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3.
Nervenarzt ; 90(10): 987-994, 2019 Oct.
Artículo en Alemán | MEDLINE | ID: mdl-31407044

RESUMEN

Significant advances in the acute treatment of patients with intracerebral hemorrhage (ICH) have been achieved in recent years. While many randomized trials have provided neutral results, important findings have been generated for the design of follow-up studies. Furthermore, a number of observational studies have been published, which in turn provide the basis for further methodologically stronger investigations. The focus is on avoidance of early bleeding progression, which can be influenced by blood pressure management and hemostasis. Furthermore, ICH surgery may experience a renaissance through minimally invasive techniques. In addition, perihemorrhagic edema and its pharmacological modulation are becoming increasingly more important. Optimal treatment of ventricular involvement is continuing to develop dynamically. Finally, long-term antithrombotic treatment has been intensely studied in observational analyses and is currently being investigated in randomized trials. This article addresses these most relevant topics in acute and long-term treatment of ICH patients and provides an overview of current debates in these areas of treatment.


Asunto(s)
Hemorragia Cerebral , Hemorragia Cerebral/tratamiento farmacológico , Hemorragia Cerebral/cirugía , Fibrinolíticos/uso terapéutico , Humanos , Procedimientos Quirúrgicos Mínimamente Invasivos/tendencias
4.
Med Klin Intensivmed Notfmed ; 114(7): 613-619, 2019 Oct.
Artículo en Alemán | MEDLINE | ID: mdl-31468107

RESUMEN

BACKGROUND: Intracerebral hemorrhage (ICH) represents one of the most severe forms of stroke with high morbidity and mortality; however, effective treatment options to significantly improve patient outcome do not exist so far. OBJECTIVE: This review article evaluates the most recent developments in acute ICH treatment. MATERIAL AND METHODS: Analysis and interpretation of currently available evidence regarding ICH treatment, focusing on the most important studies from the last 3 years. RESULTS: Hematoma enlargement, perhaps the most important prognostic factor, should be counteracted by aggressive blood pressure management (targeted systolic pressure 140 mm Hg). In cases of ICH under oral anticoagulation, inhibition of coagulation must be immediately antagonized: vitamin K antagonists with prothrombin complex concentrates (PCC), idarucizumab for dabigatran and andexanet if available or high-dose PCC for factor Xa inhibitors. Currently, surgical treatment strategies, both open and minimally invasive, to evacuate the hematoma can currently not be routinely recommended. In patients with intraventricular ICH, treatment with intraventricular fibrinolysis with or without additional lumbar drainage represents a promising treatment option. CONCLUSION: In recent years, several randomized controlled and observational studies have generated robust evidence regarding ICH treatment; however, there is still no single breakthrough intervention, which significantly improves patient functional outcome. Nevertheless, the sum of various, possibly interacting treatment concepts may potentially improve outcome after ICH.


Asunto(s)
Anticoagulantes , Hemorragia Cerebral , Anticoagulantes/uso terapéutico , Antihipertensivos/uso terapéutico , Factores de Coagulación Sanguínea/uso terapéutico , Hemorragia Cerebral/tratamiento farmacológico , Hemorragia Cerebral/cirugía , Dabigatrán , Inhibidores del Factor Xa , Hematoma , Humanos
5.
J Biomed Sci ; 26(1): 53, 2019 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-31307481

RESUMEN

BACKGROUND: Intracerebral hemorrhage (ICH) induces a complex sequence of apoptotic cascades that contribute to secondary neuronal damage. Tropomyosin-related kinase receptor B (TrkB) signaling plays a crucial role in promoting neuronal survival following brain damage. METHODS: The present study investigated the protective effects and underlying mechanisms of TrkB activation by the specific TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF), in a model of collagenase-induced ICH and in neuronal cultures. Mice subjected to collagenase-induced ICH were intraperitoneally injected with either 7,8-DHF or vehicle 10 min after ICH and, subsequently, daily for 3 days. Behavioral studies, brain edema measurement, and histological analysis were conducted. Levels of TrkB signaling-related molecules and apoptosis-related proteins were analyzed by western blots. RESULTS: Treatment with 20 mg/kg 7,8-DHF significantly improved functional recovery and reduced brain damage up to 28 days post-ICH. Reduction in neuronal death, apoptosis, and brain edema were also observed in response to 7,8-DHF treatment at 3 days post-ICH. These changes were accompanied by a significant increase in the phosphorylation of TrkB and Akt (Ser473/Thr308) at 1 and 3 days, but had no effect on Erk 44/42 phosphorylation. 7,8-DHF also enhanced the phosphorylation of Ask-1 Ser967 and FOXO-1, downstream targets of Akt at 1 and 3 days. Moreover, 7,8-DHF increased brain-derived neurotrophic factor levels at 1 day. In primary cultured neurons stimulated with hemin, 7,8-DHF promoted survival and reduced apoptosis. Furthermore, delaying the administration of 7,8-DHF to 3 h post-ICH reduced brain tissue damage and neuronal death. CONCLUSIONS: Our findings demonstrate that the activation of TrkB signaling by 7,8-DHF protects against ICH via the Akt, but not the Erk, pathway. These data provide new insights into the role of TrkB signaling deficit in the pathophysiology of ICH and highlight TrkB/Akt as possible therapeutic targets in this disease.


