RESUMEN
BACKGROUND: Iron content is increased in the substantia nigra of persons with Parkinson's disease and may contribute to the pathophysiology of the disorder. Early research suggests that the iron chelator deferiprone can reduce nigrostriatal iron content in persons with Parkinson's disease, but its effects on disease progression are unclear. METHODS: We conducted a multicenter, phase 2, randomized, double-blind trial involving participants with newly diagnosed Parkinson's disease who had never received levodopa. Participants were assigned (in a 1:1 ratio) to receive oral deferiprone at a dose of 15 mg per kilogram of body weight twice daily or matched placebo for 36 weeks. Dopaminergic therapy was withheld unless deemed necessary for symptom control. The primary outcome was the change in the total score on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 260, with higher scores indicating more severe impairment) at 36 weeks. Secondary and exploratory clinical outcomes at up to 40 weeks included measures of motor and nonmotor disability. Brain iron content measured with the use of magnetic resonance imaging was also an exploratory outcome. RESULTS: A total of 372 participants were enrolled; 186 were assigned to receive deferiprone and 186 to receive placebo. Progression of symptoms led to the initiation of dopaminergic therapy in 22.0% of the participants in the deferiprone group and 2.7% of those in the placebo group. The mean MDS-UPDRS total score at baseline was 34.3 in the deferiprone group and 33.2 in the placebo group and increased (worsened) by 15.6 points and 6.3 points, respectively (difference, 9.3 points; 95% confidence interval, 6.3 to 12.2; P<0.001). Nigrostriatal iron content decreased more in the deferiprone group than in the placebo group. The main serious adverse events with deferiprone were agranulocytosis in 2 participants and neutropenia in 3 participants. CONCLUSIONS: In participants with early Parkinson's disease who had never received levodopa and in whom treatment with dopaminergic medications was not planned, deferiprone was associated with worse scores in measures of parkinsonism than those with placebo over a period of 36 weeks. (Funded by the European Union Horizon 2020 program; FAIRPARK-II ClinicalTrials.gov number, NCT02655315.).
Asunto(s)
Antiparkinsonianos , Deferiprona , Quelantes del Hierro , Hierro , Enfermedad de Parkinson , Sustancia Negra , Humanos , Deferiprona/administración & dosificación , Deferiprona/efectos adversos , Deferiprona/farmacología , Deferiprona/uso terapéutico , Hierro/análisis , Hierro/metabolismo , Levodopa/uso terapéutico , Neutropenia/inducido químicamente , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/fisiopatología , Quelantes del Hierro/administración & dosificación , Quelantes del Hierro/efectos adversos , Quelantes del Hierro/farmacología , Quelantes del Hierro/uso terapéutico , Sustancia Negra/química , Sustancia Negra/diagnóstico por imagen , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismo , Progresión de la Enfermedad , Método Doble Ciego , Administración Oral , Encéfalo/diagnóstico por imagen , Química Encefálica , Dopaminérgicos/administración & dosificación , Dopaminérgicos/efectos adversos , Dopaminérgicos/farmacología , Dopaminérgicos/uso terapéutico , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/efectos adversos , Antiparkinsonianos/farmacología , Antiparkinsonianos/uso terapéuticoRESUMEN
BACKGROUND/AIMS: The Clinical Trials Coordination and Facilitation Group has issued recommendations on contraception and pregnancy testing to help sponsors meet regulatory expectations and harmonize practices to limit embryofetal risks in clinical trials. Our objective was to assess the compliance of French academic clinical trials with these recommendations and to describe the mitigation measures required by sponsors in their trials. METHODS: A cross-sectional study was performed on the French academic drug trials authorized by the national competent authority between January 2015 and June 2018. We included trials which tested systemic administration of drugs and enrolled men or women of childbearing potential. RESULTS: Data from 97 trials included were compiled. One-third of the trials (23.8%-43.3%, 95% confidence interval) complied with the Clinical Trial Facilitation and Coordination Group recommendations. No improvement over time or according to embryofetotoxic status or drug duration exposure was found. Contraception was required in 56.7% of trials and was more often required in case of potentially embryofetotoxic drugs (68.5% vs 41.9%, p = 0.013) or exposure over 1 month (71.7% vs 43.8%, p = 0.006). Pregnancy testing at inclusion was required in 59.1% of trials and additional testing in 17.2%. Pregnancy testing at inclusion was more often required in trials with drug exposure above 1 month (67.4% vs 45.8%, p = 0.035). CONCLUSION: French academic sponsors barely met the recommendations on contraception and pregnancy testing potentially leading to potential embryofetal risks in case of pregnancy. They need to implement these recommendations quickly.
