RESUMEN
OBJECTIVES: Primary systemic vasculitis associated with anti-neutrophil cytoplasm antibodies (ANCA) differs in its frequency and clinical expression between Japan and Europe. We sought to ascertain whether such differences arise from the performance of enzyme-linked immunosorbent assays (ELISAs) for ANCA. METHODS: Plasma samples from 64 consecutive Japanese patients with a clinical and histological diagnosis of primary systemic vasculitis including microscopic polyangiitis (MPA; n=52), Churg-Strauss syndrome (CSS; n=1), and Wegener's granulomatosis (WG; n=11), or those from disease controls with non-vasculitic glomerulonephritis (n=54) and healthy controls (n=55) were tested for the presence of myeloperoxidase (MPO) by ELISAs available in Japan (Nipro and MBL) and compared with those in Europe (Wieslab). The sensitivity and specificity were calculated for each ELISA, and its diagnostic performance was assessed by receiver operating characteristic curve analysis. RESULTS: The sensitivity and specificity of either MPO-ANCA assays for a diagnosis of MPA were 90.4% and 98.2% (Nipro), 88.2% and 96.3% (MBL), and 86.5% and 99.1% (Wieslab). The overall diagnostic performance, assessed as the area under curve of the MPO-ANCA ELISAs for MPA were 0.946+/-0.022 (Nipro), 0.970+/-0.017 (MBL), and 0.971+/-0.017 (Wieslab), while that of PR3-ANCA ELISAs for WG were 0.986+/-0.025 (Nipro), 0.993+/-0.017 (MBL), and 0.916+/-0.059 (Wieslab). CONCLUSIONS: The MPO-ANCA ELISAs commercially available in Japan exhibited high sensitivity and specificity for the diagnosis of ANCA-associated vasculitides and provided similar diagnostic value to those in Europe. These results facilitate further international comparison of ANCA-associated vasculitides between Japanese and European populations.
Asunto(s)
Anticuerpos Anticitoplasma de Neutrófilos/análisis , Anticuerpos Anticitoplasma de Neutrófilos/sangre , Ensayo de Inmunoadsorción Enzimática/métodos , Ensayo de Inmunoadsorción Enzimática/normas , Vasculitis/diagnóstico , Vasculitis/inmunología , Síndrome de Churg-Strauss/diagnóstico , Síndrome de Churg-Strauss/etnología , Síndrome de Churg-Strauss/inmunología , Europa (Continente)/epidemiología , Granulomatosis con Poliangitis/diagnóstico , Granulomatosis con Poliangitis/etnología , Granulomatosis con Poliangitis/inmunología , Humanos , Japón/epidemiología , Mieloblastina/inmunología , Curva ROC , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Estreptavidina , Vasculitis/etnologíaRESUMEN
MOTIVATION: An increasing number of observations support the hypothesis that most biological functions involve the interactions between many proteins, and that the complexity of living systems arises as a result of such interactions. In this context, the problem of inferring a global protein network for a given organism, using all available genomic data about the organism, is quickly becoming one of the main challenges in current computational biology. RESULTS: This paper presents a new method to infer protein networks from multiple types of genomic data. Based on a variant of kernel canonical correlation analysis, its originality is in the formalization of the protein network inference problem as a supervised learning problem, and in the integration of heterogeneous genomic data within this framework. We present promising results on the prediction of the protein network for the yeast Saccharomyces cerevisiae from four types of widely available data: gene expressions, protein interactions measured by yeast two-hybrid systems, protein localizations in the cell and protein phylogenetic profiles. The method is shown to outperform other unsupervised protein network inference methods. We finally conduct a comprehensive prediction of the protein network for all proteins of the yeast, which enables us to propose protein candidates for missing enzymes in a biosynthesis pathway. AVAILABILITY: Softwares are available upon request.
