RESUMEN
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.
Asunto(s)
Antineoplásicos/efectos adversos , Infarto de la Arteria Cerebral Media/etiología , Arteriosclerosis Intracraneal/inducido químicamente , Accidente Cerebrovascular Isquémico/etiología , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversos , Pirimidinas/efectos adversos , Estado Funcional , Humanos , Infarto de la Arteria Cerebral Media/diagnóstico por imagen , Infarto de la Arteria Cerebral Media/terapia , Arteriosclerosis Intracraneal/diagnóstico por imagen , Arteriosclerosis Intracraneal/terapia , Accidente Cerebrovascular Isquémico/diagnóstico por imagen , Accidente Cerebrovascular Isquémico/terapia , Masculino , Persona de Mediana Edad , Recuperación de la Función , Factores de Riesgo , Resultado del TratamientoRESUMEN
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.
Asunto(s)
Compuestos de Bencidrilo/toxicidad , Encéfalo , Dopamina/metabolismo , Disruptores Endocrinos/toxicidad , Carpa Dorada/metabolismo , Arteriosclerosis Intracraneal , Fenoles/toxicidad , Contaminantes Químicos del Agua/toxicidad , Animales , Encéfalo/irrigación sanguínea , Encéfalo/patología , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Perfilación de la Expresión Génica , Arteriosclerosis Intracraneal/inducido químicamente , Arteriosclerosis Intracraneal/metabolismo , Arteriosclerosis Intracraneal/patologíaRESUMEN
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 .
Asunto(s)
Contaminantes Atmosféricos/toxicidad , Arteriosclerosis Intracraneal/inducido químicamente , Arteria Cerebral Media/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Material Particulado/toxicidad , Animales , Modelos Animales de Enfermedad , Inflamación , Arteriosclerosis Intracraneal/inmunología , Arteriosclerosis Intracraneal/patología , Masculino , Arteria Cerebral Media/inmunología , Arteria Cerebral Media/patología , Tamaño de la Partícula , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismoRESUMEN
No disponible
Asunto(s)
Humanos , Masculino , Persona de Mediana Edad , Anciano , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Accidente Cerebrovascular/inducido químicamente , Arteriosclerosis Intracraneal/inducido químicamente , Enfermedad Arterial Periférica/inducido químicamente , Factores de Riesgo , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológicoRESUMEN
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.
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Anticonvulsivantes/efectos adversos , Epilepsia/tratamiento farmacológico , Arteriosclerosis Intracraneal/inducido químicamente , Arteriosclerosis Intracraneal/epidemiología , Adulto , Carbamazepina/efectos adversos , Colesterol/sangre , Estudios Transversales , Femenino , Humanos , Arteriosclerosis Intracraneal/sangre , Lamotrigina/efectos adversos , Masculino , Estudios Retrospectivos , Estadísticas no Paramétricas , Ácido Valproico/efectos adversosRESUMEN
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.
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Anticonvulsivantes/efectos adversos , Arteriosclerosis Intracraneal/inducido químicamente , Adolescente , Anticonvulsivantes/uso terapéutico , Carbamazepina/efectos adversos , Carbamazepina/uso terapéutico , Arterias Carótidas/diagnóstico por imagen , Arterias Carótidas/efectos de los fármacos , Grosor Intima-Media Carotídeo , Estudios Transversales , Ensayo de Inmunoadsorción Enzimática , Epilepsias Parciales/diagnóstico por imagen , Epilepsias Parciales/tratamiento farmacológico , Epilepsias Parciales/metabolismo , Epilepsia Generalizada/diagnóstico por imagen , Epilepsia Generalizada/tratamiento farmacológico , Epilepsia Generalizada/metabolismo , Femenino , Fructosa/efectos adversos , Fructosa/análogos & derivados , Fructosa/uso terapéutico , Humanos , Arteriosclerosis Intracraneal/diagnóstico por imagen , Arteriosclerosis Intracraneal/metabolismo , Lamotrigina , Levetiracetam , Masculino , Piracetam/efectos adversos , Piracetam/análogos & derivados , Piracetam/uso terapéutico , Topiramato , Triazinas/efectos adversos , Triazinas/uso terapéutico , Ácido Valproico/efectos adversos , Ácido Valproico/uso terapéuticoRESUMEN
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.