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Ensayos Clínicos como Asunto/métodos , Anticoncepción/estadística & datos numéricos , Adhesión a Directriz/estadística & datos numéricos , Pruebas de Embarazo/estadística & datos numéricos , Adulto , Estudios Transversales , Femenino , Francia , Humanos , Masculino , Guías de Práctica Clínica como Asunto , EmbarazoRESUMEN
Midlife cognitive decline is now recognized as a factor of poor prognosis for late-life dementia. Although an epidemiological link has been suggested with high fat diet (HFD)-induced metabolic disorders, the effect of a long period of HFD on midlife cerebrovascular and cognitive functions remains unproven. A cohort of 216 young mice was fed with HFD up to middle age (12â¯months), and kinetically characterized for metabolic status, including weight, blood lipid profile, hepatic fat accumulation, glucose intolerance, and visceral adiposity. Metabolic disorders were evidenced from 3â¯months of HFD. Visual recognition memory and flexibility were significantly altered and associated to a visceral adiposity whereas spatial reference memory and working memory did not. Concomitantly, a progressive dysfunction of the vascular endothelium-dependent relaxation was detected in both middle cerebral artery and parenchymal arterioles, with consequences on the regulation of cerebral blood flow, but without any modification of the basal brain tissue MRI perfusion signal. Our data collection empowered us to stratify the mice according to their heterogeneous response to diet, and to propose a statistical prediction model for cognitive impairment, combining visceral adiposity and cerebral vasomotion in a diagnostic perspective of early neurological deficits.
Asunto(s)
Adiposidad/fisiología , Trastornos Cerebrovasculares/complicaciones , Disfunción Cognitiva/complicaciones , Grasa Intraabdominal/metabolismo , Animales , Trastornos Cerebrovasculares/metabolismo , Disfunción Cognitiva/metabolismo , Dieta Alta en Grasa , Modelos Animales de Enfermedad , RatonesRESUMEN
BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) is a pharmacologic agent inducing neutrophil mobilization and a new candidate for neuroprotection and neuroregeneration in stroke. Its effects when used in combination with tissue plasminogen activator (tPA) were explored during the acute phase of ischemic stroke. METHODS: We used a middle cerebral artery occlusion (MCAO) model of cerebral ischemia, associated with treatment with tPA, in male spontaneously hypertensive rats (SHR). Granulocyte colony-stimulating factor (G-CSF; 60 µg/kg) was injected just before tPA. Neutrophil response in peripheral blood and in the infarct area was quantified in parallel to the infarct volume. Protease matrix metallopeptidase 9 (MMP-9) release from circulating neutrophils was analyzed by immunochemistry and zymography. Vascular reactivity and hemorrhagic volume in the infarct area was also assessed. RESULTS: Twenty four hours after ischemia and tPA, G-CSF administration induced a significant increase of neutrophils in peripheral blood (P <0.05). At 72 hours post-ischemia, G-CSF was significantly associated with an increased risk of hemorrhage in the infarct area (2.5 times more likely; P <0.05) and significant cerebral endothelium-dependent dysfunction. Ex vivo, an increased MMP-9 release from neutrophils after tPA administration correlated to the increased hemorrhagic risk (P <0.05). In parallel, G-CSF administration was associated with a decreased neutrophil infiltration in the infarct area (-50%; P <0.05), with a concomitant significant neuroprotective effect (infarct volume: -40%; P <0.05). CONCLUSIONS: We demonstrate that G-CSF potentiates the risk of hemorrhage in experimental stroke when used in combination with tPA by inducing neutrophilia. This effect is concomitant to an increased MMP-9 release from peripheral neutrophils induced by the tPA treatment. These results highlight the potential hemorrhagic risk of associating G-CSF to thrombolysis during the acute phase of stroke.
