RESUMO
Nilotinib, a BCR-ABL tyrosine kinase inhibitor (TKI), has been associated with vascular events and accelerated arterial stenosis, presumably of atherosclerotic etiology. Studies of nilotinib-associated atherosclerosis are mainly associated with progressive peripheral artery occlusive disease (PAOD), and only a few cases of coronary artery disease (CAD), and cerebrovascular disease (CVD) have been reported. The mechanisms by which nilotinib promotes atherosclerosis are poorly understood but endothelial and perivascular factors, mast cell depletion, and metabolic factors such as promotion of dyslipidemia and impaired glucose metabolism are thought to play a role. We present a case of a patient with chronic myelogenous leukemia (CML) treated with nilotinib who developed intracranial atherosclerosis leading to acute onset of stroke. Our patient had no cardiovascular risk factors prior to treatment with nilotinib and developed accelerated atheromatous cerebrovascular disease with severe left middle cerebral artery (MCA) stenosis. These findings suggest that nilotinib may be associated with the development of intracranial atherosclerotic disease (ICAD) independently of any preexisting vascular risk factors leading to acute stroke. Clinicians should have increased awareness of the association between nilotinib and the development of progressive atheromatous disease and vascular adverse events including PAOD, CAD, and CVD. In certain patients, these events can be severe and life threatening. Thus, screening for vascular risk factors including CVD prior to starting nilotinib and close follow up during treatment is crucial.
Assuntos
Antineoplásicos/efeitos adversos , Infarto da Artéria Cerebral Média/etiologia , Arteriosclerose Intracraniana/induzido quimicamente , AVC Isquêmico/etiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Estado Funcional , Humanos , Infarto da Artéria Cerebral Média/diagnóstico por imagem , Infarto da Artéria Cerebral Média/terapia , Arteriosclerose Intracraniana/diagnóstico por imagem , Arteriosclerose Intracraniana/terapia , AVC Isquêmico/diagnóstico por imagem , AVC Isquêmico/terapia , Masculino , Pessoa de Meia-Idade , Recuperação de Função Fisiológica , Fatores de Risco , Resultado do TratamentoRESUMO
Bisphenol A (BPA) is an abundant contaminant found in aquatic environments. While a large number of toxicological studies have investigated the effects of BPA, the potential effects of BPA exposure on fish brain have rarely been studied. To understand how BPA impacts goldfish brains, we performed a transcriptome analysis of goldfish brains that had been exposed to 50 µg L-1 and 0 µg L-1 BPA for 30 days. In the analysis of unigene expression profiles, 327 unigenes were found to be upregulated and 153 unigenes were found to be downregulated in the BPA exposure group compared to the control group. Dopaminergic signaling pathway-related genes were significantly downregulated in the BPA exposure group. Furthermore, we found that serum dopamine concentrations decreased and TUNEL (terminal deoxynucleotidyl transferase 2-deoxyuridine, 5-triphosphate nick end labeling) staining was present in dopamine neurons enriched regions in the brain after BPA exposure, suggesting that BPA may disrupt dopaminergic processes. A KEGG analysis revealed that genes involved in the fluid shear stress and atherosclerosis pathway were highly significantly enriched. In addition, the qRT-PCR results for fluid shear stress and atherosclerosis pathway-related genes and the vascular histology of the brain showed that BPA exposure could damage blood vessels and induce brain atherosclerosis. The results of this work provide insights into the biological effects of BPA on dopamine synthesis and blood vessels in goldfish brain and could lay a foundation for future BPA neurotoxicity studies.
