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1.
Int J Stroke ; : 1747493019895654, 2020 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-31955706

RESUMO

BACKGROUND: Idarucizumab is a monoclonal antibody fragment with high affinity for dabigatran reversing its anticoagulant effects within minutes. Thereby, patients with acute ischemic stroke who are on dabigatran treatment may become eligible for thrombolysis with recombinant tissue-type plasminogen activator (rt-PA). In patients on dabigatran with intracerebral hemorrhage idarucizumab could prevent lesion growth. AIMS: To provide insights into the clinical use of idarucizumab in patients under effective dabigatran anticoagulation presenting with signs of acute ischemic stroke or intracranial hemorrhage. METHODS: Retrospective data collected from German neurological/neurosurgical departments administering idarucizumab following product launch from January 2016 to August 2018 were used. RESULTS: One-hundred and twenty stroke patients received idarucizumab in 61 stroke centers. Eighty patients treated with dabigatran presented with ischemic stroke and 40 patients suffered intracranial bleeding (intracerebral hemorrhage (ICH) in n = 27). In patients receiving intravenous thrombolysis with rt-PA following idarucizumab, 78% showed a median improvement of 7 points in National Institutes of Health Stroke Scale. No bleeding complications were reported. Hematoma growth was observed in 3 out of 27 patients with ICH. Outcome was favorable with a median National Institutes of Health Stroke Scale improvement of 4 points and modified Rankin score 0-3 in 61%. Six out of 40 individuals (15%) with intracranial bleeding died during hospital stay. CONCLUSION: Administration of rt-PA after reversal of dabigatran activity with idarucizumab in case of acute ischemic stroke seems feasible, effective, and safe. In dabigatran-associated intracranial hemorrhage, idarucizumab appears to prevent hematoma growth and to improve outcome.

2.
Int J Stroke ; 12(4): 383-391, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28494694

RESUMO

Background Idarucizumab is a monoclonal antibody fragment with high affinity for dabigatran that reverses its anticoagulant effects within minutes. It may exhibit the potential for patients under dabigatran therapy suffering ischemic stroke to regain eligibility for thrombolysis with rt-PA and may inhibit lesion growth in patients with intracerebral hemorrhage on dabigatran. Aims To provide insights into the clinical use of idarucizumab in patients under effective dabigatran anticoagulation presenting with signs of ischemic stroke or intracranial hemorrhage. Methods Retrospective data collected from German neurological/neurosurgical departments administering idarucizumab following product launch from January to August 2016 were used. Results Thirty-one patients presenting with signs of stroke received idarucizumab in 22 stroke centers. Nineteen patients treated with dabigatran presented with ischemic stroke and 12 patients suffered from intracranial bleeding. In patients receiving rt-PA thrombolysis following idarucizumab, 79% benefitted from i.v. thrombolysis with a median improvement of five points in NIHSS. No bleeding complications occurred. Hematoma growth was observed in 2 out of 12 patients with intracranial hemorrhage. The outcome was favorable with a median NIHSS improvement of 5.5 points and mRS 0-3 in 67%. Overall, mortality was low with 6.5% (one patient in each group). Conclusion Administration of rt-PA after reversing dabigatran activity with idarucizumab in case of ischemic stroke is feasible, easy to manage, effective, and appears to be safe. In dabigatran-associated intracranial hemorrhage, idarucizumab has the potential to prevent hematoma growth and improve outcome. Idarucizumab represents a new therapeutic option for patients under dabigatran treatment presenting with ischemic stroke or intracranial hemorrhage.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antitrombinas/uso terapêutico , Dabigatrana/uso terapêutico , Hemorragias Intracranianas/tratamento farmacológico , Acidente Vascular Cerebral/tratamento farmacológico , Idoso , Isquemia Encefálica/tratamento farmacológico , Feminino , Alemanha , Humanos , Hemorragias Intracranianas/complicações , Masculino , Estudos Retrospectivos , Acidente Vascular Cerebral/complicações , Terapia Trombolítica/métodos , Ativador de Plasminogênio Tecidual/uso terapêutico
3.
Neuroimmunomodulation ; 21(4): 189-94, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24504116