Asunto(s)
Inteligencia Artificial , Mapeo Cromosómico/métodos , Bases de Datos Genéticas , Perfilación de la Expresión Génica/métodos , Mapeo de Interacción de Proteínas/métodos , Proteoma/metabolismo , Transducción de Señal/fisiología , Modelos Biológicos , Proteínas de Saccharomyces cerevisiae/metabolismo , Integración de SistemasRESUMEN
The OLETF rat develops microangiopathic complications similar to human diabetes and is considered a useful model of Type 2 DM. Erythrocyte, platelet and leucocyte abnormalities described in diabetic patients are thought to play a role in the development of diabetic microangiopathy. This study was designed to investigate whether OLETF rats show hematological alterations and the effect of sucrose treatment on metabolic and blood parameters. Hematological parameters, body weight, food and water intake, fasting and non-fasting blood glucose (BG) and HbA1c were measured in OLETF rats treated for two months with 30% sucrose added to drinking water. Non-treated OLETF rats and non-diabetic Long-Evans Tokushima Otsuka (LETO) rats were used as controls. In the control OLETF rats the number of platelets (Plt) and red blood cells (RBC) was higher, while the mean cell volume (MCV) and the mean cell hemoglobin content (MCH) were lower compared with LETO. Mean cell hemoglobin concentration (MCHC) was significantly higher in the diabetic rats. Sucrose administration decreased food intake and body weight and increased fasting blood glucose and HbA1c. It resulted in a decrease of RBC, Hb, Hct, MCV and MCH compared with control OLETF, while Plt count increased significantly. Our results point to significant alterations in erythrocyte count and morphology and Plt count in diabetic OLETF rats compared with non-diabetic LETO. Sucrose administration accelerated the development of diabetes, affected blood cells inducing the suppression of RBC and an increase in Plt count and some of its effects persisted after sucrose withdrawal.
Asunto(s)
Diabetes Mellitus Tipo 2/sangre , Angiopatías Diabéticas/inducido químicamente , Modelos Animales de Enfermedad , Sacarosa/toxicidad , Animales , Glucemia/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Angiopatías Diabéticas/sangre , Conducta de Ingestión de Líquido/efectos de los fármacos , Recuento de Eritrocitos , Hemoglobina Glucada , Masculino , Ratas , Ratas Endogámicas OLETFRESUMEN
MOTIVATION: A major issue in computational biology is the reconstruction of pathways from several genomic datasets, such as expression data, protein interaction data and phylogenetic profiles. As a first step toward this goal, it is important to investigate the amount of correlation which exists between these data. RESULTS: These methods are successfully tested on their ability to recognize operons in the Escherichia coli genome, from the comparison of three datasets corresponding to functional relationships between genes in metabolic pathways, geometrical relationships along the chromosome, and co-expression relationships as observed by gene expression data.
Asunto(s)
Algoritmos , Perfilación de la Expresión Génica/métodos , Regulación de la Expresión Génica/fisiología , Familia de Multigenes/genética , Alineación de Secuencia/métodos , Análisis de Secuencia de ADN/métodos , Transducción de Señal/genética , Mapeo Cromosómico/métodos , Escherichia coli/genética , Genómica/métodos , Modelos Genéticos , Modelos Estadísticos , Homología de Secuencia de Ácido Nucleico , Estadística como AsuntoRESUMEN
Considering the characteristics of RA synovial tissues such as marked proliferation and invasion to adjacent tissues, comparisons with transformed or neoplastic tissue are natural. RA synovial tissues or cells are not truly malignant, but they have many features of transformation, denoted as "partial transformation" in this article. These features include anchorage-independent growth, loss of contact inhibition, oncogene activation, monoclonal or oligoclonal expansion, detectable telomerase activity, and somatic gene mutations. Although it is not possible to conclude whether most of these cells are permanently changed in association with some genetic alterations or are passively changed by virtue of environmental factors (i.e., cytokine-mediated imprinting), the presence of p53 mutations in RA synovial tissues is especially persuasive. A number of transcription factors play a critical role in the activation, differentiation, and proliferation of RA synovial cells. In particular, the roles of AP-1, MAPKs, and NF-kappa B have been investigated carefully because of their ability to regulate numerous inflammation-related genes. These transcription factors also control expression and activation of matrix-degrading enzymes, including MMPs, aggrecanase, and cysteine proteases, which are the primary enzymes responsible for joint destruction. Elucidation of gene mutations and detailed signal transduction pathways that are specific to RA as well as mechanisms of action of matrix-degrading enzymes may lead to development of a novel therapy for RA. Careful mapping of cytokine networks a decade ago led to groundbreaking advances in therapy. Similarly, methodical evaluation and prioritization of intracellular targets might provide the basis for therapeutic interventions.