Asunto(s)
Hemorragia Cerebral/tratamiento farmacológico , Flavonas/farmacología , Glicoproteínas de Membrana/agonistas , Fármacos Neuroprotectores/farmacología , Transducción de Señal/efectos de los fármacos , Animales , Hemorragia Cerebral/inducido químicamente , Colagenasas/toxicidad , Inyecciones Intraperitoneales , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas Tirosina Quinasas , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo
6.
J Stroke Cerebrovasc Dis ; 28(8): 2262-2267, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31178359

RESUMEN

BACKGROUND AND PURPOSE: Uncertainty persists over the effects of blood pressure-lowering treatment in acute intracerebral hemorrhage (ICH). We assessed the effects of treatment with candesartan in acute ICH and according to different types of hematoma. METHODS: Post-hoc analysis of the Scandinavian Candesartan Acute Stroke Trial, a randomized- and placebo-controlled, double-masked trial of candesartan in patients with any stroke within the acute phase (<30 hours) and high systolic blood pressure (≥140 mm Hg). We collected baseline computed tomography scans of participants with ICH, and characterized hematoma volume (planimetric approach), location (deep versus lobar or infratentorial), hemisphere side, and presence of intraventricular hemorrhage. The trial's 2 coprimary effect variables were the composite endpoint of vascular death, stroke or myocardial infarction, and functional outcome at 6 months according to the modified Rankin scale. We used Cox, ordinal, and binary logistic regression for analysis and adjusted for key, predefined prognostic variables. RESULTS: Of 274 participants with ICH, computed tomography scans were available in 205 patients (74.8%). There were no significant differences between the candesartan and placebo groups with respect to hematoma volume (median 15.6 mL versus 13.5 mL, P = .96), deep location (77% versus 72%, P = .64), right hemisphere (49% versus 51%, P = .46), and presence of intraventricular hemorrhage (18% versus 11%, P = .22). Candesartan was associated with a significant increase in poor functional outcome in patients with deep hematoma (adjusted common odds ratio 2.27, 95% confidence interval 1.23-4.18, P = .009, P for interaction .015), but there was no differential effect on functional outcome or vascular events in any of the other imaging subgroups. CONCLUSIONS: Candesartan was not associated with any beneficial effect when initiated in the acute phase of ICH, a possible adverse effect on functional outcome in patients with deep hematomas cannot be ruled out by this study alone.


Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Antihipertensivos/uso terapéutico , Bencimidazoles/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Hemorragia Cerebral/tratamiento farmacológico , Hematoma/tratamiento farmacológico , Tetrazoles/uso terapéutico , Anciano , Anciano de 80 o más Años , Bloqueadores del Receptor Tipo 1 de Angiotensina II/efectos adversos , Antihipertensivos/efectos adversos , Bencimidazoles/efectos adversos , Hemorragia Cerebral/diagnóstico por imagen , Hemorragia Cerebral/fisiopatología , Método Doble Ciego , Femenino , Hematoma/diagnóstico por imagen , Hematoma/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Países Escandinavos y Nórdicos , Tetrazoles/efectos adversos , Factores de Tiempo , Tomografía Computarizada por Rayos X , Resultado del Tratamiento
7.
Int J Pharm ; 566: 342-351, 2019 Jul 20.
Artículo en Inglés | MEDLINE | ID: mdl-31158456

RESUMEN

In situ keratin hydrogel offer a promising strategy to relieve the brain injury after intracerebral hemorrhage (ICH) by delivering the iron chelator directly to the stroke site. However, the injectable property of traditional keratin hydrogel is unsatisfactory, which can't provide adaptable filling of lesion defects with irregular shapes. Herein, the thermo sensitive keratin-g-PNIPAM polymers with different graft ratios were synthesized, and deferoxamine mesylate (DFO) loaded thermo sensitive keratin hydrogels (TKGs) were prepared using the oxidative crosslinking method. The lower critical solution temperature of TKGs can be tailored from 28.5 to 31.8 °C by varying the graft ratios of keratin to NIPAM, and TKG can fill up the complex shapes of lesion cavities easily due to the characteristic of sol-gel transition. In addition, TKGs exhibit stronger adsorption and clearance capacities for the Fe2+ than keratin gel. Meanwhile, in situ injection of TKG with different DFO loadings (0.1, 1.0, and 10 mg/mL) into the hematoma region after ICH surgery showed a stronger effect on the reduction of ICH-induced iron deposits, brain non-heme iron content, brain edema and ROS level compared to the DFO treatment by intraperitoneal administration. Thus, the developed TKG can be potentially exploited for iron-induced brain injury after ICH.


