined and all prescribed concomitant medication identified for potential drug-drug interactions (PDDI)-serious events occurring during treatment were adjudicated for clinical DDI. RESULTS: There were 150 treatment episodes with antifungal agent in 105 patients. Fluconazole was used in 48% of the treatment episodes, amphotericin B in 46%, itraconazole in 4.7% and flucytosine in 1.3%. One hundred and sixteen PDDIs were identified related to the use of amphotericin B (81.0%), fluconazole (17.2%) or itraconazole (1.7%). Of these, 22 were associated with a clinical evidence of adverse interaction (hypokalemia, increased creatininemia or nephrotoxicity). All these clinical drug-drug interactions (CDDIs) were with amphotericin B. They were due to furosemide (36.4%), cyclosporine (31.8%) and hydrocortisone (18.2%). PDDIs were mostly associated with leukaemia (40.4%), HIV infection (24.6%) and cancer (10.5%). CONCLUSIONS: In ICU and IDU, systemic antifungal treatments lead to many PDDIs, mainly related to the type of antifungal used and to the pathology treated. Clinical DDI seem more common with amphotericin.


Assuntos
Anfotericina B/efeitos adversos , Antifúngicos/efeitos adversos , Fluconazol/efeitos adversos , Itraconazol/efeitos adversos , Adulto , Idoso , Anfotericina B/farmacologia , Antifúngicos/farmacologia , Creatinina/sangue , Ciclosporina/efeitos adversos , Ciclosporina/farmacologia , Interações Medicamentosas , Feminino , Fluconazol/farmacologia , França , Furosemida/efeitos adversos , Furosemida/farmacologia , Infecções por HIV/tratamento farmacológico , Hospitais Universitários , Humanos , Hidrocortisona/efeitos adversos , Hidrocortisona/farmacologia , Hipopotassemia/induzido quimicamente , Unidades de Terapia Intensiva , Itraconazol/farmacologia , Nefropatias/induzido quimicamente , Leucemia/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Estudos Retrospectivos
14.
Brain Res Mol Brain Res ; 138(2): 156-63, 2005 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-15922486

RESUMO

In young rodents, peripheral injection of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) results in a dopaminergic nigrostriatal denervation (during the first week after injection), followed by a spontaneous dopaminergic reinnervation. Sprouting from residual neurons has been proposed to account for this event. It has been shown that an inflammatory process takes place during striatal dopaminergic denervation but its consequences remain controversial. Some clues notably indicate that interleukin (IL)-1alpha may participate in MPTP-induced inflammation and promote recovery. We therefore studied the immunohistochemical localization of IL-1alpha expression in the striatum and ventral mesencephalon at different times (1, 3, 6, 16, and 30 days) after MPTP injection in mice. IL-1alpha-immunoreactivity (ir) was observed in striatum, substantia nigra pars compacta, and ventral tegmental area. Apart from a few localization in mesencephalic activated microglia, IL-1alpha was almost exclusively found in activated astrocytes. However, in the striatal parenchyma, another component of IL-1alpha-ir colocalized with tyrosine hydroxylase (TH)-ir, a marker for dopaminergic neurons. Moreover, some parenchymal TH-positive axons were also found to express the growth cone-associated protein (GAP)-43, a marker for axonal growth cones. In the striatum, IL-1alpha-ir was also detected in a non-astrocytic perivascular component, with a distribution similar to GAP-43-ir. IL-1alpha could thus directly or indirectly influence striatal reorganization after MPTP.