RESUMO

BACKGROUND: Glutamate and its specific ionotropic receptors, including N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, are supposed to play an important role in neurodegeneration as well as neuronal regeneration. Although autoantibodies (aab) to glutamate receptors (GluR) have been identified in several neurologic diseases, including paraneoplastic encephalitis and Rasmussen's encephalitis (RE) with an increasing prevalence, the presence and role of anti-GluR aab in multiple sclerosis (MS) have not been studied yet. OBJECTIVES AND METHODS: In this study, we tested the serum samples of 56 subjects, including patients with relapsing-remitting MS (n = 25), patients with RE (n = 8), and healthy donors (HD; n = 23), for anti-GluR aab by immunoblot analysis of a panel of recombinantly expressed GluR proteins, including GluN1, GluN2C, GluA3, GluK2, and GluD2. RESULTS: aab were mainly found directed against GluN1 and, except for one aab positive to GluK2 in 1 MS patient and 2 HD controls positive for GluA3, no other anti-GluR aab were detected. In the sera of RE patients, no anti-GluR aab were found. In patients with MS, 8 of the 25 sera (32%) tested positive for GluN1. Compared to the HD (6/23; 26%), this difference was not statistically significant (p = 0.28). CONCLUSIONS: Our study showed that if anti-GluR aab were detectable in HD and MS patients, they were mainly directed against GluN1 (in particular to oligomeric protein complexes) and were not found in RE. Those antibodies may have low titers and low affinities and might be considered an immune epiphenomenon. Hence, further studies will have to clarify their potential role as a surrogate marker for the extent of neuronal destruction or regeneration, respectively.


Assuntos
Autoanticorpos/sangue , Encefalite/imunologia , Esclerose Múltipla Recidivante-Remitente/imunologia , Receptores de Glutamato/imunologia , Adulto , Autoantígenos/imunologia , Encefalite/sangue , Feminino , Humanos , Immunoblotting , Masculino , Esclerose Múltipla Recidivante-Remitente/sangue
4.
Epilepsia ; 55(1): 184-92, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24299259

RESUMO

PURPOSE: The contribution of glial cells, mainly astrocytes and microglia, to the pathophysiology of epilepsy is increasingly appreciated. Glia play a pivotal role in the initiation and maintenance of the central nervous system (CNS) immune response and neuronal metabolic and trophic supply. Recent clinical and experimental evidence suggests a direct relationship between epileptic activity and CNS inflammation, which is characterized by accumulation, activation, and proliferation of microglia and astrocytes. Concomitant glia-mediated mechanisms of action of several antiepileptic drugs (AEDs) have been proposed. However, their direct effects on glial cells have been rarely investigated. We aimed to investigate the effect of commonly used AEDs on glial viability, the gap junctional network, the microglial activation, and cytokine expression in an in vitro astroglia/microglia co-culture model. METHODS: Primary astrocytic cultures were prepared from brains of postnatal (P0-P2) Wistar rats and co-cultured with a physiologic amount of 5%, as well as 30% microglia in order to mimic inflammatory conditions. Co-cultures were treated with valproic acid (VPA), carbamazepine (CBZ), phenytoin (PHE), and gabapentin (GBT). Viability and proliferation were measured using the tetrazolium (MTT) assay. The microglial activation state was determined by immunocytochemical labeling. The astroglial connexin 43 (Cx43) expression was measured by Western blot analysis. The transforming growth factor-ß1 (TGF-ß1) and tumor necrosis factor-α (TNF-α) cytokine levels were measured by the quantitative sandwich enzyme immunosorbent assay (ELISA). KEY FINDINGS: Astrocytes, co-cultured with 5% microglia (M5 co-cultures), showed a dose-dependent, significant reduction in glial viability after incubation with PHE and CBZ. Furthermore, VPA led to highly significant microglial activation at all doses examined. The antiinflammatory cytokine TGF-ß1 release was induced by high doses of GBT and PHE. Astrocytes co-cultured with 30% microglia (M30 co-cultures) revealed a dose-dependent significant reduction in glial viability after incubation with PHE, accompanied by increased TGF-ß1 and TNF-α levels. However, CBZ significantly reduced the amount of activated microglial cells and increased the total number of inactivated microglia. Finally, CBZ resulted in reduced viability at all doses examined. SIGNIFICANCE: CNS inflammation is characterized by a disturbance of glial cell functions. Strong microglial activation, a typical hallmark of inflammation, was induced by VPA in M5 and continued in M30 co-cultures. With regard to the direct relation between CNS inflammation and seizures, VPA seems to be unsuitable for reducing inflammatory conditions. The reverse effect was achieved after CBZ. We noticed significant microglial inactivation, after incubation of the M30 co-cultures. In conclusion, we suggest that AEDs with antiinflammatory glial features are beneficial for seizures caused by persistent brain inflammation.


Assuntos
Anticonvulsivantes/farmacologia , Astrócitos/fisiologia , Epilepsia/etiologia , Inflamação/fisiopatologia , Microglia/fisiologia , Neuroglia/fisiologia , Aminas/farmacologia , Aminas/uso terapêutico , Animais , Anticonvulsivantes/uso terapêutico , Astrócitos/efeitos dos fármacos , Western Blotting , Carbamazepina/farmacologia , Carbamazepina/uso terapêutico , Células Cultivadas , Técnicas de Cocultura , Conexina 43/biossíntese , Ácidos Cicloexanocarboxílicos/farmacologia , Ácidos Cicloexanocarboxílicos/uso terapêutico , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Epilepsia/tratamento farmacológico , Epilepsia/fisiopatologia , Gabapentina , Junções Comunicantes/efeitos dos fármacos , Junções Comunicantes/fisiologia , Inflamação/tratamento farmacológico , Microglia/efeitos dos fármacos , Neuroglia/efeitos dos fármacos , Fenitoína/farmacologia , Fenitoína/uso terapêutico , Ratos , Ratos Wistar , Fator de Crescimento Transformador beta1/biossíntese , Ácido Valproico/farmacologia , Ácido Valproico/uso terapêutico , Ácido gama-Aminobutírico/farmacologia , Ácido gama-Aminobutírico/uso terapêutico
5.
Brain Res ; 1329: 45-54, 2010 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-20230803