Asunto(s)
Resinas Acrílicas/administración & dosificación , Lesiones Encefálicas/tratamiento farmacológico , Deferoxamina/administración & dosificación , Hidrogeles/administración & dosificación , Hierro , Queratinas/administración & dosificación , Sideróforos/administración & dosificación , Resinas Acrílicas/química , Adsorción , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Lesiones Encefálicas/inducido químicamente , Hemorragia Cerebral/tratamiento farmacológico , Deferoxamina/química , Modelos Animales de Enfermedad , Liberación de Fármacos , Hidrogeles/química , Hierro/química , Queratinas/química , Masculino , Ratas Sprague-Dawley , Sideróforos/química , Temperatura Ambiental
8.
J Clin Neurosci ; 66: 33-37, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31160199

RESUMEN

Antiplatelet therapy at the time of spontaneous intracerebral hemorrhage (sICH) may increase risk for hemorrhage expansion and mortality. Current guidelines recommend considering a single dose of desmopressin in sICH associated with cyclooxygenase-1 inhibitors or adenosine diphosphate receptor inhibitors. Adult subjects with sICH and concomitant antiplatelet therapy admitted to a large, tertiary care center were included. We sought to compare the risk of hematoma expansion in patients that received desmopressin for antiplatelet reversal in the setting of sICH to similar patients that did not receive desmopressin. The primary outcomes were the incidence of relative and absolute hematoma expansion. In total, 71 patients (29 received desmopressin, 42 did not receive desmopressin) were analyzed. All patients in the desmopressin group received a 0.3 mcg/kg intravenous dose prior to hematoma expansion assessment. Relative hematoma expansion occurred in 5/29 (17%) with desmopressin compared to 11/42 (26%) without desmopressin (OR 0.59 [95% CI 0.18-1.92]). Absolute hematoma expansion occurred in 9/29 (30%) with desmopressin compared to 12/42 (28%) without desmopressin (OR 1.13 [95% CI 0.40-3.16]). Multiple logistic regression controlling for significant covariates did not reveal a significant effect of desmopressin on relative or absolute hematoma expansion (OR 0.65 [95% CI 0.18-2.43] and OR 1.55 [0.48-4.99], respectively). We failed to find evidence that desmopressin administration for antiplatelet reversal in sICH reduces the incidence of hematoma expansion. Larger studies, focusing on the early phase of sICH, are needed to characterize the clinical efficacy and safety of desmopressin for antiplatelet reversal before widespread implementation.


Asunto(s)
Hemorragia Cerebral/tratamiento farmacológico , Hemorragia Cerebral/epidemiología , Desamino Arginina Vasopresina/administración & dosificación , Hematoma/tratamiento farmacológico , Hematoma/epidemiología , Hemostáticos/administración & dosificación , Inhibidores de Agregación Plaquetaria/administración & dosificación , Administración Intravenosa , Adulto , Anciano , Anciano de 80 o más Años , Hemorragia Cerebral/inducido químicamente , Estudios de Cohortes , Femenino , Hematoma/inducido químicamente , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de Agregación Plaquetaria/efectos adversos , Estudios Retrospectivos , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/epidemiología , Factores de Tiempo , Resultado del Tratamiento
9.
Crit Care ; 23(1): 206, 2019 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-31171018

RESUMEN

In light of an aging population with increased cardiovascular comorbidity, the use of oral anticoagulation (OAC) is steadily expanding. A variety of pharmacological alternatives to vitamin K antagonists (VKA) have emerged over recent years (direct oral anticoagulants, DOAC, i.e., dabigatran, rivaroxaban, apixaban, and edoxaban) which show a reduced risk for the occurrence of intracerebral hemorrhage (ICH). Yet, in the event of ICH under OAC (OAC-ICH), hematoma characteristics are similarly severe and clinical outcomes likewise substantially limited in both patients with VKA- and DOAC-ICH, which is why optimal acute hemostatic treatment in all OAC-ICH needs to be guaranteed. Currently, International Guidelines for the hemostatic management of patients with OAC-ICH are updated as several relevant large-sized observational studies and recent trials have established treatment approaches for both VKA- and DOAC-ICH. While the management of VKA-ICH is mainly based on the immediate reversal of elevated levels of international normalized ratio using prothrombin complex concentrates, hemostatic management of DOAC-associated ICH is challenging requiring specific antidotes, notably idarucizumab and andexanet alfa. This review will provide an overview of the latest studies and trials on hemostatic reversal agents and timing and summarizes the effects on hemorrhage progression and clinical outcomes in patients with OAC-ICH.