Assuntos
Corpo Estriado/imunologia , Encefalite/imunologia , Interleucina-1/metabolismo , Regeneração Nervosa/imunologia , Plasticidade Neuronal/imunologia , Transtornos Parkinsonianos/imunologia , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/efeitos adversos , Animais , Astrócitos/imunologia , Astrócitos/metabolismo , Biomarcadores/metabolismo , Corpo Estriado/metabolismo , Corpo Estriado/fisiopatologia , Modelos Animais de Doenças , Dopamina/metabolismo , Encefalite/metabolismo , Encefalite/fisiopatologia , Proteína GAP-43/metabolismo , Gliose/imunologia , Gliose/metabolismo , Gliose/fisiopatologia , Cones de Crescimento/metabolismo , Cones de Crescimento/ultraestrutura , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/fisiopatologia , Tirosina 3-Mono-Oxigenase/metabolismo
15.
Brain Res Mol Brain Res ; 136(1-2): 267-70, 2005 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-15893609
16.
Brain Res ; 1045(1-2): 31-7, 2005 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-15910760

RESUMO

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces dopaminergic neuron death in substantia nigra and dopamine loss in striatum, similar to those observed in Parkinson disease. Given MPTP can also induce alterations in brain cytokines and in peripheral immune parameters, we hypothesize that MPTP can induce an elevation of plasma cytokines. We have previously shown that cytokine production depends on behavioral lateralization in certain conditions. Therefore, we further postulate that the MPTP-induced plasma cytokines are related to behavioral lateralization. To answer these questions, C57BL/6J male mice, selected for paw preference, were injected with 25 mg/kg MPTP ip for five consecutive days and were decapitated at day 1, day 3, or day 14 after the last injection. Striatal DA and DOPAC concentration were measured by HPLC and plasma levels of IL-1beta and IL-6 were quantified by ELISA. The results showed that after MPTP treatment, striatal DA content was dramatically decreased, IL-1beta levels increased on day 3, while IL-6 levels increased on day 14. Interestingly, behavioral lateralization influenced DA/DOPAC ratio as well as plasma IL-1beta and IL-6 levels. In left-pawed mice, MPTP induced a higher decrease of DA/DOPAC ratio than in right-pawed mice. The increase of IL-1beta was observed in left-pawed but not in right-pawed mice. The elevation of IL-6 was higher in right-pawed mice than in left-pawed mice. These results have clearly demonstrated our hypotheses, that MPTP can induce increase of plasma IL-1beta and IL-6 levels in mice, and this effect is shaped by behavioral lateralization.


Assuntos
Encéfalo/imunologia , Encefalite/imunologia , Lateralidade Funcional/efeitos dos fármacos , Interleucina-1/imunologia , Interleucina-6/imunologia , Transtornos Parkinsonianos/imunologia , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Corpo Estriado/fisiopatologia , Modelos Animais de Doenças , Dopamina/metabolismo , Encefalite/induzido quimicamente , Encefalite/fisiopatologia , Membro Anterior/inervação , Membro Anterior/fisiologia , Lateralidade Funcional/fisiologia , Interleucina-1/sangue , Interleucina-6/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Movimento/efeitos dos fármacos , Movimento/fisiologia , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/fisiopatologia
17.
Neuroimmunomodulation ; 12(3): 189-94, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15905628

RESUMO

The central nervous system can regulate the peripheral immune system. Moreover, differences between left and right hemispheres (neurochemical brain asymmetries) and behavioral lateralization (functional brain asymmetries) affect immune responses. The molecular basis of brain-immune interactions remains insufficiently understood. Cytokines regulate immune responses, possibly through activation of the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis activities are related to behavioral lateralization and brain asymmetry. Given IL-6 plays a role in asymmetrical brain immunomodulation, one might expect the IL-6 distribution in brain to be asymmetrical and to depend on behavioral lateralization. In order to start to test this hypothesis, male C57BL/6J mice were selected for paw preference and assessed for IL-6 levels in right and left cortex and hippocampus by enzyme linked immunosorbent assay. The results showed asymmetrical distribution of brain IL-6 in left-pawed animals and ambidextrous animals, but not in right-pawed animals, both in cortex and hippocampus. Furthermore, we found a correlation between IL-6 hemispheric distribution and the degree of behavioral lateralization both in cortex and hippocampus. Altogether, these results suggest that brain IL-6 could be a mediator of asymmetrical immunomodulation by the central nervous system.