Asunto(s)
Fibrinolíticos/efectos adversos , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Hemorragia/inducido químicamente , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Neutrófilos/efectos de los fármacos , Activador de Tejido Plasminógeno/efectos adversos , Animales , Infarto Encefálico/etiología , Modelos Animales de Enfermedad , Esquema de Medicación , Endotelio/efectos de los fármacos , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Infiltración Neutrófila/efectos de los fármacos , Neutrófilos/metabolismo , Peroxidasa/metabolismo , Ratas , Ratas Endogámicas SHR , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/etiología , Estadísticas no Paramétricas , Factores de TiempoRESUMEN
BACKGROUND: Even with optimal dopaminergic treatments, many patients with Parkinson's disease (PD) are frequently incapacitated by apathy prior to the development of dementia. We sought to establish whether rivastigmine's ability to inhibit acetyl- and butyrylcholinesterases could relieve the symptoms of apathy in dementia-free, non-depressed patients with advanced PD. METHODS: We performed a multicentre, parallel, double-blind, placebo-controlled, randomised clinical trial (Protocol ID: 2008-002578-36; clinicaltrials.gov reference: NCT00767091) in patients with PD with moderate to severe apathy (despite optimised dopaminergic treatment) and without dementia. Patients from five French university hospitals were randomly assigned 1:1 to rivastigmine (transdermal patch of 9.5 mg/day) or placebo for 6 months. The primary efficacy criterion was the change over time in the Lille Apathy Rating Scale (LARS) score. FINDING: 101 consecutive patients were screened, 31 were eligible and 16 and 14 participants were randomised into the rivastigmine and placebo groups, respectively. Compared with placebo, rivastigmine improved the LARS score (from -11.5 (-15/-7) at baseline to -20 (-25/-12) after treatment; F(1, 25)=5.2; p=0.031; adjusted size effect: -0.9). Rivastigmine also improved the caregiver burden and instrumental activities of daily living but failed to improve quality of life. No severe adverse events occurred in the rivastigmine group. INTERPRETATION: Rivastigmine may represent a new therapeutic option for moderate to severe apathy in advanced PD patients with optimised dopaminergic treatment and without depression dementia. These findings require confirmation in a larger clinical trial. Our results also confirmed that the presence of apathy can herald a pre-dementia state in PD. REGISTRATION: Clinicaltrials.gov reference: NCT00767091.
Asunto(s)
Apatía , Inhibidores de la Colinesterasa/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/psicología , Fenilcarbamatos/uso terapéutico , Actividades Cotidianas , Adulto , Anciano , Demencia/diagnóstico , Depresión/diagnóstico , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Rivastigmina , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: The origin of pre-existing cognitive impairment in stroke patients remains controversial, with a vascular or a degenerative hypothesis. OBJECTIVE: To determine whether endothelial dysfunction is associated with pre-existing cognitive problems, lesion load and biological anomalies in stroke patients. METHODS: Patients originated from the prospective STROKDEM study. The baseline cognitive state, assessed using the IQ-CODE, and risk factors for stroke were recorded at inclusion. Patients with an IQ-CODE score >64 were excluded. Endothelial function was determined 72 h after stroke symptom onset by non-invasive digital measurement of endothelium-dependent flow-mediated dilation and calculation of the reactive hyperemia index (RHI). RHI ≤ 1.67 indicated endothelial dysfunction. Different biomarkers of endothelial dysfunction were analysed in blood or plasma. All patients underwent MRI 72 h after stroke symptom onset. RESULTS: A total of 86 patients were included (52 males; mean age 63.5 ± 11.5 years). Patients with abnormal RHI have hypertension or antihypertensive treatment more often. The baseline IQ-CODE was abnormal in 33 (38.4%) patients, indicating a pre-existing cognitive problem. Baseline IQ-CODE > 48 was observed in 15 patients (28.3%) with normal RHI and in 18 patients (54.6%) with abnormal RHI (p = 0.016). The RHI median was significantly lower in patients with abnormal IQ-CODE. Abnormal RHI was associated with a significantly higher median FAZEKAS score (2.5 vs. 2; p = 0.008), a significantly higher frequency of periventricular lesions (p = 0.015), more white matter lesions (p = 0.007) and a significantly higher cerebral atrophy score (p < 0.001) on MRI. Vascular biomarkers significantly associated with abnormal RHI were MCP-1 (p = 0.009), MIP_1a (p = 0.042), and homocysteinemia (p < 0.05). CONCLUSIONS: A vascular mechanism may be responsible for cognitive problems pre-existing stroke. The measurement of endothelial dysfunction after stroke could become an important element of follow-up, providing an indication of the functional and cognitive prognosis of stroke patients.
Asunto(s)
Endotelio Vascular , Accidente Cerebrovascular , Humanos , Masculino , Femenino , Persona de Mediana Edad , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/fisiopatología , Anciano , Endotelio Vascular/fisiopatología , Estudios Prospectivos , Disfunción Cognitiva/fisiopatología , Biomarcadores/sangre , Imagen por Resonancia Magnética , Factores de RiesgoRESUMEN
Cerebral microhemorrhages (CMHs) are considered as asymptomatic lesions, but might impair cognition in non-demented elderly individuals. The aging process includes poor vascular health, enhanced at midlife by metabolic disturbances upon high-fat diet (HFD). The onset of CMHs could thus have more serious consequences in midlife subjects with metabolic disturbances. This hypothesis was tested through the induction of multiple CMHs, using cyclodextrin nanoparticles injection, in mice at midlife (14 month old) or at a younger stage (5 month old) after 12 months or 3 months of normal diet or HFD (40% of animal fat) respectively. When induced at 14 months of age, CMHs were not larger but were more numerous (+25%) in mice on HFD compared with mice on normal diet. They slowed down the locomotor activity significantly but caused neither a change in the working memory nor a difference in the visual recognition memory decline. When induced at 5 months of age, CMHs provoked slighter locomotor and cognitive symptoms, regardless the diet. No spontaneous progression of CMHs toward larger hemorrhages was observed after onset when HFD was prolonged up to midlife. Consistently, no precipitated cognitive decline was observed. Middle-age plus time of metabolic disturbances represent enhanced risk factors for CMH outcome.