Asunto(s)
Anticoagulantes/efectos adversos , Antídotos/farmacología , Hemorragia Cerebral/tratamiento farmacológico , Administración Oral , Anticoagulantes/uso terapéutico , Antídotos/efectos adversos , Antídotos/uso terapéutico , Antitrombinas/efectos adversos , Antitrombinas/uso terapéutico , Coagulación Sanguínea/efectos de los fármacos , Hemorragia Cerebral/complicaciones , Factor Xa/uso terapéutico , Inhibidores del Factor Xa/efectos adversos , Inhibidores del Factor Xa/uso terapéutico , Humanos , Proteínas Recombinantes/uso terapéutico , Ácido Tranexámico/efectos adversos , Ácido Tranexámico/uso terapéutico
10.
Neuroscience ; 409: 43-57, 2019 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-31047976

RESUMEN

Inflammation aggravates the lethal consequences of intracerebral hemorrhage. Recently, many studies have found that nuclear factor-κB (NF-κB) is a crucial transcription factor that initiates inflammation in the perihematomal region of ICH. NF-κB essential modulator (NEMO)-binding domain (NBD) peptide, a cell-permeable peptide spanning the NBD of IKKα or IKKß, functions as a highly specific inhibitor of NF-κB. This peptide can negatively regulate the NF-κB pathway. The present study aimed to explore the effects and underlying pathomechanisms of NBD peptides after ICH. Striatum infusion of whole blood or saline was performed on C57BL/6 mice (n = 198). Experimental animals were administered NBD or control (mutated) peptides 2 h before or after ICH by intracerebroventricular injection (icv.). NBD peptides significantly inhibited edema formation, ameliorated the neurological deficits, markedly reduced IκBα and p65 phosphorylation, blocked nuclear translocation of p65, and upregulated IκBα expression by NF-κB after ICH induction. Using an in vitro hemin toxicity model, we investigated the effects of NBD peptides on microglial inflammation. We found that NBD peptides suppressed microglia inflammation and lowered the expression of TNF-α and IL-1ß in both in vivo and in vitro experiments. Further experiments were performed in mice and cultured microglia, which treated with NBD peptides in the presence of p65 siRNA confirmed that the specificity of NBD peptides inhibit ICH-induced NF-κB activation. This study demonstrated that NBD peptides exert a neuroprotective role after ICH and might be a potential candidate for a novel therapeutic strategy for ICH.


Asunto(s)
Edema Encefálico/tratamiento farmacológico , Hemorragia Cerebral/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Péptidos/uso terapéutico , Regulación hacia Arriba/efectos de los fármacos , Animales , Edema Encefálico/metabolismo , Hemorragia Cerebral/metabolismo , Quinasa I-kappa B/metabolismo , Interleucina-1beta/metabolismo , Ratones , Microglía/efectos de los fármacos , Microglía/metabolismo , FN-kappa B/metabolismo , Fármacos Neuroprotectores/farmacología , Péptidos/farmacología , Fosforilación/efectos de los fármacos , ARN Interferente Pequeño , Transducción de Señal/efectos de los fármacos , Factor de Transcripción ReIA/metabolismo , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/metabolismo
11.
Seizure ; 69: 140-146, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31048270

RESUMEN

PURPOSE: The purpose of this analysis is to assess the effect of antiepileptics (AEDs) on seizure prevention and short and long term functional outcomes in patients with acute intracerebral hemorrhage. METHOD: The meta-analysis was conducted using the PRISMA guidelines. A literature search was performed of the PubMed, the Cochrane Library, and EMBASE databases. Search terms included "Anticonvulsants", "Intracerebral Hemorrhage", and related subject headings. Articles were screened and included if they were full-text and in English. Articles that did not perform multivariate regression were not included. Overall effect size was evaluated with forest plots and publication bias was assessed with the Begg's and Egger's tests. RESULTS: A total of 3912 articles were identified during the initial review. After screening, 54 articles remained for full review and 6 articles were included in the final analysis. No significant association between the use of AEDs after ICH and functional outcome (OR 1.53 [95%CI: 0.81-2.88] P = 0.18, I2 = 81.7%). Only one study evaluated the effect AEDs had in preventing post-ICH seizures. CONCLUSIONS: The use of prophylactic AEDs was not associated with improved short and long outcomes after acute ICH. This analysis supports the 2015 AHA/ASA recommendation against prophylactic AEDs (class III; level of evidence b).


