RESUMEN
BACKGROUND AND PURPOSE: Intravenous nicardipine is generally used to treat hypertension in acute stroke patients but is associated with frequent phlebitis. We aimed to identify the incidence and risk factors of phlebitis in such patients. METHODS: The incidence and risk factors of phlebitis were investigated in 358 acute stroke patients from July 2014 to June 2015. RESULTS: In total, 138 patients received intravenous nicardipine. Of 45 (12.6%) phlebitis patients in 358 acute stroke patients, 42 (93.3%) were administered nicardipine, which was significantly associated with phlebitis occurrence (P < .01). Other candidate risk factors of phlebitis of acute stroke patients in univariate analysis were intracerebral hemorrhage (P < .01), nicardipine injection to paralyzed limbs (P = .023), dilution of nicardipine with normal saline (P < .01), higher maximum flow rate of nicardipine (7.2 ± 4.1 mg/h versus 1.6 ± 3.1 mg/h; P < .01), and higher maximum concentration of nicardipine (271.5 ± 145.0 µg/mL versus 37.6 ± 75.0 µg/mL; P < .01). The only statistically significant independent factor following multivariate logistic regression analysis, according to the optimal cutoff values defined from receiver operating characteristic curve analyses, was the maximum concentration of nicardipine greater than 130 µg/mL (OR 57.9; 95% CI 21.5-156; P < .01). A gradual decline of pH below 4.3 was observed when the concentration of nicardipine solution increased to greater than or equal to 130 µg/mL in vitro. CONCLUSIONS: Nicardipine-related phlebitis is frequently observed in acute stroke patients and is significantly associated with administration of a maximum concentration of nicardipine greater than 130 µg/mL.
Asunto(s)
Antihipertensivos/efectos adversos , Hipertensión/tratamiento farmacológico , Nicardipino/efectos adversos , Flebitis/inducido químicamente , Accidente Cerebrovascular/epidemiología , Administración Intravenosa , Anciano , Anciano de 80 o más Años , Antihipertensivos/administración & dosificación , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Hipertensión/diagnóstico , Hipertensión/epidemiología , Incidencia , Japón/epidemiología , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Nicardipino/administración & dosificación , Oportunidad Relativa , Flebitis/diagnóstico , Flebitis/epidemiología , Estudios Retrospectivos , Factores de Riesgo , Accidente Cerebrovascular/diagnóstico , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Mirtazapine, a noradrenergic and specific serotonergic antidepressant (NaSSA), shows multiple pharmacological actions such as inhibiting presynaptic α2 noradrenaline receptor (NAR) and selectively activating 5-hydroxytriptamine (5-HT) 1A receptor (5-HT1AR). Mirtazapine was also reported to increase dopamine release in the cortical neurons with 5-HT dependent manner. To examine whether mirtazapine has a therapeutic potency in Parkinson's disease (PD), we examined this compound in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice model of PD. RESULTS: Male C57BL/6 mice were subjected to MPTP treatment to establish a PD model. Mirtazapine was administered once a day for 3 days after MPTP treatment. MPTP-induced motor dysfunction, assessed by beam-walking and rota-rod tests, was significantly improved by administration of mirtazapine. Biochemical examinations by high performance liquid chromatography and western blot analysis suggested mirtazapine facilitated utilization of dopamine by increasing turnover and protein expression of transporters, without affecting on neurodegenerative process by MPTP. These therapeutic effects of mirtazapine were reduced by administration of WAY100635, an inhibitor for 5HT1AR, or of clonidine, a selective agonist for α2-NAR, or of prazosin, an inhibitor for α1-NAR, respectively. CONCLUSION: Our results showed mirtazapine had a therapeutic potency against PD in a mouse model. Because PD patients sometimes show depression together, it will be a useful drug for a future PD treatment.