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Envejecimiento/fisiología , Hemorragia Cerebral/etiología , Dieta Alta en Grasa/efectos adversos , Enfermedad Aguda , Animales , Hemorragia Cerebral/fisiopatología , Hemorragia Cerebral/psicología , Cognición , Trastornos del Conocimiento/etiología , Ratones , Actividad Motora , Trastornos Motores/etiología , Pronóstico , Factores de RiesgoRESUMEN
PURPOSE: To follow the European Directive 2001/20/EC, institutional sponsors created or reinforced their vigilance units. Since 2007, the working group "REflexion sur la VIgilance et la Sécurité des Essais" (REVISE) rallies French institutional vigilance units (IVUs) to share their experience. The group decided to elaborate a collective work to provide a real-life descriptive picture of French IVUs activities and resources over the 2011-2016 period. METHOD: A questionnaire was sent to the 60 IVUs of the group. It included questions on staff and activities, such as the number of received and analyzed serious adverse events (SAEs). All results and proposals were discussed and consensus was achieved in general meeting. RESULTS/CONCLUSION: The results highlight the commitment of IVU staffs at many steps of CTs, but also the frailty of some units, leading to 6 proposals intended to institutional sponsors and competent authorities for ensuring (1) IVU visibility to all actors; (2) sustainable IVU staff; (3) IVU resources adapted to sponsor's ambitions; (4) valorization of IVUs in publications; (5) recognition of IVU's value in clinical research quality; (6) involvement of IVUs in regulatory changes and their procedures of implementation.
RESUMEN
Thrombolysis remains the main therapeutic strategy used in stroke, but with a limited use to only a part of stroke patients. A neuroprotective approach would be necessary with a double objective : (1) to serve as an add-on treatment with thrombolysis to improve safety and increase therapeutic window ; (2) to limit infarct area by delaying neuronal death. While numerous molecules failed in clinical trials in stroke, pharmacological development is on-going with pleiotropic drugs targeting both neuronal and vascular parts of neurovascular unit. Another approach targets the functional rehabilitation and the neurorepair using pharmacological ways or cell therapy.
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Isquemia Encefálica/terapia , Apoptosis , Astrocitos/fisiología , Azoles/uso terapéutico , Isquemia Encefálica/tratamiento farmacológico , Infarto Cerebral/patología , Infarto Cerebral/prevención & control , Diagnóstico Diferencial , Endotelio Vascular/fisiopatología , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Humanos , Isoindoles , Neuronas/patología , Neuronas/fisiología , Fármacos Neuroprotectores/uso terapéutico , Compuestos de Organoselenio/uso terapéutico , Reperfusión , Transmisión Sináptica/fisiologíaRESUMEN
While being increasingly recognized in clinical routine, brain microbleeds remain a puzzling finding for physicians. These small dot-like lesions are thought to be old perivascular collections of hemosiderin deposits. They can be found in different neurological settings such as cerebrovascular or neurodegenerative diseases. While their microscopic size would suggest considering these lesions as anecdotal, they are now regarded as biomarkers of severity of an underlying cerebrovascular disease. Their natural history and the interactions with surrounding brain cells remain unknown. However, their presence may impact therapeutic decisions. Deciphering the biological mechanisms leading to, or following microbleeds would enable us to address a key question: do microbleeds arise and impact the surrounding parenchyma like a miniature version of intracerebral hemorrhages or do they represent a different kind of injury? We hereby discuss, based on both clinical and experimental literature, the gap between the definition of microbleeds coming from neuroimaging and the pathophysiological hypotheses raised from histopathological and experimental data. Our analysis supports the need for a convergent effort from clinicians and basic scientists to go beyond the current "macro" view and disclose the cellular and molecular insights of these cerebral hemorrhagic microlesions.