Asunto(s)
Artritis Reumatoide/etiología , Artritis Reumatoide/patología , Membrana Sinovial/patología , Artritis Reumatoide/metabolismo , Humanos , Membrana Sinovial/metabolismoRESUMEN
Polymorphisms at three loci in the thiopurine methyltransferase (TPMT) gene are known to be responsible for azathioprine and 6-mercaptopurine (6MP) toxicity. Among them, only TPMT*3C variant allele with A719G mutation was found in 15/522 (2.9%; 17/1044 alleles; 1.6%) Japanese individuals including two homozygotes. The allele frequency was different from that in Caucasians, and investigation of TPMT polymorphisms with consideration of ethnic differences before administration of azathioprine or 6MP may provide clinically useful information.
Asunto(s)
Alelos , Pueblo Asiatico/genética , Genética de Población , Metiltransferasas/genética , Polimorfismo Genético , Cartilla de ADN/química , Frecuencia de los Genes , Genotipo , Humanos , Japón/epidemiología , Reacción en Cadena de la Polimerasa , Población Blanca/genéticaRESUMEN
This study was designed to investigate the central and peripheral activity profile of cholinesterase inhibitors in rats. Intravenous injection of cholinesterase inhibitors caused fasciculation, a fine involuntary muscular movement. This peripheral cholinergic sign was tightly correlated with in vitro anti-acetylcholinesterase activity by cholinesterase inhibitors, suggesting that fasciculation is a valid index of peripheral cholinergic activation. Yawning, used as a marker of central cholinergic activation, was also monitored. E2030 (3-(2-(1-(1,3-dioxolan-2-ylmethyl)-4-piperidyl)ethyl)-2H-3,4-dihydro-1,3-benzoxazin-2,4-dione hydrochloride) elicited yawning at more than 4 mg/kg, while fasciculation was significantly intensified only at a dose of 16 mg/kg. Donepezil and tacrine induced both yawning and fasciculation at doses greater than 4 mg/kg, whereas physostigmine induced both behaviors at a dose of 8 mg/kg and above. Finally, ipidacrine elicited yawning at a dose of 16 mg/kg and fasciculation at doses greater than 8 mg/kg. Thus, all putative centrally acting cholinesterase inhibitors elicited yawning. TAK-147 (3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-benzazepin-8-yl)-1-propanone fumarate) did not significantly elicit yawning at doses under 16 mg/kg, but elicited fasciculation at a dose of more than 4 mg/kg. Distigmine, a peripherally acting cholinesterase inhibitor, evoked fasciculations, but not yawning. When mild to moderate fasciculation was evoked, donepezil and E2030 elicited more than nine yawns over 30 min, while the other cholinesterase inhibitors elicited approximately five yawns at most during this period. These results indicated that E2030 and donepezil exhibited the most marked preferential central cholinergic activity, relative to peripheral activity, among cholinesterase inhibitors tested. Scopolamine, a centrally acting antimuscarinic drug, completely inhibited E2030-induced yawning, while peripherally acting methylscopolamine did not. Haloperidol, a dopamine receptor antagonist, partially blocked E2030-induced yawning, but did not block donepezil-induced yawning. These results suggest that central cholinergic and, in part, dopaminergic mechanisms are involved in E2030-induced yawning.