Asunto(s)
Encéfalo/fisiopatología , Modelos Animales de Enfermedad , Intoxicación por MPTP/tratamiento farmacológico , Intoxicación por MPTP/fisiopatología , Mianserina/análogos & derivados , Animales , Antidepresivos Tricíclicos/uso terapéutico , Encéfalo/efectos de los fármacos , Estudios de Factibilidad , Intoxicación por MPTP/diagnóstico , Masculino , Mianserina/uso terapéutico , Ratones , Ratones Endogámicos C57BL , Mirtazapina , Resultado del TratamientoRESUMEN
Dysfunction of the proteasome has been suggested to contribute in the degeneration of nigrostriatal dopaminergic neurons. Here, we investigated to determine whether systematic administration of proteasome inhibitor, carbobenzoxy-L: -gamma-t-butyl-L: -glutamyl-L: -alanyl-L: -leucinal (PSI) protects against MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) neurotoxicity in mice. Three administrations of MPTP at 1-h intervals to mice reduced significantly the concentration of dopamine, DOPAC (3,4-dihydroxyphenylacetic acid) and HVA (homovanillic acid) in the striatum after 5 days. In contrast, PSI (0.3 and 1.0 mg/kg) prevented a significant decrease in dopamine, DOPAC and HVA contents of the striatum 5 days after MPTP treatment. In our Western blot analysis study, PSI at a dose of 1.0 mg/kg prevented a significant decrease in TH (tyrosine hydroxylase) protein and a significant increase in glial fibrillary acidic protein 5 days after MPTP treatment. Furthermore, our immunohistochemical study showed that PSI at a dose of 1.0 mg/kg prevented a significant loss in TH immunopositive neurons in the striatum and substantia nigra 5 days after MPTP treatment. In contrast, PSI caused a significant increase in the number of intense ubiquitin immunopositive cells in the striatum and substantia nigra 5 days after MPTP treatment. These results indicate that proteasome inhibitors can protect against MPTP neurotoxicity in mice. The neuroprotective effect of PSI against dopaminergic cell damage may be mediated by the elevation of ubiquitination. Thus, our findings provide further valuable information for the pathogenesis of Parkinson's disease.
Asunto(s)
1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacología , Neuronas/efectos de los fármacos , Inhibidores de Proteasoma , Animales , Western Blotting , Cromatografía Líquida de Alta Presión , Dopamina/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismo , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos C57BL , Neostriado/citología , Neostriado/efectos de los fármacos , Neostriado/enzimología , Neuronas/citología , Neuronas/enzimología , Sustancia Negra/citología , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismo , Tirosina 3-Monooxigenasa/metabolismo , Ubiquitina/metabolismoRESUMEN
We investigated to determine whether acute administration of proteasome inhibitor can cause dopaminergic cell loss in mice, in comparison with that of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The four intraperitoneally administrations of MPTP at 1-h intervals to mice decreased significantly the concentration of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum after 5 days, in comparison with vehicle-treated animals. In contrast, the three subcutaneously administrations of carbobenzoxy-L-gamma-t-butyl-L-glutamyl-L-alanyl-L-leucinal (PSI) did not show significant changes in the concentration of dopamine, DOPAC and HVA in the striatum after 5 days, in comparison with vehicle-treated animals. Our Western blot analysis also showed that the four administrations of MPTP at 1-h intervals to mice produced a significant reduction of anti-tyrosine hydroxylase antibody (TH) protein levels in the striatum after 5 days after. In PSI-treated mice. In contrast, no significant change of TH protein levels was observed in the striatum 5 days after the final treatment with PSI. Furthermore, a significant decrease of TH protein levels was observed in the striatum of MPTP-treated mice, as compared with PSI-treated animals. The present study demonstrates that the acute treatment with proteasome inhibitor PSI did not cause the dopaminergic neurotoxicity in mice, as compared with acute treatment with MPTP. Thus, our findings suggest that acute proteasome inhibition is not a reliable model for Parkinson's disease.