RESUMO

We analyzed the effect of dexamethasone on gram-negative bacteria derived lipopolysaccharide (LPS) induced inflammation in astroglial/microglial co-cultures. At the cellular level the microglial phenotype converted to an activated type after LPS incubation. Furthermore, LPS compromised functional astroglial properties like membrane resting potential, intracellular coupling and connexin 43 (Cx43) expression. This change in Cx43 expression was not due to a downregulation of Cx43 mRNA expression. Morphological and functional changes were accompanied by a time-dependent release of inflammation related cytokines. Co-incubation of dexamethasone with LPS prevented these LPS-induced changes within our glial co-culture model. The ability of dexamethasone to reconstitute astrocytic properties and to decrease microglial activation in vitro could be one possible explanation for the beneficial effects of dexamethasone in the treatment of acute bacterial meningitis in vivo.


Assuntos
Anti-Inflamatórios/farmacologia , Astrócitos/efeitos dos fármacos , Dexametasona/farmacologia , Glucocorticoides/farmacologia , Meningites Bacterianas/tratamento farmacológico , Microglia/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Astrócitos/metabolismo , Astrócitos/patologia , Encéfalo/citologia , Técnicas de Cocultura , Conexina 43/genética , Conexina 43/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Bactérias Gram-Negativas/química , Imuno-Histoquímica , Lipopolissacarídeos , Meningites Bacterianas/metabolismo , Microglia/metabolismo , Microglia/patologia , RNA Mensageiro/efeitos dos fármacos , Ratos , Ratos Wistar
7.
Epilepsy Behav ; 14(1): 66-70, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18762279

RESUMO

OBJECTIVE: The goal of this study was to examine the influence of seizure freedom on executive function in outpatients with generalized epilepsy and extrafrontal partial epilepsy. Recent investigations of cognitive function in epilepsy have revealed executive deficits in persons with focal temporal as well as generalized epilepsies. Additional studies have suggested an influence of seizure freedom on cognitive function. METHODS: Thirty-five consecutive outpatients were divided into seizure free 3 months (n=17). The neuropsychological tests administered included: verbal fluency tasks, the Cognitive Estimation Test, the Hayling and Brixton Test, and the Behavioural Assessment of the Dysexecutive Syndrome (BADS) battery. Both patient groups were compared with matched healthy controls (n=16). RESULTS: The extensive testing revealed significant differences between patients with shorter seizure-free periods and healthy controls with respect to overall errors and phonemic verbal fluency, response suppression, and BADS overall profile scores. Subjects seizure free >3 months exhibited a trend toward impairment in the phonemic fluency task only. CONCLUSIONS: The results suggest that deficits in executive function were present in patients with extrafrontal partial epilepsy and generalized epilepsy, indicating the potential influence of epileptic activity on the ability to focus on relevant information and switch attention to other relevant information, to plan tasks and subtasks, and to check on and encode working memory content. The results also suggest that those deficits may be more pronounced in patients with relatively short seizure-free periods.


Assuntos
Epilepsias Parciais/psicologia , Epilepsia Generalizada/psicologia , Desempenho Psicomotor/fisiologia , Convulsões/psicologia , Adulto , Cognição/fisiologia , Interpretação Estatística de Dados , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Comportamento Verbal/fisiologia
8.
J Neurooncol ; 86(2): 143-52, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17690839

RESUMO

Human gliomas are the most common class of brain neoplasm. In order to better characterize their response to inflammation, we evaluated the influence of tumor necrosis factor alpha (TNF-alpha) on the coupling behaviour and the membrane resting potential (MRP) of glioma cells (F98 glioma cell line) compared to primary astrocytes. In contrast to cultured primary astrocytes which exhibited a profound inhibition of gap junction mediated intercellular communication (GJIC), extracellular exposure of TNF-alpha to F98 glioma cells gained no effect on the functional coupling. Whereas, intracellular application of TNF-alpha into the glioma cells elicited similar effects as those found in primary astrocytes indicating a compromised accessibility of the TNF-alpha receptor in F98 cells. Western blotting, immunocytochemical staining and real time RT PCR analysis revealed a differential expression and distribution of TNF-alpha receptor 1 (TNFR1) in the glioma cells. Connexin 43 (Cx43) is the major astrocytic gap junction protein which when phosphorylated has been shown to reveal altered gating properties. Here we show that TNF-alpha increases the level of phosphorylated Cx43 in primary astrocytes but not in the F98 glioma cells. Our observations could account for the decreased regulatory effects of TNF-alpha on GJIC of F98 glioma cells.