Assuntos
Compostos Benzidrílicos/toxicidade , Encéfalo , Dopamina/metabolismo , Disruptores Endócrinos/toxicidade , Carpa Dourada/metabolismo , Arteriosclerose Intracraniana , Fenóis/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Perfilação da Expressão Gênica , Arteriosclerose Intracraniana/induzido quimicamente , Arteriosclerose Intracraniana/metabolismo , Arteriosclerose Intracraniana/patologiaRESUMO
OBJECTIVES: Exposure to airborne particle (PM2.5 ) is a risk factor for intracranial atherosclerosis (ICA). Because of the established role of systemic inflammation and oxidative stress by PM2.5 , we determined whether these processes account for PM2.5 -mediated ICA, and also whether omega-3 fatty acid (O3FA) dietary supplementation could attenuate them. METHODS: Adult Sprague-Dawley rats were exposed to filtered air (FA) or PM2.5 and fed either a normal chow diet (NCD) or a high-cholesterol diet (HCD), administered with or without O3FA (5 mg/kg/day by gavage) for 12 weeks. The lumen and thickness of the middle cerebral artery (MCA) were assessed. Serum tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin-1ß (IL-1ß), and interferon gamma (IFN-γ) were detected by ELISA. Reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD) activity, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) activity, mRNA levels of Nrf2, HO-1, NQO-1, and protein level of NOX subunit gp91 were quantified to determine the oxidative profile of brain vessels. RESULTS: PM2.5 increased (P < .05) ICA, especially in the HCD group; elevated serum TNF-α, IL-6, IL-1ß, and IFN-γ; increased cerebrovascular ROS, MDA, NOX activity, and gp91 protein levels; and decreased cerebrovascular SOD activity. Nrf2, HO-1, and NQO-1 mRNA levels were upregulated (P < .05) by PM2.5 exposure, especially in the HCD group. O3FA attenuated (P < .05) PM2.5 -induced systemic inflammation, vascular oxidative injury, and ICA. CONCLUSIONS: PM2.5 exposure induced systemic inflammation, cerebrovascular oxidative injury, and ICA in rats with HCD. O3FA prevented ICA development, and may therefore exert a protective effect against the atherogenic potential of PM2.5 .
Assuntos
Poluentes Atmosféricos/toxicidade , Arteriosclerose Intracraniana/induzido quimicamente , Artéria Cerebral Média/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Material Particulado/toxicidade , Animais , Modelos Animais de Doenças , Inflamação , Arteriosclerose Intracraniana/imunologia , Arteriosclerose Intracraniana/patologia , Masculino , Artéria Cerebral Média/imunologia , Artéria Cerebral Média/patologia , Tamanho da Partícula , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismoRESUMO
No disponible
Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Idoso , Proteínas Tirosina Quinases/antagonistas & inibidores , Acidente Vascular Cerebral/induzido quimicamente , Arteriosclerose Intracraniana/induzido quimicamente , Doença Arterial Periférica/induzido quimicamente , Fatores de Risco , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológicoRESUMO
OBJECTIVE: To compare the long-term effects of carbamazepine (CBZ), valproic acid (VPA), and lamotrigine (LTG) as monotherapy on the markers of vascular risk. METHODS: The present cross-sectional study was carried out at the Department of Neurology, Jinnah Postgraduate Medical Centre (JPMC), Karachi, Pakistan, from 2012 to 2013. We selected 120 adult patients with epilepsy and 40 control subjects. The patients with epilepsy were divided into 3 groups according to the use of antiepileptic drugs (AEDs) (CBZ, n = 40; VPA, n = 40; and LTG, n = 40). All participants` total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-c), very low-density lipoprotein cholesterol (VLDL-c), high-density lipoprotein cholesterol (HDL-c), ratio of TC/HDL-c, ratio of LDL-c/HDL-c, body mass index (BMI), and blood pressure was determined. RESULTS: In patients with epilepsy, CBZ and VPA treatment caused a noteworthy increase in the concentrations of TG, TC, and LDL-c compared with LTG treatment and the control group (p<0.001). The HDL-c significantly decreased in CBZ, VPA, and LTG-treated patients as compared with controls (p<0.001). The ratio of LDL-c/HDL-c and TC/HDL-c significantly increased in VPA- and CBZ-treated groups compared with the LTG-treated, and control group, while the ratio was also considerably elevated in patients treated with CBZ as compared with the patients treated with VPA. The weight and BMI of the patients treated with AEDs were higher (p<0.01). CONCLUSION: Patients with epilepsy on CBZ or VPA have changed vascular risk markers that may lead to atherosclerosis, while LTG-treated patients have less alteration in lipid profile.