Asunto(s)
Hemorragia Cerebral/patología , Animales , Hemorragia Cerebral/complicaciones , Trastornos Cerebrovasculares/complicaciones , Modelos Animales de Enfermedad , Humanos , Modelos NeurológicosRESUMEN
This study aims at determining the ability of clinical-based doses of four oral anticoagulants to transform the onset of a cerebral microhemorrhages (CMH) burden into a symptomatic intracerebral hemorrhage (ICH) in the healthy brain, and precipitate cognitive impairment. Wild-type mice were anticoagulated for 10 days using apixaban, rivaroxaban or dabigatran as direct oral anticoagulants (DOACs), or warfarin as vitamin K-antagonist. Meanwhile, a burden of â¼20 CMHs was induced in the Sylvian territory by intra-carotid injection of cyclodextrin nanoparticles. At bleeding onset, only warfarin provoked deadly hematoma, and dramatically increased mortality (+45%). All the DOACs enhanced CMH burden through a greater number of intermediate-sized microhemorrhages (+80% to +180%). Although silent at onset, both baseline- and anticoagulant-enhanced CMH burdens increased mortality (+11% to +58%) along the following year without statistical difference among groups, and despite cessation of anticoagulation and absence of CMH progression or transformation into ICH. All survivor mice exhibited reduction in visual recognition memory from 9 months. In the healthy brain, DOACs preserve the onset of microhemorrhages from transformation into ICH, and do not precipitate cognitive impairment despite enhancement of CMH burden. High CMH burdens should however be considered for early detection and preventive memory care apart from anticoagulation decisions.
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Anticoagulantes/administración & dosificación , Hemorragia Cerebral/fisiopatología , Cognición/efectos de los fármacos , Cognición/fisiología , Microvasos/efectos de los fármacos , Microvasos/fisiología , Administración Oral , Animales , Anticoagulantes/efectos adversos , Hemorragia Cerebral/inducido químicamente , Hemorragia Cerebral/prevención & control , Masculino , Memoria/efectos de los fármacos , Memoria/fisiología , Ratones , Ratones Endogámicos C57BLRESUMEN
The risk of intracerebral hemorrhage still greatly limits the use of tPA in stroke patients. Research is ongoing in order to identify the pathophysiological mechanisms at play, detect predictive biomarkers and discover new pharmacological targets to develop preventive or curative treatments. Going through experimental and clinical studies, this review focuses on the role of neutrophils as key predictive biomarkers for thrombolysis-induced hemorrhages and as pharmacological targets to limit their occurrence. To date, there are no established pharmacological modulators of neutrophils for ischemic stroke and its hemorrhagic complications. Several strategies are under evaluation, including lipid-lowering drugs, free radical scavengers, or minocycline, as well as non-pharmacological interventions such as physical exercise.
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Hemorragia Cerebral/inducido químicamente , Fibrinolíticos/efectos adversos , Neutrófilos/efectos de los fármacos , Accidente Cerebrovascular/inmunología , Activador de Tejido Plasminógeno/efectos adversos , Animales , Biomarcadores , Hemorragia Cerebral/inmunología , Humanos , Neutrófilos/inmunología , Accidente Cerebrovascular/tratamiento farmacológicoRESUMEN
Analgesics such as opioid agonists are usually not given during the postoperative phase of experimental stroke because they are susceptible to interfere with the evaluation of neuroprotective therapies. Here, we investigate the potential of acetaminophen and nefopam, two nonopioid analgesic drugs, to exert an analgesic effect without inducing neuroprotection in a murine model of ischemic stroke. We demonstrate that acetaminophen (200 mg/kg, PO) induces a significant decrease in the infarct volume, particularly in the cortex (VEHICLE: 200.1 mm3 vs. ACETAMINOPHEN: 140.9 mm3 , P < 0.05), while nefopam (2, 20 or 40 mg/kg, IM), administered at the end of middle cerebral artery occlusion (MCAO), do not influence the infarct size (VEHICLE: 268.6 mm3 vs. NEFOPAM 2: 248.8 mm3 , NEFOPAM 20: 250.6 mm3 and NEFOPAM 40: 215.9 mm3 , P > 0.05). Moreover, we find that nefopam administration (20 mg/kg, IM) in the acute postoperative phase do not change the level of neuroprotection induced by MK801 (3 mg/kg, IV), a well-known neuroprotectant (VEHICLE: 268.6 mm3 vs. MK801: 194.4 mm3 and vs. MK801 + NEFOPAM 20: 195.2 mm3 ). On the other hand, although nefopam induces analgesia in healthy animals, it is not the case when administered during MCAO (behavior scores at 5 min: HEALTHY: 2.1 vs. HEALTHY + NEFOPAM 20: 0.6, P < 0.5; IR: 0.40 vs. IR + NEFOPAM 20: 0.67, P > 0.05). Our data suggest that neither acetaminophen nor nefopam can be used as analgesic agents to meet the needs of limiting rodent pain and distress during experimental stroke surgery.