Asunto(s)
Benzazepinas/farmacología , Inhibidores de la Colinesterasa/farmacología , Fasciculación/inducido químicamente , Indanos/farmacología , Piperidinas/farmacología , Tacrina/farmacología , Bostezo/efectos de los fármacos , Acetilcolinesterasa/efectos de los fármacos , Acetilcolinesterasa/metabolismo , Animales , Benzoxazinas , Butirilcolinesterasa/efectos de los fármacos , Butirilcolinesterasa/metabolismo , Donepezilo , Masculino , Antagonistas Muscarínicos/farmacología , Oxazinas/farmacología , Ratas , Ratas Wistar , Bostezo/fisiologíaRESUMEN
The mac-1 gene of Myxococcus xanthus TA, an antibiotic TA producer, encoded a protein with strong sequence similarity to the antibiotic ATP-binding cassette (ABC) transporter for macrolide antibiotics. The mac-1 gene encoding protein (Mac-1) had two ATP-binding domains containing Walker A and B motifs, and no hydrophobic transmembrane regions. Insertional inactivation of mac-1 caused enhanced sensitivity to oleandomycin, a macrolide antibiotic, while the mac-1 mutant showed normal export of antibiotic TA into the extracellular fluid. The mac-1 mutant could form mounds, but was unable to form fruiting bodies or sporulate under nutrient starvation. A primary role for Mac-1 in M. xanthus may be as a transporter which exports or imports a molecule required for the sporulation process.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Myxococcus xanthus/genética , Transportadoras de Casetes de Unión a ATP/química , Transportadoras de Casetes de Unión a ATP/metabolismo , Adenosina Trifosfato/metabolismo , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Antibacterianos/metabolismo , Antibacterianos/farmacología , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Secuencia de Bases , Sitios de Unión , Transporte Biológico , Clonación Molecular , Genes Bacterianos/genética , Macrólidos , Pruebas de Sensibilidad Microbiana , Datos de Secuencia Molecular , Myxococcus xanthus/efectos de los fármacos , Myxococcus xanthus/crecimiento & desarrollo , Myxococcus xanthus/metabolismo , Oleandomicina/farmacología , Mutación Puntual/genética , Estructura Terciaria de Proteína , ARN Bacteriano/genética , ARN Bacteriano/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Alineación de Secuencia , Esporas Bacterianas/fisiología , Relación Estructura-ActividadRESUMEN
IkappaB kinase (IKK) plays a key role in the regulation of nuclear factor kappaB (NF-kappaB). We previously demonstrated the expression of two kinases, IKK1 and IKK2, in fibroblast-like synoviocytes (FLS) and determined their functional consequences for inflammatory gene expression in vitro and in vivo. Recently, a novel inducible IkappaB kinase has been described, namely, IKK-i or IKK-epsilon, which is functionally and structurally distinct from constitutively expressed IKK1 and IKK2. Therefore, we investigated the expression and regulation of this novel kinase in FLS from patients with rheumatoid arthritis and osteoarthritis. Interestingly, constitutive gene expression and protein expression were observed in all cell lines examined. TNFalpha stimulation for 24 h increased IKK-i expression 7.2 +/- 1.8-fold in FLS (P < 0.02). IL-1 also significantly increased IKK-i gene expression. Time course experiments demonstrated that IKK-i gene expression increased within 3 h of TNFalpha stimulation and persisted for at least 24 h. Dose-response studies showed that as little as 1 ng/ml of TNFalpha increased IKK-i gene expression. Constitutive IKK-1 gene expression was also noted in rheumatoid arthritis, osteoarthritis, and normal synovium. This is the first report demonstrating constitutive expression and cytokine regulation of this novel kinase in primary human synovial cells.