Assuntos
Anticonvulsivantes/efeitos adversos , Epilepsia/tratamento farmacológico , Arteriosclerose Intracraniana/induzido quimicamente , Arteriosclerose Intracraniana/epidemiologia , Adulto , Carbamazepina/efeitos adversos , Colesterol/sangue , Estudos Transversais , Feminino , Humanos , Arteriosclerose Intracraniana/sangue , Lamotrigina/efeitos adversos , Masculino , Estudos Retrospectivos , Estatísticas não Paramétricas , Ácido Valproico/efeitos adversosRESUMO
This work aimed to evaluate the metabolic and atherogenic effects of long-term antiepileptic drugs in a group of Egyptian epileptic patients. Sixty-nine epileptic patients on antiepileptic drug monotherapy for at least 2 years and 34 control subjects were recruited in this study. Patients were divided into 5 subgroups according to antiepileptic drugs used (valproate, carbamazepine, lamotrigine, topiramate, and levetiracetam). Fasting lipid profile (total cholesterol, triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol), lipoprotein(a), homocysteine, free thyroxine, thyroid-stimulating hormone, and common carotid artery intima-media thickness were measured for all subjects. Significant higher mean values of low-density lipoprotein cholesterol, low-density lipoprotein / high-density lipoprotein ratio, lipoprotein(a), homocysteine, significantly lower mean value of high-density lipoprotein cholesterol, and significantly larger diameter of common carotid artery intima-media thickness were observed in each drug-treated group versus control group. Our study supports that long-term monotherapy treatment with valproate, carbamazepine, lamotrigine, and topiramate had altered markers of vascular risk that might enhance atherosclerosis, whereas levetiracetam exerted minimal effect.
Assuntos
Anticonvulsivantes/efeitos adversos , Arteriosclerose Intracraniana/induzido quimicamente , Adolescente , Anticonvulsivantes/uso terapêutico , Carbamazepina/efeitos adversos , Carbamazepina/uso terapêutico , Artérias Carótidas/diagnóstico por imagem , Artérias Carótidas/efeitos dos fármacos , Espessura Intima-Media Carotídea , Estudos Transversais , Ensaio de Imunoadsorção Enzimática , Epilepsias Parciais/diagnóstico por imagem , Epilepsias Parciais/tratamento farmacológico , Epilepsias Parciais/metabolismo , Epilepsia Generalizada/diagnóstico por imagem , Epilepsia Generalizada/tratamento farmacológico , Epilepsia Generalizada/metabolismo , Feminino , Frutose/efeitos adversos , Frutose/análogos & derivados , Frutose/uso terapêutico , Humanos , Arteriosclerose Intracraniana/diagnóstico por imagem , Arteriosclerose Intracraniana/metabolismo , Lamotrigina , Levetiracetam , Masculino , Piracetam/efeitos adversos , Piracetam/análogos & derivados , Piracetam/uso terapêutico , Topiramato , Triazinas/efeitos adversos , Triazinas/uso terapêutico , Ácido Valproico/efeitos adversos , Ácido Valproico/uso terapêuticoRESUMO
RATIONALE: Many recent studies suggest that the kallikrein-kinin system play a protective role in the impairment of vascular smooth muscle cells and vascular endothelial cell. AIMS: The study aims to determine whether tissue kallikrein is efficacy for preventing the long-term in-stent restenosis after stenting of symptomatic atherosclerotic stenosis of the middle cerebral artery M1 segment. DESIGN: This is a Phase II, randomized, single-blinded, controlled trial. In line with SAMMPRIS stenting indications, patients (n = 90) with the symptomatic the middle cerebral artery M1 segment stenosis ≥ 70% and successfully