Assuntos
Córtex Cerebral/imunologia , Lateralidade Funcional/fisiologia , Hipocampo/imunologia , Interleucina-6/metabolismo , Neuroimunomodulação/imunologia , Animais , Química Encefálica/genética , Química Encefálica/imunologia , Córtex Cerebral/anatomia & histologia , Ensaio de Imunoadsorção Enzimática , Membro Anterior/inervação , Membro Anterior/fisiologia , Hipocampo/anatomia & histologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
18.
Neurosci Lett ; 349(3): 191-5, 2003 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-12951201

RESUMO

Injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice results in a retrograde nigrostriatal dopaminergic pathway denervation and subsequent tissue reorganization. Since the role of inflammatory mediators after MPTP remains unclear, proinflammatory cytokine and matrix metalloproteinase (MMP) expression were evaluated by comparative RT-PCR during denervation and tissue reorganization following a single-dose of MPTP (40 mg/kg, s.c.) in young (8-week-old) mice. The time-course of denervation/reorganization was assessed through [(3)H]GBR-12935 binding on dopamine transporter and tyrosine hydroxylase immunohistochemistry. In the striatum, TNF-alpha, IL-1alpha, IL-1beta, IL-6 and MMP-9 mRNA expression peaked on day 1. In the ventral mesencephalon, cytokines (TNF-alpha, IL-1alpha, IL-1beta) and MMP-9 mRNA expression peaked on day 3. During tissue reorganization (day 6 through 16), the only change observed in the striatum consisted of IL-1alpha mRNA and protein overexpression together with MMP-2 downregulation. Whereas the early expression of proinflammatory cytokines and MMP might participate in the retrograde nigrostriatal denervation, the late component of IL-1alpha expression suggests a possible role for this cytokine in the subsequent striatal reorganization.


Assuntos
Citocinas/genética , Encefalite/fisiopatologia , Metaloproteinases da Matriz/genética , Glicoproteínas de Membrana , Neostriado/fisiopatologia , Proteínas do Tecido Nervoso , Vias Neurais/fisiopatologia , Transtornos Parkinsonianos/fisiopatologia , Substância Negra/fisiopatologia , Animais , Modelos Animais de Doenças , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina , Encefalite/enzimologia , Encefalite/imunologia , Mediadores da Inflamação/metabolismo , Interleucina-1/genética , Masculino , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neostriado/enzimologia , Neostriado/imunologia , Vias Neurais/enzimologia , Vias Neurais/imunologia , Transtornos Parkinsonianos/enzimologia , Transtornos Parkinsonianos/imunologia , Piperazinas/farmacologia , RNA Mensageiro/metabolismo , Tempo de Reação/fisiologia , Substância Negra/enzimologia , Substância Negra/imunologia , Tirosina 3-Mono-Oxigenase/metabolismo
19.
J Enzyme Inhib Med Chem ; 18(2): 147-53, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12943198

RESUMO

The syntthesis of new N-propargyl-3-pyrrol-1-ylindanamine derivatives, analogues of rasagiline, is described in ten steps starting from the corresponding arylaldehydes via the corresponding cis-3-pyrrol-1-ylindanamines. The cis-configuration of some intermediates has been established using X-ray analysis and NOE experiments. The new N-propargyl-3-pyrrol-1-ylindanamine derivatives were evaluated for their potential MAO-B inhibitor activity in an in vivo model of MPTP-induced Parkinsonism in mice with respect to the potent MAO-B inhibitor rasagiline.


Assuntos
Indanos/química , Inibidores da Monoaminoxidase , Monoaminoxidase/metabolismo , Animais , Modelos Animais de Doenças , Indanos/síntese química , Indanos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Transtornos Parkinsonianos/enzimologia , Transtornos Parkinsonianos/prevenção & controle , Pirróis/síntese química , Pirróis/química , Pirróis/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade
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