Asunto(s)
Fibroblastos/enzimología , Proteínas Serina-Treonina Quinasas/biosíntesis , Membrana Sinovial/enzimología , Artritis Reumatoide/enzimología , Artritis Reumatoide/genética , Células Cultivadas , Fibroblastos/efectos de los fármacos , Humanos , Quinasa I-kappa B , Interleucina-1/farmacología , Cinética , Osteoartritis/enzimología , Osteoartritis/genética , Proteínas Serina-Treonina Quinasas/genética , ARN Mensajero/biosíntesis , Membrana Sinovial/citología , Transcripción Genética , Activación Transcripcional , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
One of the most consistent changes associated with Alzheimer's disease (AD) is a deficit in central cholinergic neurotransmission. Donepezil hydrochloride (DPZ), a novel class of cholinesterase (ChE) inhibitors, inhibits degradation of acetylcholine (ACh) and activates central cholinergic system. In in vitro studies, DPZ more selectively inhibited acetylcholinesterase (IC50: 6.7 nM) than butyrylcholinesterase (IC50: 7400 nM), while tacrine inhibited both acetylcholinesterase (IC50: 77 nM) and butyrylcholinesterase (IC50: 69 nM). After oral dosing, DPZ (ID50: 2.6 mg/kg) inhibited brain ChE dose-dependently without any remarkable effect on ChE in the heart and small intestine, whereas tacrine (ID50: 9.5 mg/kg) inhibited ChE equally in the brain and peripheral tissues. Brain microdialysis revealed that DPZ (2.5 mg/kg) enhanced extracellular ACh concentrations in the cerebral cortex and hippocampus in rats. In behavioral studies, DPZ counteracted both the deficit in passive avoidance induced by lesioning of the nucleus basalis magnocellularis (0.125-1.0 mg/kg) and the impairment in acquisition of a hidden-platform water maze task after lesioning of the medial septum in rats (0.5 mg/kg). DPZ also inhibited the scopolamine-induced impairment of radial maze performance (0.5 mg/kg). Placebo-controlled clinical studies of 12- and 24-week treatments of DPZ (5 mg, 10 mg/day) clearly showed an improvement in cognitive scores of probable AD patients.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/uso terapéutico , Indanos/uso terapéutico , Piperidinas/uso terapéutico , Acetilcolina/metabolismo , Enfermedad de Alzheimer/metabolismo , Animales , Encéfalo/metabolismo , Inhibidores de la Colinesterasa/farmacocinética , Inhibidores de la Colinesterasa/farmacología , Ensayos Clínicos como Asunto , Donepezilo , Humanos , Indanos/farmacocinética , Indanos/farmacología , Discapacidades para el Aprendizaje/tratamiento farmacológico , Piperidinas/farmacocinética , Piperidinas/farmacologíaRESUMEN
Donepezil is a member of a new class of centrally acting cholinesterase inhibitors which preferentially inhibit acetylcholinesterase rather than butyrylcholinesterase. The effects of donepezil on learning impairments were investigated in some hypocholinergic models in rats. In nucleus basalis magnocellularis (NBM)-lesioned rats, donepezil alleviated deficits in passive avoidance response at a dose of 0.125 mg/kg and higher, while tacrine had only a tendency toward improved performance. Donepezil at 0.5 mg/kg effectively counteracted acquisition impairments in the water maze task induced by lesions of the medial septum; tacrine had no significant effects on impairments in this task. Scopolamine caused an increase of errors in the 8-arm radial maze. Donepezil significantly decreased scopolamine-induced errors in the radial maze at 0.5 mg/kg, whereas tacrine decreased errors at 2 mg/kg. These results suggest that donepezil can clearly minimize learning impairments induced by treatments that cause central cholinergic deficiencies in rats. These findings support the clinical efficacy of donepezil in Alzheimer's disease.
Asunto(s)
Núcleo Basal de Meynert/efectos de los fármacos , Inhibidores de la Colinesterasa/uso terapéutico , Indanos/uso terapéutico , Discapacidades para el Aprendizaje/tratamiento farmacológico , Piperidinas/uso terapéutico , Animales , Reacción de Prevención/efectos de los fármacos , Núcleo Basal de Meynert/fisiología , Donepezilo , Relación Dosis-Respuesta a Droga , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratas , Ratas Wistar , Escopolamina/farmacología , Tacrina/uso terapéuticoRESUMEN
Systemic lupus erythematosus (SLE) is sometimes reported to complicate fatal pulmonary hypertension. A 46-year-old woman, with a ten-year history of SLE and pulmonary hypertension, was admitted to our hospital complaining of dyspnea and chest pain. She suffered pulmonary hemorrhage and after steroid pulse therapy, she underwent continuous intravenous infusion of epoprostenol (prostaglandin I2) with corticosteroid for four weeks, which reduced the pulmonary artery pressure and resistance. Following the successful treatment, beraprost sodium, an oral PGI2 analogue, was given and it maintained pulmonary hypertension remittance for four years.