Assuntos
Astrócitos/metabolismo , Neoplasias Encefálicas/metabolismo , Junções Comunicantes/metabolismo , Glioma/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Astrócitos/patologia , Neoplasias Encefálicas/patologia , Comunicação Celular/fisiologia , Conexina 43/metabolismo , Glioma/patologia , Humanos , Líquido Intracelular/metabolismo , Ratos , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Células Tumorais Cultivadas
9.
Eur Arch Psychiatry Clin Neurosci ; 258(1): 35-9, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17990054

RESUMO

Detailed neuropsychological assessment was performed in 86 women (48 patients with stable relapsing-remitting multiple sclerosis (MS) and 38 matched healthy controls (HC)). Patients were categorized into patients without (EDSS < or =1, n = 26) and with physical disability (EDSS > or =2, n = 22). Patients with EDSS > or =2 scored significantly (P < 0.05) higher in Beck's depression inventory (BDI) and depression scores (DS) compared to HC and patients with EDSS < or =1. No significant differences were found with respect to the use of specific coping strategies between the patient groups, who preferred active (EDSS < or =1) or distracting (EDSS > or =2) strategies. Cognitive deficits were significantly increased in MS with EDSS > or =2 with regard to visuo-construction and visual memory, in particular with respect to geometric figures, compared to MS with EDSS < or =1. Significant positive correlations of depression variables (BDI, DS and BL) and depressive as well as denying coping strategies were found. Our results showed increased depression scores and increased cognitive deficits in advanced physically disabled patients, without selection of specific coping strategies. This supports an individual MS-specific neuropsychological therapeutic approach in order to improve disease related deficits together with social functioning.


Assuntos
Adaptação Psicológica , Avaliação da Deficiência , Esclerose Múltipla/fisiopatologia , Esclerose Múltipla/psicologia , Adulto , Afeto , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/fisiopatologia , Transtornos Cognitivos/psicologia , Efeitos Psicossociais da Doença , Emoções/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/complicações , Testes Neuropsicológicos , Escalas de Wechsler
10.
Artigo em Inglês | MEDLINE | ID: mdl-15866357

RESUMO

Assessment of cerebral blood flow velocities (CBFV) can be used as a non-invasive tool to evaluate specific drug effects, like caffeine (CAF), acetazolamide (AA) as well as cognition. Their influences on each others CBFV were evaluated in detail, using a randomized, double-blind, double-dummy, placebo-controlled three-fold cross-over study design in 18 right-handed healthy male volunteers. CBFV (maximal, mean, minimal) and pulsatility index of both middle cerebral arteries were recorded by transcranial Doppler ultrasound simultaneously, during a verbal memory test, oral CAF, intravenous AA or placebo. AA led to increase in CBFV of 25-32%. Caffeine resulted in decreased V(mean) and V(min) of 10-13%. Cognitive stimulation resulted in a slight increase of CBVF of about 4%, but was overruled by effects of AA and CAF. We conclude that pharmacological effects can easily be assessed by TCD during clinical pharmacological studies of vasoactive drugs. However intraindividual variability and effects of neuropsychological stimulation needs to be taken into account.


Assuntos
Acetazolamida/farmacologia , Anticonvulsivantes/farmacologia , Cafeína/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Circulação Cerebrovascular/efeitos dos fármacos , Circulação Cerebrovascular/fisiologia , Cognição/fisiologia , Adulto , Estudos Cross-Over , Método Duplo-Cego , Hemodinâmica/efeitos dos fármacos , Humanos , Masculino , Memória/efeitos dos fármacos , Psicometria , Mecânica Respiratória/efeitos dos fármacos , Ultrassonografia Doppler Transcraniana , Aprendizagem Verbal/efeitos dos fármacos
11.
Glia ; 52(2): 85-97, 2005 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-15920725