Asunto(s)
Anticonvulsivantes/uso terapéutico , Hemorragia Cerebral/tratamiento farmacológico , Convulsiones/prevención & control , Hemorragia Cerebral/complicaciones , Humanos , Convulsiones/etiología , Factores de Tiempo , Resultado del Tratamiento
12.
PLoS One ; 14(5): e0215952, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31042750

RESUMEN

The sulfonylurea 1 transient receptor potential melastatin 4 (Sur1-Trpm4) receptor is selectively expressed after intracerebral hemorrhage (ICH). This upregulation contributes to increases in intracellular sodium. Water follows sodium through aquaporin channels, leading to cytotoxic edema. Even after edema is thought to have resolved, ionic dyshomeostasis persists, as does blood-brain barrier (BBB) damage. Glibenclamide, a hypoglycemic agent that inhibits Sur1-Trpm4, has been shown to reduce BBB damage and edema following infusion of autologous blood into the brain (ICH) as well as after other brain injuries. In order to further assess efficacy, we used the collagenase ICH model in rats to test whether glibenclamide reduces edema, attenuates ion dyshomeostasis, improves BBB damage, and reduces lesion volume. We tested a widely-used glibenclamide dose shown effective in other studies (10 µg/kg loading dose followed by 200 ng/hr for up to 7 days). Early initiation of glibenclamide did not significantly impact edema (72 hours), BBB permeability (72 hours), or lesion volume after ICH (28 days). Recovery from neurological impairments was also not improved by glibenclamide. These results suggest that glibenclamide will not improve outcome in ICH. However, the treatment appeared to be safe as there was no effect on bleeding or other physiological variables.


Asunto(s)
Hemorragia Cerebral/tratamiento farmacológico , Colagenasas/metabolismo , Gliburida/uso terapéutico , Hipoglucemiantes/uso terapéutico , Animales , Conducta Animal/efectos de los fármacos , Glucemia/análisis , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Edema Encefálico/patología , Hemorragia Cerebral/etiología , Hemorragia Cerebral/patología , Colagenasas/toxicidad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Gliburida/farmacología , Hipoglucemiantes/farmacología , Masculino , Ratas , Ratas Sprague-Dawley , Sodio/metabolismo , Receptores de Sulfonilurea/antagonistas & inhibidores , Receptores de Sulfonilurea/metabolismo , Canales Catiónicos TRPM/antagonistas & inhibidores , Canales Catiónicos TRPM/metabolismo , Temperatura Ambiental
13.
Int Immunopharmacol ; 72: 473-478, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31039464

RESUMEN

BACKGROUND: Intracerebral hemorrhage (ICH) is a severe type of stroke without effective treatment. The coagulation cascade is activated after blood flows into the brain parenchyma. The conversion of fibrinogen to fibrin is an essential step of coagulation processes, but its influences on neuroinflammation and long-term outcome after ICH have not been adequately studied. Hirudin binds to thrombin and inhibits the conversion of fibrinogen to fibrin. We therefore investigated the impact of hirudin treatment on brain inflammation and long-term outcome of ICH in mice. METHODS: Fibrinogen levels were measured in plasma samples from patients with ICH. In mice subjected to collagenase injection, fibrinogen levels were measured in the plasma and brain. The impact of hirudin on neuroinflammation and long-term neurological outcome was determined in ICH mice. RESULTS: Circulating fibrinogen level was increased in patients with ICH at day 1 and day 4 after onset. In ICH mice, fibrinogen levels in the blood and brain were increased at day 7. Delayed daily administration of hirudin from day 7 to day 28 significantly improved long-term outcome in ICH mice. Hirudin treatment reduced leukocyte accumulation in the brain and shifted microglia toward an anti-inflammatory phenotype. In addition, depletion of microglia in ICH mice diminished the benefit of hirudin in ICH mice. CONCLUSIONS: These results suggest that inhibition of fibrin formation alleviates brain inflammation and improves long-term outcome after ICH.


Asunto(s)
Encéfalo/efectos de los fármacos , Hemorragia Cerebral/sangre , Encefalitis/sangre , Fibrina/metabolismo , Fibrinógeno/metabolismo , Hirudinas/farmacología , Animales , Encéfalo/metabolismo , Hemorragia Cerebral/tratamiento farmacológico , Encefalitis/tratamiento farmacológico , Femenino , Terapia con Hirudina , Humanos , Masculino , Ratones Endogámicos C57BL
14.
Stroke ; 50(6): 1539-1547, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-31084334

RESUMEN

Background and Purpose- Our previous studies found that erythrocyte CD47 has a role in regulating hematoma resolution following experimental intracerebral hemorrhage (ICH). The current study examined whether or not a CD47 blocking antibody enhances hematoma clearance in a mouse ICH. Methods- ICH was induced by intracaudate injection of autologous blood in adult C57BL/6 mice. Mice had an ICH or ICH with CD47 blocking antibody or IgG coinjection. In subgroups of CD47 blocking antibody-treated mice, clodronate (to deplete microglia/macrophages) or control liposomes were coinjected. The effects of CD47 blocking antibody on ICH-induced brain injury were also tested in both males and females. Mice had magnetic resonance imaging to examine clot volume, iron deposition, brain swelling, and brain tissue loss. Behavioral tests were performed in all mice, and brains were harvested for brain immunohistochemistry. Results- In male mice, CD47 blocking antibody speeded up hematoma/iron clearance by macrophages/microglia and reduced ICH-induced brain swelling, neuronal loss, and neurological deficits. In contrast, clodronate liposome-induced microglia/macrophage depletion caused more severe brain swelling, neuronal loss, and functional deficits. In addition, similar injury severity in males and females was found in IgG control group and CD47 blocking antibody was also effective in females. Conclusions- Blocking CD47 in the hematoma speeded hematoma clearance and reduced brain injury after ICH suggesting it could be a treatment for ICH patients with surgical clot removal.