Asunto(s)
Epoprostenol/uso terapéutico , Hipertensión Pulmonar/tratamiento farmacológico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Administración Oral , Angiografía , Quimioterapia Combinada , Epoprostenol/administración & dosificación , Femenino , Humanos , Hipertensión Pulmonar/complicaciones , Hipertensión Pulmonar/diagnóstico por imagen , Infusiones Intravenosas , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/diagnóstico por imagen , Persona de Mediana Edad , Prednisolona/administración & dosificación , Prednisolona/uso terapéutico , Tomografía Computarizada por Rayos XAsunto(s)
Antiinflamatorios/uso terapéutico , Asma/tratamiento farmacológico , Eosinofilia/tratamiento farmacológico , Fascitis/tratamiento farmacológico , Prednisolona/uso terapéutico , Asma/complicaciones , Eosinofilia/complicaciones , Eosinofilia/patología , Fascitis/complicaciones , Fascitis/patología , Femenino , Humanos , Persona de Mediana Edad , Músculo Esquelético/patología , Recurrencia , Inducción de RemisiónAsunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa , Diseño de Fármacos , Indanos , Nootrópicos , Piperidinas , Animales , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Ensayos Clínicos como Asunto , Donepezilo , Evaluación Preclínica de Medicamentos , Humanos , Indanos/síntesis química , Indanos/química , Nootrópicos/síntesis química , Nootrópicos/química , Piperidinas/síntesis química , Piperidinas/químicaRESUMEN
Intercollicular decerebration in animals induces sustained facilitation of muscle tone of the limbs and this animal model has been used to assess centrally acting muscle relaxants. We have examined the involvement of central and spinal cord serotonergic pathways in the onset of excessive muscle tone in an intercollicularly decerebrated rat. Descending serotonergic pathways are known to modulate, directly or indirectly, the excitability of spinal cord motoneurons and it is inferred that serotonin (5-HT) plays an important role in locomotion. Alteration of muscle tone has been investigated in 5-HT-depleted rats with a neurotoxin, 5, 7-dihydroxytryptamine (5,7-DHT) after pretreatment with desipramine. Intracerebroventricular (i.c.v.) administration of 5,7-DHT reduced 5-HT content in the forebrain to 50.5% and that in the spinal cord to 10.5%, while intrathecal (i.t.) administration of 5,7-DHT decreased 5-HT content in the spinal cord to 8.9% without causing any change in the forebrain. In contrast, noradrenaline or dopamine content was not affected by the neurotoxin in both tissues. These treatments significantly attenuated the muscle tone in the animal models. Moreover, the measurement of 5-HT and 5-hydroxyindoleacetic acid content in intact rats after decerebration showed that facilitation of the 5-HT turnover in the spinal cord, but not in the forebrain, was enhanced compared with sham-operated rats. These findings suggest that the descending serotonergic pathways are essential to induce excessive muscle tone in the intercollicular decerebrated rats and that 5-HT antagonists might be candidates for centrally acting muscle relaxants.