RESUMO

Cytokines play an important role in the onset, regulation, and propagation of immune and inflammatory responses within the central nervous system (CNS). The main source of cytokines in the CNS are microglial cells. Under inflammatory conditions, microglial cells are capable of producing pro- and antiinflammatory cytokines, which convey essential impact on the glial and neuronal environment. One paramount functional feature of astrocytes is their ability to form a functionally coupled syncytium. The structural link, which is responsible for the syncytial behavior of astrocytes, is provided by gap junctions. The present study was performed to evaluate the influence of inflammation related cytokines on an astroglial/microglial inflammatory model. Primary astrocytic cultures of newborn rats were cocultured with either 5% (M5) or 30% (M30) microglial cells and were incubated with the following proinflammatory cytokines: tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), interferon-gamma (IFN-gamma), and the antiinflammatory cytokines transforming growth factor-beta1 (TGF-beta1) and IFN-beta. Under these conditions, i.e., incubation with the inflammatory cytokines and the high fraction of microglia (M30), microglial cells revealed a significant increase of activated round phagocytotic cells accompanied by a reduction of astroglial connexin 43 (Cx43) expression, a reduced functional coupling together with depolarization of the membrane resting potential (MRP). When the antiinflammatory mediator TGF-beta1 was added to proinflammatory altered M30 cocultures, a reversion of microglial activation and reconstitution of functional coupling together with recovery of the astroglial MRP was achieved. Finally IFN-beta, added to M5 cocultures was able to prevent the effects of the proinflammatory cytokines TNF-alpha, IL-1beta, and IFN-gamma.


Assuntos
Astrócitos/efeitos dos fármacos , Citocinas/farmacologia , Inflamação/patologia , Microglia/efeitos dos fármacos , Animais , Astrócitos/patologia , Comunicação Celular/efeitos dos fármacos , Técnicas de Cocultura , Conexina 43/fisiologia , Citocinas/antagonistas & inibidores , Eletrofisiologia , Imunofluorescência , Humanos , Interferon Tipo I/farmacologia , Masculino , Potenciais da Membrana/fisiologia , Microglia/patologia , Fenótipo , Ratos , Ratos Wistar , Proteínas Recombinantes , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta1
12.
Eur Arch Psychiatry Clin Neurosci ; 255(5): 319-26, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15645161

RESUMO

This study investigated the relationship between clinical symptoms and cognitive dysfunction in multiple sclerosis. Cognitive dysfunction and visual evoked potentials (VEPs) were studied in patients free of physical disability and mildly to moderately disabled patients with multiple sclerosis (MS). Disability-free patients (EDSS < or = 1.5; n = 13), mildly to moderately disabled patients (EDSS ranging from 2 to 6; n = 13) and a healthy matched control group (n = 16) were examined with respect to attention, verbal and nonverbal memory and early visual processing (VEPs). Disability-free patients showed mild impairments on phasic alertness and divided attention. Deficits were more pronounced in mildly to moderately disabled patients who were additionally impaired with respect to non-verbal memory. Despite adequate visual acuity, one half of all patients showed abnormal VEP latencies for both eyes at the same time. The findings suggest that cognitive deficits are already present in multiple sclerosis even in the absence of physical disability. Even with normal visual acuity, perceptual impairments should be considered as part of the CNS affection.


Assuntos
Atenção/fisiologia , Transtornos da Memória/etiologia , Esclerose Múltipla/complicações , Adulto , Análise de Variância , Estudos de Casos e Controles , Tomada de Decisões/fisiologia , Potenciais Evocados Visuais/fisiologia , Feminino , Humanos , Esclerose Múltipla/fisiopatologia , Testes Neuropsicológicos/estatística & dados numéricos , Estimulação Luminosa/métodos , Tempo de Reação/fisiologia , Estatística como Assunto , Aprendizagem Verbal/fisiologia
13.
J Clin Oncol ; 23(5): 965-72, 2005 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-15613696

RESUMO

PURPOSE: BAY 43-9006 is a novel dual-action Raf kinase and vascular endothelial growth factor receptor inhibitor that inhibits tumor cell proliferation and angiogenesis. This study established the safety and pharmacokinetics of BAY 43-9006 in 69 patients with advanced refractory solid tumors. PATIENTS AND METHODS: BAY 43-9006 (50 to 800 mg) was administered once or twice daily on a varying weekly schedule. Pharmacokinetic sampling was performed in all patients; preliminary tumor response was also assessed. The effect of BAY 43-9006 on phorbol myristate acetate-stimulated ERK phosphorylation in peripheral blood lymphocytes was studied using flow cytometry. RESULTS: Mild to moderate diarrhea was the most common (55%) treatment-related adverse event. The maximum-tolerated dose was 400 mg bid continuous. Dose-limiting toxicities were grade 3 diarrhea and fatigue at 800 mg bid, and grade 3 skin toxicity at 600 mg bid. BAY 43-9006 pharmacokinetics were highly variable for single and multiple dosing, and toxicity did not appear to be dose dependent. Significant decreases of phorbol myristate acetate-stimulated ERK phosphorylation (P < .01) were identified at doses >/= 200 mg bid continuous. Forty-five patients were assessable for efficacy; one patient had a partial response (hepatocellular carcinoma at 400 mg bid continuous), 25 patients had stable disease, with eight lasting > 6 months and five for >12 months. Eighteen patients had progressive disease, and tumor response could not be evaluated in one patient. CONCLUSION: Oral BAY 43-9006 was well tolerated and appeared to provide some clinical benefits. Based on the results of this study, BAY 43-9006 at 400 mg bid continuous is recommended for ongoing and future studies.