Asunto(s)
Infarto de la Arteria Cerebral Media/cirugía , Arteriosclerosis Intracraneal/inducido químicamente , Arteriosclerosis Intracraneal/prevención & control , Stents/efectos adversos , Calicreínas de Tejido/uso terapéutico , Adulto , Angiografía de Substracción Digital , Femenino , Estudios de Seguimiento , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Método Simple Ciego , Factores de TiempoRESUMEN
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.
Asunto(s)
Anticonvulsivantes/efectos adversos , Epilepsia/tratamiento farmacológico , Arteriosclerosis Intracraneal/inducido químicamente , Adulto , Enfermedades de las Arterias Carótidas/inducido químicamente , Estudios de Casos y Controles , Epilepsia/clasificación , Epilepsia/etiología , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Análisis de Regresión , Estudios Retrospectivos , Factores de RiesgoAsunto(s)
Hiperhomocisteinemia/inducido químicamente , Arteriosclerosis Intracraneal/inducido químicamente , Ácido Valproico/efectos adversos , Factores de Edad , Anticonvulsivantes/efectos adversos , Estenosis Carotídea/inducido químicamente , Estenosis Carotídea/metabolismo , Estenosis Carotídea/fisiopatología , Niño , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Células Endoteliales/patología , Epilepsia/tratamiento farmacológico , Ácido Fólico/uso terapéutico , Homocisteína/sangre , Humanos , Hiperhomocisteinemia/complicaciones , Hiperhomocisteinemia/fisiopatología , Arteriosclerosis Intracraneal/metabolismo , Arteriosclerosis Intracraneal/fisiopatología , Trastornos del Metabolismo de los Lípidos/sangre , Trastornos del Metabolismo de los Lípidos/inducido químicamente , Trastornos del Metabolismo de los Lípidos/fisiopatología , Factores de Riesgo , Túnica Íntima/efectos de los fármacos , Túnica Íntima/metabolismo , Túnica Íntima/patologíaRESUMEN
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.
Asunto(s)
Aorta Torácica/fisiopatología , Arteria Basilar/fisiopatología , Dieta Aterogénica , Grasas de la Dieta/efectos adversos , Fructosa/efectos adversos , Arteriosclerosis Intracraneal/fisiopatología , Vasoconstricción , Animales , Aorta Torácica/metabolismo , Aorta Torácica/ultraestructura , Arteria Basilar/metabolismo , Arteria Basilar/ultraestructura , Cerebelo/irrigación sanguínea , Cerebelo/metabolismo , Cerebelo/fisiopatología , Cerebelo/ultraestructura , Arterias Cerebrales/metabolismo , Arterias Cerebrales/fisiopatología , Arterias Cerebrales/ultraestructura , LDL-Colesterol/sangre , Grasas de la Dieta/administración & dosificación , Femenino , Células Espumosas/metabolismo , Células Espumosas/ultraestructura , Fructosa/administración & dosificación , Arteriosclerosis Intracraneal/sangre , Arteriosclerosis Intracraneal/inducido químicamente , Arteriosclerosis Intracraneal/patología , Arteriosclerosis Intracraneal/veterinaria , Macaca fascicularis , Enfermedades de los Monos/sangre , Enfermedades de los Monos/inducido químicamente , Enfermedades de los Monos/patología , Enfermedades de los Monos/fisiopatología , Cloruro de Potasio/administración & dosificación , Serotonina/administración & dosificación , Serotoninérgicos/administración & dosificación , Vasoconstricción/efectos de los fármacosRESUMEN
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.