Asunto(s)
5,7-Dihidroxitriptamina/uso terapéutico , Estado de Descerebración/fisiopatología , Hipertonía Muscular/tratamiento farmacológico , Relajantes Musculares Centrales/uso terapéutico , Prosencéfalo/metabolismo , Serotoninérgicos/uso terapéutico , Serotonina/fisiología , Médula Espinal/metabolismo , 5,7-Dihidroxitriptamina/administración & dosificación , 5,7-Dihidroxitriptamina/farmacología , Animales , Dopamina/metabolismo , Vías Eferentes/fisiología , Ácido Hidroxiindolacético/metabolismo , Inyecciones Intraventriculares , Inyecciones Espinales , Masculino , Microdiálisis , Hipertonía Muscular/fisiopatología , Relajantes Musculares Centrales/administración & dosificación , Relajantes Musculares Centrales/farmacología , Tono Muscular/efectos de los fármacos , Norepinefrina/metabolismo , Ratas , Ratas Wistar , Serotoninérgicos/farmacologíaRESUMEN
Donepezil hydrochloride ((+/-)-2-[(1-benzylpiperidin-4-yl)methyl]-5, 6-dimethoxy-indan-1-one monohydrochloride: E2020: donepezil) is a potent and selective acetylcholinesterase inhibitor developed for the treatment of Alzheimer's disease. The present experiments were designed to compare the inhibitory effects of orally administered donepezil and other cholinesterase inhibitors, tacrine (9-amino-1,2, 3,4-tetrahydroacridine hydrochloride), (S)-N-ethyl-3-[(1-dimethyl-amino)ethyl]-N-methyl-phenylcarbamate hydrogentartrate (ENA-713, rivastigmine) and 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4, 5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanone fumarate (TAK-147), on the cholinesterase activity in the brain and plasma of rats. Moreover, in order to validate the cholinesterase inhibition data, we measured the brain and plasma concentrations of these drugs. Oral administration of donepezil, tacrine, ENA-713 or TAK-147, caused a dose-dependent inhibition of brain and plasma cholinesterase activities. The ID(50) values of these compounds for brain cholinesterase activity were 6.3, 40.5, 7.2 and 26.8 micromol/kg, respectively. On the other hand, the ID(50)170, 9.7 and 51.2 micromol/kg, respectively. Thus, the ratios of the ID(50)4.2, 1.3 and 1.9, respectively. Brain and plasma concentrations of donepezil, tacrine and TAK-147 increased dose-dependently. The ratios of the concentrations (brain/plasma) of these compounds were 6.1-8.4 for donepezil, 14.5-54.6 for tacrine and 7.0-20.6 for TAK-147. The values of 50% inhibitory concentration of these drugs in the brain were 0.42, 3.5 and 1.1 nmol/g, respectively. In contrast, the brain and plasma concentrations of ENA-713 at all doses, except the two highest doses, were below the quantification limit. These results suggest that orally administered donepezil satisfactorily penetrates into the brain and inhibits cholinesterase there, and that donepezil is a potent and selective inhibitor of brain cholinesterase in comparison with plasma cholinesterase in vivo.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/farmacología , Indanos/farmacología , Fenilcarbamatos , Piperidinas/farmacología , Administración Oral , Animales , Benzazepinas/farmacocinética , Benzazepinas/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/enzimología , Carbamatos/farmacocinética , Carbamatos/farmacología , Donepezilo , Relación Dosis-Respuesta a Droga , Indanos/farmacocinética , Aprendizaje/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , Piperidinas/farmacocinética , Ratas , Ratas Wistar , Rivastigmina , Tacrina/farmacocinética , Tacrina/farmacologíaRESUMEN
A wide range of evidence shows that acetylcholinesterase (AChE) inhibitors can interfere with the progression of Alzheimer's disease (AD). The successful development of these compounds was based on a well-accepted theory that the decline in cognitive and mental functions associated with AD is related to the loss of cortical cholinergic neurotransmission. The earliest known AChE inhibitors, namely, physostigmine and tacrine, showed modest improvement in the cognitive function of Alzheimer's patients. However, clinical studies show that physostigmine has poor oral activity, brain penetration and pharmacokinetic parameters while tacrine has hepatotoxic liability. Studies were then focused on finding a new type of acetylcholinesterase inhibitor that would overcome the disadvantages of these two compounds. Donepezil hydrochloride inaugurates a new class of AChE inhibitors with longer and more selective action with manageable adverse effects. Currently, there are about 19 new Alzheimer's drugs in various phases of clinical development.