Asunto(s)
Oligopéptidos/toxicidad , Trastornos Parkinsonianos/inducido químicamente , Inhibidores de Proteasoma , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/enzimología , Cuerpo Estriado/fisiopatología , Inhibidores de Cisteína Proteinasa/toxicidad , Modelos Animales de Enfermedad , Dopamina/metabolismo , Esquema de Medicación , Ácido Homovanílico/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Degeneración Nerviosa/inducido químicamente , Degeneración Nerviosa/enzimología , Degeneración Nerviosa/fisiopatología , Neuronas/efectos de los fármacos , Neuronas/enzimología , Neuronas/patología , Neurotoxinas/farmacología , Trastornos Parkinsonianos/enzimología , Trastornos Parkinsonianos/fisiopatología , Complejo de la Endopetidasa Proteasomal/metabolismo , Reproducibilidad de los Resultados , Factores de Tiempo , Tirosina 3-Monooxigenasa/efectos de los fármacos , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Dysfunction of the proteasome function is known to be a potential mechanism for dopaminergic neuron degeneration. Here, we investigated to determine whether systematic administration of proteasome inhibitor, carbobenzoxy-L-gamma-t-butyl-L-glutamyl-L-alanyl-L-leucinal (PSI), causes the increased susceptibility in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. PSI was injected into MPTP-treated mice over a period of 2 weeks. Thereafter, we evaluated the effect of PSI 2, 4, and 8 weeks after the cessation of treatment with PSI. In the present study with HPLC analysis, PSI did not enhance MPTP-induced dopaminergic neurotoxicity in mice. Our present study with Western blot analysis also demonstrated that the reduction of tyrosine hydroxylase (TH) and glial fibrillary acidic protein (GFAP) protein levels in MPTP-treated mice was more pronounced than that in MPTP + PSI-treated animals. These results suggest that proteasome inhibitor did not enhance MPTP neurotoxicity in mice. Our findings suggest that proteasome inhibition is not a reliable model for PD. Thus, our findings provide further valuable information for the pathogenesis of Parkinson's disease.
Asunto(s)
Oligopéptidos/toxicidad , Trastornos Parkinsonianos/inducido químicamente , Complejo de la Endopetidasa Proteasomal/efectos de los fármacos , Sustancia Negra/efectos de los fármacos , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Animales , Inhibidores de Cisteína Proteinasa/toxicidad , Modelos Animales de Enfermedad , Dopamina/metabolismo , Sinergismo Farmacológico , Proteína Ácida Fibrilar de la Glía/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Neurotoxinas/farmacología , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/fisiopatología , Complejo de la Endopetidasa Proteasomal/fisiología , Sustancia Negra/metabolismo , Sustancia Negra/fisiopatología , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes the damage of dopaminergic neurons as seen in Parkinson's disease. Oxidative stress has been as one of several pathogenic hypotheses for Parkinson's disease. Here we investigated whether arundic acid, an astrocyte-modulating agent, can protect against alterations of nitric oxide synthase (NOS) and superoxide dismutase (SOD) expression on MPTP neurotoxicity in mice, utilizing an immunohistochemistry. For this purpose, anti-tyrosine hydroxylase (TH) antibody, anti-dopamine transporter (DAT) antibody, anti-Cu/Zn-SOD antibody, anti-Mn-SOD antibody, anti-nNOS antibody, anti-eNOS antibody and anti-iNOS antibody were used. The present study showed that the arundic acid had a protective effect against MPTP-induced neuronal damage in the striatum and substantia nigra of mice. The protective effect may be, at least in part, caused by the reductions of the levels of reactive nitrogen (RNS) and oxygen species (ROS) against MPTP neurotoxicity. These results suggest that the pharmacological modulation of astrocyte may offer a novel therapeutic strategy for the treatment of Parkinson's disease. Furthermore, our results provide further evidence that a combination of nNOS inhibitors, iNOS inhibitors and free radical scavengers may be effective in the treatment of neurodegenerative diseases. Thus our present results provide valuable information for the pathogenesis of degeneration of the nigrostriatal dopaminergic neuronal pathway.