Assuntos
Antineoplásicos/administração & dosagem , Benzenossulfonatos/administração & dosagem , Proteína de Ligação a Fosfatidiletanolamina/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Piridinas/administração & dosagem , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Adolescente , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Benzenossulfonatos/farmacocinética , Carcinoma Hepatocelular/tratamento farmacológico , Estudos de Coortes , Neoplasias do Colo/tratamento farmacológico , Diarreia/induzido quimicamente , MAP Quinases Reguladas por Sinal Extracelular/efeitos dos fármacos , Fadiga/induzido quimicamente , Feminino , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Linfócitos/efeitos dos fármacos , Linfócitos/enzimologia , Masculino , Pessoa de Meia-Idade , Niacinamida/análogos & derivados , Compostos de Fenilureia , Proteína de Ligação a Fosfatidiletanolamina/efeitos adversos , Proteína de Ligação a Fosfatidiletanolamina/farmacocinética , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Piridinas/farmacocinética , Neoplasias Retais/tratamento farmacológico , Segurança , Sorafenibe
14.
Neuroimmunomodulation ; 11(6): 365-72, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15467351

RESUMO

OBJECTIVES: In multiple sclerosis (MS), several neuroimmunomodulatory effectors are known, including melatonin. They are able to influence disease-related neurophysiogical changes (disability or impaired vision) as well as neuropsychological performance (e.g. cognition and depression). In this study we assessed the relationship between immunomodulation on psycho-neuroimmunological functions in benign multiple sclerosis. METHODS: We evaluated 26 young female patients with benign MS treated with/without immunomodulating therapies with regard to their physical disabilities (Expanded Disability Status Scale, EDSS), their visually evoked potentials (VEP), their plasma melatonin concentrations as well as their performance regarding emotional and cognitive tests and compared them with healthy matched controls. RESULTS: Patients with MS showed deficits in cognitive and emotional functions compared to healthy controls, which were in accordance with their increase in EDSS over time. However, in contrast to untreated patients, patients receiving immunotherapy showed significantly increased dysfunction with respect to actual mood (p = 0.02) and a tendency to increased depression scores (p = 0.072). However, neither treatment subgroup had cognitive deficits. In untreated patients, melatonin levels correlated with reduced scores in the cognitive tests (p = 0.045) but not with depression or VEP latencies. Patients with long-standing MS (>10 years) showed a significant correlation (p = 0.01) to their increased depression scores and their melatonin levels, but no correlation with VEP or cognitive dysfunction, compared to patients with shorter disease duration (< or =10 years). CONCLUSION: These results indicate that in MS all aspects of the psycho-neuroimmunological network can be affected. Despite the potential influence of immunomodulation on depression, no connection with melatonin representing the retinohypothalamic tract/pineal gland circuits could be detected. However, visual perception as well as visuoconstructive abilities were affected in MS patients. Neuropsychological tests in MS should concentrate on cognitive variables, which reflect the clinical status more accurately and may be used to monitor disease-modifying therapies.


Assuntos
Transtornos Cognitivos/imunologia , Transtorno Depressivo/imunologia , Fatores Imunológicos/uso terapêutico , Esclerose Múltipla/imunologia , Esclerose Múltipla/psicologia , Neuroimunomodulação/imunologia , Adulto , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/fisiopatologia , Transtorno Depressivo/diagnóstico , Transtorno Depressivo/fisiopatologia , Avaliação da Deficiência , Potenciais Evocados Visuais/efeitos dos fármacos , Potenciais Evocados Visuais/imunologia , Feminino , Humanos , Fatores Imunológicos/efeitos adversos , Melatonina/sangue , Melatonina/metabolismo , Pessoa de Meia-Idade , Esclerose Múltipla/tratamento farmacológico , Neuroimunomodulação/efeitos dos fármacos , Testes Neuropsicológicos/normas , Transtornos da Percepção/imunologia , Transtornos da Percepção/fisiopatologia , Glândula Pineal/imunologia , Glândula Pineal/fisiopatologia , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/imunologia , Vias Visuais/imunologia , Vias Visuais/fisiopatologia
15.
Neuroimmunomodulation ; 11(4): 273-7, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15249735