Asunto(s)
Anticuerpos Bloqueadores/farmacología , Encéfalo/diagnóstico por imagen , Antígeno CD47/antagonistas & inhibidores , Hemorragia Cerebral , Hematoma , Imagen por Resonancia Magnética , Animales , Encéfalo/patología , Edema Encefálico/diagnóstico por imagen , Edema Encefálico/tratamiento farmacológico , Hemorragia Cerebral/diagnóstico por imagen , Hemorragia Cerebral/tratamiento farmacológico , Hemorragia Cerebral/patología , Modelos Animales de Enfermedad , Femenino , Hematoma/diagnóstico por imagen , Hematoma/tratamiento farmacológico , Masculino , Ratones
15.
Stroke ; 50(6): 1392-1402, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-31092170

RESUMEN

Background and Purpose- Given inconclusive studies, it is debated whether clinical and imaging characteristics, as well as functional outcome, differ among patients with intracerebral hemorrhage (ICH) related to vitamin K antagonists (VKA) versus non-vitamin K antagonist (NOAC)-related ICH. Notably, clinical characteristics according to different NOAC agents and dosages are not established. Methods- Multicenter observational cohort study integrating individual patient data of 1328 patients with oral anticoagulation-associated ICH, including 190 NOAC-related ICH patients, recruited from 2011 to 2015 at 19 tertiary centers across Germany. Imaging, clinical characteristics, and 3-months modified Rankin Scale (mRS) outcomes were compared in NOAC- versus VKA-related ICH patients. Propensity score matching was conducted to adjust for clinically relevant differences in baseline parameters. Subgroup analyses were performed regarding NOAC agent, dosing and present clinically relevant anticoagulatory activity (last intake <12h/24h or NOAC level >30 ng/mL). Results- Despite older age in NOAC patients, there were no relevant differences in clinical and hematoma characteristics between NOAC- and VKA-related ICH regarding baseline hematoma volume (median [interquartile range]: NOAC, 14.7 [5.1-42.3] mL versus VKA, 16.4 [5.8-40.6] mL; P=0.33), rate of hematoma expansion (NOAC, 49/146 [33.6%] versus VKA, 235/688 [34.2%]; P=0.89), and the proportion of patients with unfavorable outcome at 3 months (mRS, 4-6: NOAC 126/179 [70.4%] versus VKA 473/682 [69.4%]; P=0.79). Subgroup analyses revealed that NOAC patients with clinically relevant anticoagulatory effect had higher rates of intraventricular hemorrhage (n/N [%]: present 52/109 [47.7%] versus absent 9/35 [25.7%]; P=0.022) and hematoma expansion (present 35/90 [38.9%] versus absent 5/30 [16.7%]; P=0.040), whereas type of NOAC agent or different NOAC-dosing regimens did not result in relevant differences in imaging characteristics or outcome. Conclusions- If effectively anticoagulated, there are no differences in hematoma characteristics and functional outcome among patients with NOAC- or VKA-related ICH. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT03093233.


Asunto(s)
Anticoagulantes/administración & dosificación , Hemorragia Cerebral/tratamiento farmacológico , Fibrinolíticos/administración & dosificación , Vitamina K/antagonistas & inhibidores , Administración Oral , Anciano , Anciano de 80 o más Años , Hemorragia Cerebral/diagnóstico por imagen , Hemorragia Cerebral/epidemiología , Femenino , Alemania/epidemiología , Humanos , Masculino , Estudios Retrospectivos
16.
Int J Pharm ; 566: 46-56, 2019 Jul 20.
Artículo en Inglés | MEDLINE | ID: mdl-31121211

RESUMEN

Intranasal drug delivery provided an alternative and effective approach for the intervention of an intracerebral hemorrhage (ICH). However, the short retention time at the absorption site and slow drug transport in intranasal gel influence the drug bioavailability and outcome of ICH. Herein, we fabricated a novel intranasal gel with oriented drug migration utilizing a charge-driven strategy to attenuate brain injury after ICH. Nicardipine hydrochloride (NCD) was entrapped in chitosan nanoparticles (CS NPs) and dispersed in an HAMC gel. Subsequently, one side of the gel was coated with a positively charged film. The oriented migration of CS NPs in the HAMC gel was determined, and the drug bioavailability was also enhanced. Furthermore, a blood-induced ICH rat model was established to evaluate the therapeutic effect of CS NPs + HAMC composites. Intranasal administration of the CS NPs + HAMC (+) composite showed a stronger neuroprotective effect in terms of brain edema reduction and neural apoptosis inhibition compared to the CS NPs + HAMC composite. These results suggested that the oriented and rapid drug transport from nose to brain can be achieved using the charge-driven strategy, and this intranasal drug delivery system has the potential to provide a new therapeutic strategy for the treatment of ICH.