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Acetaminofén/farmacología , Analgésicos no Narcóticos/farmacología , Nefopam/farmacología , Dolor Postoperatorio/tratamiento farmacológico , Acetaminofén/administración & dosificación , Analgésicos no Narcóticos/administración & dosificación , Animales , Isquemia Encefálica/prevención & control , Modelos Animales de Enfermedad , Maleato de Dizocilpina/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Infarto de la Arteria Cerebral Media , Masculino , Nefopam/administración & dosificación , Fármacos Neuroprotectores/farmacología , Ratas , Ratas Wistar , Accidente Cerebrovascular/prevención & control , Procedimientos Quirúrgicos Operativos/métodosRESUMEN
Background: Persistent pulmonary hypertension of the newborn (PPHN) causes significant morbidity and mortality in neonates. n-3 Poly-unsaturated fatty acids have vasodilatory properties in the perinatal lung. We studied the circulatory effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in fetal sheep and in fetal pulmonary arterial rings. Methods: At 128 days of gestation, catheters were placed surgically in fetal systemic and pulmonary circulation, and a Doppler probe around the left pulmonary artery (LPA). Pulmonary arterial pressure and LPA flow were measured while infusing EPA or DHA for 120 min to the fetus, to compute pulmonary vascular resistance (PVR). The dose effects of EPA or DHA were studied in vascular rings pre-constricted with serotonin. Rings treated with EPA were separated into three groups: E+ (intact endothelium), E- (endothelium stripped) and LNA E+ (pretreatment of E+ rings with l-nitro-arginine). Results: EPA, but not DHA, induced a significant and prolonged 25% drop in PVR (n = 8, p < 0.001). Incubation of vascular rings with EPA (100 µM) caused a maximum relaxation of 60% in the E+ (n = 6), whereas vessel tone did not change in the E- (n = 6, p < 0.001). The vascular effects of EPA were significantly decreased in LNA E+ (n = 6). Incubation with DHA resulted in only a mild relaxation at the highest concentration of DHA (300 µM) compared to E+. Conclusions: EPA induces a sustained pulmonary vasodilatation in fetal lambs. This effect is endothelium- and dose-dependent and involves nitric oxide (NO) production. We speculate that EPA supplementation may improve pulmonary circulation in clinical conditions with PPHN.
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Ácidos Docosahexaenoicos/sangre , Ácidos Docosahexaenoicos/farmacología , Ácido Eicosapentaenoico/sangre , Ácido Eicosapentaenoico/farmacología , Feto/efectos de los fármacos , Circulación Pulmonar/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Femenino , Hemodinámica , Óxido Nítrico/metabolismo , Embarazo , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/metabolismo , Ovinos , Vasodilatación/efectos de los fármacosRESUMEN
Inflammatory injury and hypoperfusion following cardiopulmonary bypass (CPB) are associated with potential brain injury in relationship between CPB, memory impairment, changes in cerebral vascular reactivity and both systemic and cerebral inflammatory reaction. The objective of this study was to assess the preventive effect of a pretreatment with simvastatin or fenofibrate on neurovascular and cognitive consequences of CPB. Male Sprague-Dawley rats were treated by control diet, simvastatin 10 mg/kg/day or fenofibrate 200 mg/kg/day for 14 days before CPB surgery and were sacrificed immediately after surgery or 24h later. Cognitive function, vascular reactivity, neuronal counts in CA1 and CA3 hippocampal regions, and inflammatory markers were assessed. CPB induced memory impairment and endothelial dysfunction 24h after surgery associated with neuronal loss. Neuronal loss was reduced by simvastatin or fenofibrate treatment in parallel to memory alteration prevention. Pretreatment by simvastatin and fenofibrate prevented CPB-induced endothelial dysfunction. CPB led to early and marked release of TNFα and overexpression of ICAM-1. Both inflammatory marker expression was decreased in the pretreated groups by lipid-lowering drugs. In a rat model of CPB, we demonstrated that simvastatin and fenofibrate protected against CPB-induced endothelial dysfunction, cerebral and systemic inflammation in parallel to memory impairment prevention.