RESUMO

OBJECTIVES: Patients diagnosed with multiple sclerosis (MS) but without disability (Expanded Disability Status Scale score <2) form a specific group within those patients suffering from relapsing-remitting MS. Several neuroimmunologic effectors, including cytokines and melatonin, are known for their influence on the initiation of relapses and progression of the disease. METHODS: We evaluated 41 female patients with benign MS with respect to their clinical course, treatments and neuroimmunological parameters, including cytokines and melatonin. One subgroup was followed up for 7 years, and another group was evaluated during acute clinical relapse. RESULTS: The benign MS course in this homogeneous group of young patients was demonstrated by mild disease progression in 16% over 7 years. Initially, patients treated with azathioprine (AZA) revealed significantly reduced melatonin serum levels (p = 0.04) compared to untreated patients, but not at follow-up. During acute relapse, treatment with corticosteroids (CS) resulted in increased levels of type 2 cytokines as well as reduced type 1 cytokine levels. CONCLUSIONS: Our study supports the functional role of CS acting as an antiinflammatory protagonist during MS relapse, by inducing a shift towards predominance of type 2 cytokines. AZA showed a more subtle modulation of immune functions, reflected by reduced levels of the immune active hormone melatonin. During follow-up, it became apparent that stabilized levels of the interacting Th1/Th2-derived cytokines and melatonin are maintained in concordance with the benign course of MS. These findings are in accordance with the hypothesis that benign MS is characterized by a balanced cytokine and neuroendocrine network, which is supported by immune-modulating therapies.


Assuntos
Esclerose Múltipla Recidivante-Remitente/imunologia , Neuroimunomodulação/imunologia , Corticosteroides/administração & dosagem , Adulto , Azatioprina/administração & dosagem , Avaliação da Deficiência , Progressão da Doença , Feminino , Seguimentos , Humanos , Imunossupressores/administração & dosagem , Interferon gama/sangue , Interleucina-10/sangue , Interleucina-4/sangue , Melatonina/sangue , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Remissão Espontânea , Fator de Necrose Tumoral alfa/metabolismo
16.
J Neurol ; 250(5): 607-11, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12736743

RESUMO

Interleukin-6 (IL-6) plays an important role in the regulation of the inflammatory response in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Previous reports indicated that the C allele of a variable number tandem repeat (vntr) polymorphism located in the 3'flanking region of the IL-6 gene ( IL-6) is associated with reduced activity of IL-6 in vivo. Since disease-modifying genes are likely to contribute to phenotypic differences in MS patients, we tested the hypothesis that the IL-6 C allele is associated with the clinical course of MS. The IL-6 C allele was equally distributed between 217 MS patients of German Caucasian origin and 111 age-mached healthy controls. Stratification of patients according to the course of disease revealed no significant difference of IL-6 C allele distribution between patients with primary progressive and those with either relapsing-remitting or secondary progressive MS although IL-6 C allele was more frequent in patients with RR-MS. Since IL-6 C allele has been associated with a benign course in Sardinian MS patients, we further analysed an independent sample of 125 Sardinian MS patients revealing that IL-6 C allele was much more frequent than in German MS patients. Taken together, a disease-modifying effect of IL-6 C allele could not be demonstrated in MS patients of German Caucasian descent.


Assuntos
Variação Genética/genética , Interleucina-6/genética , Repetições Minissatélites/genética , Esclerose Múltipla/genética , Polimorfismo Genético/genética , Adulto , Alelos , Análise de Variância , Distribuição de Qui-Quadrado , Citosina , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade
17.
Behav Neurol ; 14(1-2): 39-45, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12719637

RESUMO

Cognitive and emotional capabilities were evaluated in 73 female patients with stable relapsing-remitting definite, and/or laboratory-supported multiple sclerosis (MS) and were compared with 32 matched healthy controls. Patients were categorized according to their score in the expanded disability status scale (EDSS) to either no (EDSS 0, n = 33) or few clinical signs (EDSS 1-2, n = 40) of MS without physical disability. Patients with EDSS > 0 were characterized by significantly (p < 0.001) higher scores on "von Zerssen's" depression scale, compared to controls. Patients with higher EDSS scores (1-2) showed significantly decreased performance with respect to the total score of Kimura's Recurring-Figures-Test (p < 0.001), in addition. Regarding visuo-constructive functioning, patients with EDSS=0 performed to a significantly lower level (p < 0.001), compared to controls. These results indicate that depression may present as an early sign in MS followed by cognitive impairment, in particular visuo-spatial short-term memory, before physical disability appears. Neuropsychological tests as mentioned here could serve as early diagnostic tools to detect subtle disease progression and to initiate and monitor disease modifying therapies.


Assuntos
Transtornos Cognitivos/etiologia , Transtorno Depressivo/etiologia , Esclerose Múltipla Recidivante-Remitente/psicologia , Adolescente , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Esclerose Múltipla Recidivante-Remitente/complicações , Testes Neuropsicológicos , Escalas de Graduação Psiquiátrica , Análise e Desempenho de Tarefas
18.
Glia ; 42(2): 101-8, 2003 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-12655594

RESUMO

Under inflammatory conditions, activated microglia are capable of producing proinflammatory cytokines that are reported to influence cell-to-cell communication. The present study was performed to evaluate the influence of microglial activation on the coupling efficiency of the astroglial network. Primary astrocyte cultures of newborn rats were cocultured with either 5% (M5) or 30% (M30) microglia. Microglial activation (rounded phagocytotic phenotype) was investigated using the monoclonal anti-ED1 antibody, and immunofluorescence with a polyclonal anti-Cx43 antibody was used to study astroglial Cx43 expression and distribution. Functional coupling of astrocytes was evaluated by monitoring the transfer of microinjected Lucifer yellow into neighboring cells. The data obtained can be summarized as follows: astroglia/M30 cocultures contained significantly fewer resting microglia and significantly more activated microglia than the M5 cocultures; significantly reduced astroglial Cx43 staining was found in M30 cocultures concurrently with a reduced number of dye coupled astrocytes; and the positive correlation of percent activated microglia with reduced astroglial Cx43 expression was highly significant, indicating that the degree of intercellular communication in the astroglial network may be modulated by the activation of microglia under in vitro conditions.