treated with stent will be enrolled. Eligible patients will be randomized using computer generated numbers, and allocated to receive tissue kallikrein treatment or not. Patients in tissue kallikrein treatment group will be prescribed with intravenous infusion of tissue kallikrein (0.15 PNAU/d, dissolved in 100 ml saline) for 7 days after stenting and then oral administration of pancreatic kallikrein enteric-coated tablet (240 U, 3/d) to the end of study. As the foundation treatment, all the enrolled patients will receive aspirin (100 mg/d), clopidogrel (75 mg/d), and atorvastatin (20 mg/d) for the first 6 months and continue with the combination of aspirin and atorvastatin at the previous dosage. STUDY OUTCOMES: Patients will be evaluated at 1, 6 and 12 months after stenting. The primary outcomes are the in-stent restenosis rate, new stroke or aggravation of the previous ischemic stroke ipsilateral to the severe stenotic artery. Secondary outcomes include stroke of other artery territories, myocardial infarction and vascular death. Modification of stroke knowledge, exercise and diet habit, smoking cessation and available laboratory data will also be recorded. CONCLUSION: As our pilot study, tissue kallikrein would be expected to prevent the long-term in-stent restenosis after stenting of the symptomatic middle cerebral artery dramatically.
Assuntos
Infarto da Artéria Cerebral Média/cirurgia , Arteriosclerose Intracraniana/induzido quimicamente , Arteriosclerose Intracraniana/prevenção & controle , Stents/efeitos adversos , Calicreínas Teciduais/uso terapêutico , Adulto , Angiografia Digital , Feminino , Seguimentos , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Método Simples-Cego , Fatores de TempoRESUMO
PURPOSE: Long-term antiepileptic drug (AED) therapy has been associated with an increase in risk of atherosclerosis. At issue is whether this risk is related to the duration of AED therapy. We evaluated the hypothesis that the cumulative effect of long-term exposure to AEDs plays a pivotal role in the pathogenesis of atherosclerosis in patients with epilepsy. METHODS: One hundred ninety-five patients under long-term AED therapy and 195 healthy age- and sex-matched control subjects received measurement of intima media thickness (IMT) at the far wall of the common carotid artery (CCA) by B-mode ultrasonography to assess the extent of atherosclerosis. Other measurements included body mass index (BMI) and blood lipid profile or homocysteine, folic acid, uric acid, fasting blood sugar, high sensitivity C-reactive protein (hs-CRP), thiobarbituric acid reactive substances (TBARS), and total reduced thiols. RESULTS: CCA IMT was significantly increased in patients with epilepsy, with male subjects exhibiting thicker IMT than their female counterparts. Whereas BMI, homocysteine, hs-CRP, and TBARS were significantly elevated, folic acid and thiols were significantly reduced in patients with epilepsy. Multiple linear regression analysis further revealed that duration of AED therapy, age, gender, and TBARS level (index for oxidative stress) were independently associated with CCA IMT. In addition, the log-transformed CCA IMT increased linearly with duration of AED therapy after adjustments for age, gender, and TBARS level. DISCUSSION: The duration of AED therapy is significantly associated with the acceleration of atherosclerosis in patients with epilepsy, alongside independent contributions of age, gender, and oxidative stress to the atherosclerotic process.