Asunto(s)
Lesiones Encefálicas/tratamiento farmacológico , Hemorragia Cerebral/tratamiento farmacológico , Portadores de Fármacos/administración & dosificación , Fármacos Neuroprotectores/administración & dosificación , Nicardipino/administración & dosificación , Administración Intranasal , Animales , Quitosano/administración & dosificación , Quitosano/química , Quitosano/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Liberación de Fármacos , Geles , Ácido Hialurónico/administración & dosificación , Ácido Hialurónico/química , Ácido Hialurónico/farmacocinética , Masculino , Metilcelulosa/administración & dosificación , Metilcelulosa/química , Metilcelulosa/farmacocinética , Nanopartículas/administración & dosificación , Nanopartículas/química , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/farmacocinética , Nicardipino/química , Nicardipino/farmacocinética , Ratas Sprague-Dawley
17.
Stroke ; 50(5): 1095-1099, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30935318

RESUMEN

Background and Purpose- We sought to evaluate the available literature to determine whether primary seizure prevention with antiepileptic drugs reduces the risk of poor outcomes and clinically relevant seizures among adult patients with spontaneous intracerebral hemorrhage. Methods- Meta-analysis of observational studies and randomized controlled trials evaluating the use of any antiepileptic drug for primary seizure prevention among adult (≥18 years) patients with spontaneous intracerebral hemorrhage. The primary end point was poor clinical outcome at the longest recorded follow-up, defined as either a high (>3) modified Rankin Scale score or all-cause mortality during follow-up if the modified Rankin Scale score was not recorded. Early and late seizures were secondary outcomes. A random mixed effects model was used to estimate the pooled odds ratio of outcomes and associated 95% CI. Results- We identified 7 studies with a total of 3241 patients for analysis of the primary outcome and 4 studies with a total of 1861 patients for analysis of the secondary outcomes. Overall, the use of antiepileptic drugs was not associated with a high Rankin Scale or all-cause mortality (odds ratio: 0.99; 95% CI, 0.66-1.49) or incident seizures (odds ratio: 0.89; 95% CI, 0.52-1.51) at the longest recorded follow-up time. Conclusions- The use of antiepileptic drugs as primary prevention among adult patients with spontaneous intracerebral hemorrhage is not associated with improved neurological function during long-term follow-up. Future studies should focus on the preventive use of distinct antiepileptic agents among patients at high risk of both seizures and poor outcomes.


Asunto(s)
Anticonvulsivantes/uso terapéutico , Hemorragia Cerebral/tratamiento farmacológico , Hemorragia Cerebral/epidemiología , Convulsiones/epidemiología , Convulsiones/prevención & control , Hemorragia Cerebral/diagnóstico , Humanos , Estudios Observacionales como Asunto/métodos , Prevención Primaria/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Convulsiones/diagnóstico
18.
Stroke ; 50(5): 1100-1107, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-31009357

RESUMEN

Background and Purpose- We aimed to determine incidences and predictors of major vascular events in intracerebral hemorrhage (ICH) survivors. Methods- We did a prospective observational cohort study in patients with spontaneous ICH from the Prognosis of Intracerebral Hemorrhage cohort in Lille, France. We studied incidences and predictors of long-term vascular events (cerebral and extracerebral, ischemic and hemorrhagic) in patients alive at 30 days with a prespecified subgroup analysis according to ICH location. We performed multivariable analyses (competing risk analyses, with death during follow-up as a competing event). Results- From the 560 patients with spontaneous ICH enrolled between November 2004 and March 2009, we included 310 patients (median age, 70 years). Eighty-two patients presented at least 1 major vascular event leading to an incidence rate of 20.0% (95% CI, 15.7-24.7) at 5 years after ICH. In the overall cohort, ischemic events were more frequent than hemorrhagic events. However, the incidence strikingly differed according to ICH location: deep ICH was associated with future ischemic events (subhazard ratio, 1.85; 95% CI, 1.01-3.40), whereas lobar ICH with hemorrhagic events (subhazard ratio, 2.38; 95% CI, 1.17-4.86). In deep ICH, the incidence of ischemic events at 5 years was 6× higher than the incidence of hemorrhagic events. Conclusions- ICH survivors are at high risk of both cerebral and extracerebral vascular events. The ischemic or hemorrhagic risk profile varies according to the index ICH location with a stronger ischemic risk in deep ICH. Secondary prevention, tailored on ICH location, should target not only cerebral recurrences but also extracerebral vascular events.