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/uso terapéutico , Indanos/uso terapéutico , Piperidinas/uso terapéutico , Enfermedad de Alzheimer/fisiopatología , Animales , Encéfalo/efectos de los fármacos , Inhibidores de la Colinesterasa/química , Cristalografía por Rayos X , Donepezilo , Humanos , Indanos/química , Indanos/farmacología , Modelos Moleculares , Piperidinas/química , Piperidinas/farmacología , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
This study was designed to compare the in vitro inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) of donepezil and some other cholinesterase (ChE) inhibitors which have been developed for the treatment of Alzheimer's disease. The carbamate derivatives physostigmine and rivastigmine needed preincubation to exhibit appropriate anti-ChE activity. The maximum ChE inhibition by physostigmine developed within 30-60 min, while the inhibitory effect of rivastigmine on AChE and BuChE activities reached its peak after 48 and 6 h, respectively. The order of inhibitory potency (IC50) towards AChE activity under optimal assay conditions for each ChE inhibitor was: physostigmine (0.67 nM) > rivastigmine (4.3 nM) > donepezil (6.7 nM) > TAK-147 (12 nM) > tacrine (77 nM) > ipidacrine (270 nM). The benzylpiperidine derivatives donepezil and TAK-147 showed high selectivity for AChE over BuChE. The carbamate derivatives showed moderate selectivity, while the 4-aminopyridine derivatives tacrine and ipidacrine showed no selectivity. The inhibitory potency of these ChE inhibitors towards AChE activity may illustrate their potential in vivo activity.
Asunto(s)
Acetilcolinesterasa/metabolismo , Encéfalo/efectos de los fármacos , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Fenilcarbamatos , Enfermedad de Alzheimer/tratamiento farmacológico , Aminoquinolinas/farmacología , Animales , Benzazepinas/farmacología , Encéfalo/enzimología , Carbamatos/farmacología , Donepezilo , Técnicas In Vitro , Indanos/farmacología , Concentración 50 Inhibidora , Masculino , Fisostigmina/farmacología , Piperidinas/farmacología , Ratas , Rivastigmina , Tacrina/farmacología , Factores de TiempoAsunto(s)
Queratitis , Enfermedad de Meniere , Vasculitis , Autoinmunidad , Diagnóstico Diferencial , Humanos , Inmunosupresores/uso terapéutico , Queratitis/diagnóstico , Queratitis/fisiopatología , Enfermedad de Meniere/diagnóstico , Enfermedad de Meniere/fisiopatología , Prednisolona/uso terapéutico , Pronóstico , Síndrome , Vasculitis/diagnóstico , Vasculitis/fisiopatologíaRESUMEN
Donepezil hydrochloride (donepezil), a potent and selective acetylcholinesterase inhibitor, has been developed for the treatment of Alzheimer's disease. We studied the effect of oral administration of this drug on the extracellular acetylcholine (ACh) concentration in the cerebral cortex of rats using microdialysis. We also observed fasciculation, a peripheral cholinergic sign induced by activation of neuromuscular transmission, after oral administration of the drug as an index of peripheral cholinergic activation. Other cholinesterase inhibitors, tacrine, ENA-713 and TAK-147, were used as reference drugs. Donepezil significantly and dose-dependently increased the extracellular ACh concentration in the rat cerebral cortex within the dose range of 2.5-10 mg/kg. Tacrine, ENA-713 and TAK-147 also elevated the extracellular concentration of ACh. The minimum effective doses of donepezil, tacrine, ENA-713 and TAK-147 were (< or = 2.5, 10, 10 and < or = 10 mg/kg, respectively. Donepezil produced fasciculation at doses of 2.5 mg/kg and above, with a dose-dependent increase in incidence and intensity. The reference compounds also induced fasciculation in a dose-dependent manner. The threshold doses of tacrine, ENA-713 and TAK-147 for fasciculation were 5, 2.5 and 2.5 mg/kg, respectively. The values of the ratio of the minimum effective dose for the ACh-increasing action to that for the fasciculation-producing action were: donepezil, < or = 1; tacrine, 2; ENA-713, 4; TAK-147, < or = 4. These results indicate that orally administered donepezil has a potent and selective activity on the central cholinergic system.