Assuntos
Astrócitos/metabolismo , Comunicação Celular/fisiologia , Conexina 43/metabolismo , Encefalite/metabolismo , Junções Comunicantes/metabolismo , Gliose/metabolismo , Microglia/metabolismo , Animais , Animais Recém-Nascidos , Astrócitos/imunologia , Adesão Celular/fisiologia , Tamanho Celular/fisiologia , Células Cultivadas , Quimiotaxia/fisiologia , Técnicas de Cocultura , Citocinas/imunologia , Citocinas/metabolismo , Ectodisplasinas , Encefalite/imunologia , Encefalite/fisiopatologia , Junções Comunicantes/imunologia , Gliose/imunologia , Gliose/fisiopatologia , Imuno-Histoquímica , Isoquinolinas , Proteínas de Membrana/metabolismo , Fenótipo , Ratos , Transdução de Sinais/fisiologia
19.
J Neuroimmunol ; 135(1-2): 148-53, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12576235

RESUMO

The lack of phenotype/genotype association in X-linked adrenoleukodystrophy (X-ALD) has prompted the search for disease modifying factors. We previously demonstrated increased serum antibody responses against myelin oligodendrocyte glycoprotein (MOG) in various clinical phenotypes of X-ALD allowing speculations that myelin specific humoral immune responses might be involved in phenotype generation of X-ALD. In the present study, we investigated the possible association of (1) a naturally occurring variable number tandem repeat (vntr) polymorphism (C allele) in the 3' flanking region of the interleukin-6 gene (IL-6), previously demonstrated to modify the course of Alzheimer's disease, systemic lupus erythematodes and Multiple Sclerosis (MS), (2) a tetranucleotide repeat polymorphism (TAAA)(n) in the 3' flanking region of the MOG gene and (3) HLA class II alleles with adult clinical phenotypes and serum antibody responses to MOG in 70 adult X-ALD patients. HLA class II alleles, (TAAA)(n) MOG gene polymorphisms, and IL-6 C allele were not associated with clinical phenotypes. Anti-MOG antibodies were detectable in 17/54 X-ALD patients (31.5%). Anti-MOG antibodies were associated with the 226 bp (TAAA)(n) MOG gene polymorphism but not with distinct clinical phenotypes.


Assuntos
Adrenoleucodistrofia/genética , Cromossomos Humanos X , Ligação Genética , Variação Genética , Glicoproteína Associada a Mielina/genética , Adrenoleucodistrofia/imunologia , Adulto , Idoso , Alelos , Formação de Anticorpos , Feminino , Antígenos HLA-DQ/genética , Cadeias beta de HLA-DQ , Antígenos HLA-DR/genética , Cadeias HLA-DRB1 , Humanos , Interleucina-6/genética , Masculino , Pessoa de Meia-Idade , Repetições Minissatélites , Proteínas da Mielina , Glicoproteína Associada a Mielina/imunologia , Glicoproteína Mielina-Oligodendrócito , Fenótipo , Polimorfismo Genético
20.
Neurosci Lett ; 330(3): 293-5, 2002 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-12270649

RESUMO

In the pathogenesis of multiple sclerosis (MS) genetic factors are known to influence autoreactive T-cell-actions like proliferation and chemotaxis across the blood-brain barrier via chemokine receptors (CCR) and G-protein coupled activating mechanisms. For the first time, we studied the frequencies of a recently described C825T polymorphism in the G-protein encoding gene for the beta3 subunit (GNB3) together with frequencies of a 32-base-pair deletion in the CCR5 gene (delta32 CCR5) in patients with MS (n = 253: relapsing-remitting (RR), n = 124 and chronic progressive course, n = 129). Apart from a trend to a reduced frequency of delta32 CCR5 and increased GNB3 825T polymorphism in primary chronic progressive patients, numbers did not reach statistical significance in any group of MS. These results could not support differences in the genetic background of MS based on that CCR5 mutation or the described GNB3 polymorphism.


Assuntos
Proteínas Heterotriméricas de Ligação ao GTP/genética , Esclerose Múltipla/genética , Receptores CCR5/genética , Adolescente , Adulto , Idoso , DNA , Progressão da Doença , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo Genético
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