Asunto(s)
Isquemia Encefálica/diagnóstico por imagen , Isquemia Encefálica/epidemiología , Hemorragia Cerebral/diagnóstico por imagen , Hemorragia Cerebral/epidemiología , Anciano , Anciano de 80 o más Años , Antihipertensivos/uso terapéutico , Isquemia Encefálica/tratamiento farmacológico , Hemorragia Cerebral/tratamiento farmacológico , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo , Factores de Tiempo
19.
Stroke ; 50(5): 1210-1215, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-31009358

RESUMEN

Background and Purpose- Mechanisms contributing to acute hematoma growth in intracerebral hemorrhage are not well understood. Neuropathological studies suggest that the initial hematoma may create mass effect that can tear vessels in the vicinity by shearing, causing further bleeding and hematoma growth. Methods- To test this in mice, we simulated initial intracerebral hemorrhage by intrastriatal injection of a liquid polymer that coagulates upon contact with tissue and measured the presence and volume of bleeding secondary to the mass effect using Hemoglobin ELISA 15 minutes after injection. Results- Secondary hemorrhage occurred in a volume-dependent (4, 7.5, or 15 µL of polymer) and rate-dependent (0.05, 0.5, or 5 µL/s) manner. Anticoagulation (warfarin or dabigatran) exacerbated the secondary hemorrhage volume. In a second model of hematoma expansion, we confirmed that intrastriatal whole blood injection (15 µL, 0.5 µL/s) also caused secondary bleeding, using acute Evans blue extravasation as a surrogate. Anticoagulation once again exacerbated secondary hemorrhage after intrastriatal whole blood injection. Secondary hemorrhage directly and significantly correlated with arterial blood pressures in both nonanticoagulated and anticoagulated mice, when modulated by phenylephrine or labetalol. Conclusions- Our study provides the first proof of concept for secondary vessel rupture and bleeding as a potential mechanism for intracerebral hematoma growth.


Asunto(s)
Hemorragia Cerebral/complicaciones , Hemorragia Cerebral/patología , Hemorragia/etiología , Hemorragia/patología , Enfermedad Aguda , Animales , Anticoagulantes/administración & dosificación , Hemorragia Cerebral/tratamiento farmacológico , Dabigatrán/administración & dosificación , Hemorragia/tratamiento farmacológico , Masculino , Ratones , Distribución Aleatoria , Warfarina/administración & dosificación
20.
Neurochem Res ; 44(7): 1678-1689, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-30982205

RESUMEN

Intracerebral hemorrhage (ICH) is a stroke subtype that is associated with high mortality and disability rate. Mitochondria plays a crucial role in neuronal survival after ICH. This study first showed that activation of adiponectin receptor 1 (AdipoR1) by AdipoRon could attenuate mitochondrial dysfunction after ICH. In vivo, experimental ICH model was established by autologous blood injection in mice. AdipoRon was injected intraperitoneally (50 mg/kg). Immunofluorescence staining were performed to explicit the location of AdipoR1, AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-γ coactivator-1a (PGC1α). The PI staining was used to quantify neuronal survival. The expression of AdipoR1 and its downstream signaling molecules were detected by Western blotting. In vitro, 10 µM oxyhemoglobin (OxyHb) was used to induce the neuronal injury in SH-SY5Y cells. Annexin V-FITC/PI staining was used to detect the neuronal apoptosis and necrosis. Mitochondrial membrane potential (Δψm) was measured by a JC-1 kit and mitochondrial mass was quantified by mitochondrial fluorescent probe. In vivo, PI staining showed that the administration of AdipoRon could reduce neuronal death at 72 h after ICH in mice. AdipoRon treatment enhanced ATP levels and reduced ROS levels in perihematoma tissues, and increased the protein expression of AdipoR1, P-AMPK, PGC1α, NRF1 and TFAM. In vitro, the JC-1 staining and Mito-tracker™ Green showed that AdipoRon significantly alleviated OxyHb-induced collapse of Δψm and enhanced mitochondrial mass. Moreover, flow cytometry analysis indicated that the neurons treated with AdipoRon showed low necrotic and apoptotic rate. AdipoRon alleviates mitochondrial dysfunction after intracerebral hemorrhage via the AdipoR1-AMPK-PGC1α pathway.


Asunto(s)
Hemorragia Cerebral/tratamiento farmacológico , Mitocondrias/efectos de los fármacos , Piperidinas/uso terapéutico , Receptores de Adiponectina/agonistas , Transducción de Señal/efectos de los fármacos , Proteínas Quinasas Activadas por AMP/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Apoptosis/efectos de los fármacos , Lesiones Encefálicas/prevención & control , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones Endogámicos C57BL , Necrosis/tratamiento farmacológico , Neuronas/patología , Biogénesis de Organelos , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Receptores de Adiponectina/metabolismo
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