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Puente Cardiopulmonar/efectos adversos , Trastornos Cerebrovasculares/prevención & control , Trastornos del Conocimiento/prevención & control , Hipolipemiantes/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Animales , Reacción de Prevención/efectos de los fármacos , Trastornos Cerebrovasculares/inmunología , Trastornos Cerebrovasculares/metabolismo , Trastornos Cerebrovasculares/patología , Trastornos del Conocimiento/inmunología , Trastornos del Conocimiento/metabolismo , Trastornos del Conocimiento/patología , Endotelio Vascular/efectos de los fármacos , Fenofibrato/administración & dosificación , Fenofibrato/uso terapéutico , Hemodinámica/efectos de los fármacos , Hipolipemiantes/administración & dosificación , Lípidos/sangre , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/inmunología , Neuronas/patología , Fármacos Neuroprotectores/administración & dosificación , Ratas Sprague-Dawley , Simvastatina/administración & dosificación , Simvastatina/uso terapéutico , Factor de Necrosis Tumoral alfa/sangre , Vasodilatación/efectos de los fármacosRESUMEN
OBJECTIVE: To determine whether the ratio single chain (sc)/(sc + 2 chain [tc]) recombinant tissue plasminogen activator (rtPA) influences outcomes in patients with cerebral ischemia. METHODS: We prospectively included consecutive patients treated with IV rtPA for cerebral ischemia in 13 stroke centers and determined the sc/(sc + tc) ratio in the treatment administered to each patient. We evaluated the outcome with the modified Rankin Scale (mRS) at 3 months (prespecified analysis) and occurrence of epileptic seizures (post hoc analysis). We registered Outcome of Patients Treated by IV Rt-PA for Cerebral Ischaemia According to the Ratio Sc-tPA/Tc-tPA (OPHELIE) under ClinicalTrials.gov identifier no. NCT01614080. RESULTS: We recruited 1,004 patients (515 men, median age 75 years, median onset-to-needle time 170 minutes, median NIH Stroke Scale score 10). We found no statistical association between sc/(sc + tc) ratios and handicap (mRS > 1), dependency (mRS > 2), or death at 3 months. Patients with symptomatic intracerebral hemorrhages had lower ratios (median 69% vs 72%, adjusted p = 0.003). The sc/(sc + tc) rtPA ratio did not differ between patients with and without seizures, but patients with early seizures were more likely to have received a sc/(sc + tc) rtPA ratio >80.5% (odds ratio 3.61; 95% confidence interval 1.26-10.34). CONCLUSIONS: The sc/(sc + tc) rtPA ratio does not influence outcomes in patients with cerebral ischemia. The capacity of rtPA to modulate NMDA receptor signaling might be associated with early seizures, but we observed this effect only in patients with a ratio of sc/(sc + tc) rtPA >80.5% in a post hoc analysis.
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Isquemia Encefálica/tratamiento farmacológico , Fibrinolíticos/uso terapéutico , Accidente Cerebrovascular/tratamiento farmacológico , Terapia Trombolítica , Activador de Tejido Plasminógeno/uso terapéutico , Anciano , Anciano de 80 o más Años , Isquemia Encefálica/complicaciones , Isquemia Encefálica/mortalidad , Hemorragia Cerebral/complicaciones , Evaluación de la Discapacidad , Femenino , Fibrinolíticos/química , Humanos , Masculino , Persona de Mediana Edad , Proteínas Recombinantes/química , Proteínas Recombinantes/uso terapéutico , Convulsiones/complicaciones , Índice de Severidad de la Enfermedad , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/mortalidad , Tiempo de Tratamiento , Activador de Tejido Plasminógeno/química , Resultado del TratamientoRESUMEN
1. The polymorphonuclear neutrophils (PMN) activation and mobilization observed in acute cerebral infarction contribute to the brain tissue damage, but PMN could also be involved in postischemic functional injury of ischemied blood vessel. 2. This study was undertaken to investigate whether pharmacological neutropenia could modify the postischemic endothelial dysfunction in comparison to smooth muscle whose impairment is likely more related to reperfusion and oxidative stress. 3. A cerebral ischemia-reperfusion by endoluminal occlusion of right middle cerebral artery (MCA) was performed 4 days after intravenous administration of vinblastine or 12 h after RP-3 anti-rat neutrophils monoclonal antibody (mAb RP-3) injection into the peritoneal cavity, on male Wistar rats with 1-h ischemia then followed by 24-h reperfusion period. Brain infarct volume was measured by histomorphometric analysis and vascular endothelial and smooth muscle reactivity of MCA was analysed using Halpern myograph. 4. Neutropenia induced a neuroprotective effect as demonstrated by a significant decrease of brain infarct size. In parallel to neuroprotection, neutropenia prevented postischemic impairment of endothelium-dependent relaxing response to acetylcholine. In contrast, smooth muscle functional alterations were not prevented by neutropenia. Ischemia-reperfusion-induced myogenic tone impairment remained unchanged in vinblastine and mAb RP-3-treated rats. Postischemic Kir2.x-dependent relaxation impairment was not prevented in neutropenic conditions. The fully relaxation of smooth muscle response to sodium nitroprusside was similar in all groups. 5. Our results evidenced the dissociate prevention of pharmacologically induced neutropenia on postischemic vascular endothelial and smooth muscle impairment. The selective endothelial protection by neutropenia is parallel to a neuroprotective effect suggesting a possible relationship between the two phenomena.