Assuntos
Anticonvulsivantes/efeitos adversos , Epilepsia/tratamento farmacológico , Arteriosclerose Intracraniana/induzido quimicamente , Adulto , Doenças das Artérias Carótidas/induzido quimicamente , Estudos de Casos e Controles , Epilepsia/classificação , Epilepsia/etiologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Estudos Retrospectivos , Fatores de RiscoAssuntos
Hiper-Homocisteinemia/induzido quimicamente , Arteriosclerose Intracraniana/induzido quimicamente , Ácido Valproico/efeitos adversos , Fatores Etários , Anticonvulsivantes/efeitos adversos , Estenose das Carótidas/induzido quimicamente , Estenose das Carótidas/metabolismo , Estenose das Carótidas/fisiopatologia , Criança , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Epilepsia/tratamento farmacológico , Ácido Fólico/uso terapêutico , Homocisteína/sangue , Humanos , Hiper-Homocisteinemia/complicações , Hiper-Homocisteinemia/fisiopatologia , Arteriosclerose Intracraniana/metabolismo , Arteriosclerose Intracraniana/fisiopatologia , Transtornos do Metabolismo dos Lipídeos/sangue , Transtornos do Metabolismo dos Lipídeos/induzido quimicamente , Transtornos do Metabolismo dos Lipídeos/fisiopatologia , Fatores de Risco , Túnica Íntima/efeitos dos fármacos , Túnica Íntima/metabolismo , Túnica Íntima/patologiaRESUMO
The present study examined the effect of high fat and high fructose (HFF) diet on the development of atherosclerosis and vascular contractile responses in the cerebral artery and thoracic aorta in non-human primates. Female cynomolgus monkeys (age: 3 to 4 years) were divided into normal control diet (N=5) and HFF diet groups (N=5). Twenty-eight weeks after feeding the HFF diet, total cholesterol and low-density lipoprotein-cholesterol in serum were significantly increased in the HFF diet group compared to the control group. The ultrastructural analyses of the basilar artery and aorta demonstrated the infiltration of lipid-laden foam cells and the appearance of lipid droplet-filled smooth muscle cells in the monkeys fed with the HFF diet. In terms of vascular reactivity, there was significantly greater vasoconstriction of the aorta and basilar artery in response to 5-hydroxytryptamine in the HFF diet group compared to the normal diet-fed group. In addition, KCl-induced vasoconstriction of the basilar arteries was also significantly enhanced in the HFF diet group compared to the normal diet-fed monkeys. In all, our present study has demonstrated that changes in the vascular responsiveness of the cerebral artery and its cellular architecture may manifest into cerebrovascular complications consistent with a pathological state normally observed with the onset and progression of atherosclerosis.
Assuntos
Aorta Torácica/fisiopatologia , Artéria Basilar/fisiopatologia , Dieta Aterogênica , Gorduras na Dieta/efeitos adversos , Frutose/efeitos adversos , Arteriosclerose Intracraniana/fisiopatologia , Vasoconstrição , Animais , Aorta Torácica/metabolismo , Aorta Torácica/ultraestrutura , Artéria Basilar/metabolismo , Artéria Basilar/ultraestrutura , Cerebelo/irrigação sanguínea , Cerebelo/metabolismo , Cerebelo/fisiopatologia , Cerebelo/ultraestrutura , Artérias Cerebrais/metabolismo , Artérias Cerebrais/fisiopatologia , Artérias Cerebrais/ultraestrutura , LDL-Colesterol/sangue , Gorduras na Dieta/administração & dosagem , Feminino , Células Espumosas/metabolismo , Células Espumosas/ultraestrutura , Frutose/administração & dosagem , Arteriosclerose Intracraniana/sangue , Arteriosclerose Intracraniana/induzido quimicamente , Arteriosclerose Intracraniana/patologia , Arteriosclerose Intracraniana/veterinária , Macaca fascicularis , Doenças dos Macacos/sangue , Doenças dos Macacos/induzido quimicamente , Doenças dos Macacos/patologia , Doenças dos Macacos/fisiopatologia , Cloreto de Potássio/administração & dosagem , Serotonina/administração & dosagem , Serotoninérgicos/administração & dosagem , Vasoconstrição/efeitos dos fármacosRESUMO
In a series of animal experiments to provoke atherosclerosis, angiographic evaluation of the cerebral vessels was obtained. The angiographic evaluation of cerebral changes and correlation with the pathological alterations known to occur illustrate the value of this technique in long term analysis of induced atherosclerosis in the experimental animal. Control groups, high cholesterol diet groups, and induced hypertensive groups with and without a high cholesterol diet were evaluated by serial angiographic techniques. Examples of angiographic changes are demonstrated and have proven of considerable value in following the progress of the vascular changes.