Asunto(s)
Endotelio Vascular/fisiología , Infarto de la Arteria Cerebral Media/prevención & control , Músculo Liso Vascular/fisiología , Neutropenia/inducido químicamente , Animales , Relación Dosis-Respuesta a Droga , Endotelio Vascular/efectos de los fármacos , Infarto de la Arteria Cerebral Media/fisiopatología , Masculino , Músculo Liso Vascular/efectos de los fármacos , Neutropenia/fisiopatología , Ratas , Ratas Wistar , Vinblastina/toxicidadRESUMEN
The impact of fenofibrate, a peroxisome proliferator-activated receptor-alpha (PPAR-α) agonist, on the risk of thrombolysis-induced hemorrhage during the acute phase of stroke in a rat model of stroke was studied. One-hour middle cerebral artery occlusion followed by thrombolysis with tissue plasminogen activator was made in rats receiving either fenofibrate or vehicle for 72 h after stroke. Evaluation of infarct, hemorrhage, middle cerebral artery vasoreactivity, and immunochemistry (CD11b for microglial activation, myeloperoxidase, and ICAM-1 for neutrophil infiltration) was performed. The PPAR-alpha agonist significantly reduced the risk of hemorrhage after thrombolysis in parallel with a decrease in the infarct volume and in the stroke-induced vascular endothelial dysfunction. These effects are concomitant with a reduction in microglial activation and neutrophil infiltration in infarct area. Our results strengthen the idea that using drugs such as fenofibrate, with pleiotropic properties due to PPAR-alpha agonism, may be of value to reduce thrombolysis-induced hemorrhage during acute stroke.
RESUMEN
There is now substantial data in the literature showing that statins can protect against cerebral ischemia. This neuroprotective potency is related to their pleiotropic effects that modulate various pathways implicated in the pathophysiology of stroke. It has been demonstrated that statins exert anti-inflammatory and vasculoprotective effects, thus contributing to a reduction in infarct size. The underlying mechanisms are still incompletely known. As a cross-talk between statins and the nuclear receptor PPARα has been described, we hypothesized that this cross-talk is necessary to neuroprotection in stroke. We studied the effects of a 14-day preventive atorvastatin treatment (10 mg/kg/day) on C57Bl6 wild-type and PPARα-KO mice submitted to experimental stroke. PPARα was involved in the atorvastatin-induced neuroprotective effect, as confirmed by the measurement of infarct volumes. We also evidenced that the anti-inflammatory action of atorvastatin is mediated, at least partly, by PPARα. The decrease in IL-6 plasmatic levels was PPARα dependent. The cerebral expression of the adhesion molecules ICAM-1 and vascular cell adhesion molecule was reduced by the atorvastatin treatment, and this effect was PPARα dependent in the cortex but not in the striatum of treated animals. Atorvastatin also diminished the cerebral expression of iNOS in the cortex, but had no effect in the striatum of treated mice, whatever the PPARα status. At the vascular level, we found that the atorvastatin-related endothelial nitric oxide synthase upregulation was regulated by PPARα in the aorta, while there was no effect in the brain. We demonstrate here that PPARα is a key mediator of the multitargeted neuroprotective effects of statins in stroke.
Asunto(s)
Ácidos Heptanoicos/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , PPAR alfa/metabolismo , Pirroles/uso terapéutico , Accidente Cerebrovascular/prevención & control , Animales , Atorvastatina , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Modelos Animales de Enfermedad , Expresión Génica/efectos de los fármacos , Ácidos Heptanoicos/administración & dosificación , Molécula 1 de Adhesión Intercelular/genética , Molécula 1 de Adhesión Intercelular/metabolismo , Interleucina-6/sangre , Lípidos/sangre , Ratones Endogámicos C57BL , Ratones Noqueados , Fármacos Neuroprotectores/administración & dosificación , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , PPAR alfa/genética , Pirroles/administración & dosificación , Accidente Cerebrovascular/inmunología , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/patología , Molécula 1 de Adhesión Celular Vascular/genética , Molécula 1 de Adhesión Celular Vascular/metabolismoRESUMEN
In stroke, there is an imperative need to develop disease-modifying drugs able to (1) induce neuroprotection and vasculoprotection, (2) modulate recovery and brain plasticity, and (3) limit the short-term motor and cognitive consequences. We hypothesized that fenofibrate, a peroxisome proliferator-activated receptor-α (PPAR-α) agonist, could exert a beneficial effect on immediate and short-term poststroke consequences related to its pleiotropic mechanisms. Rats or mice were subjected to focal ischemia to determine the effects of acute treatment by fenofibrate on (i) motor and memory impairment, (2) both cerebral and vascular compartments, (3) inflammation, (4) neurogenesis, and (5) amyloid cascade. We show that fenofibrate administration results in both neuronal and vascular protection and prevents the short-term motor and cognitive poststroke consequences by interaction with several mechanisms. Modulation of PPAR-α generates beneficial effects in the immediate poststroke consequences by mechanisms involving the interactions between polynuclear neutrophils and the vessel wall, and microglial activation. Fenofibrate modulates mechanisms involved in neurorepair and amyloid cascade. Our results suggest that PPAR-α agonists could check the key points of a potential disease-modifying effect in stroke.