RESUMEN
The ATP-binding cassette transporter ABCG2 is expressed in various organs, such as the small intestine, liver, and kidney, and influences the pharmacokinetics of drugs that are its substrates. ABCG2 is also expressed by cancer cells and mediates resistance to anticancer agents by promoting the efflux of these drugs. In the present study, we investigated the interactions between epidermal growth factor receptor tyrosine kinase inhibitors and ABCG2 by MTT assay, intracellular drug accumulation assay, and FACS. This study showed that four epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) (gefitinib, erlotinib, lapatinib, and afatinib) were transported from tumor cells as substrates of ABCG2. Q141K is a common single-nucleotide polymorphism of ABCG2 in Asians. We demonstrated that the extracellular efflux of gefitinib, erlotinib, and lapatinib was reduced by Q141K, whereas afatinib transport was not affected. In addition, all four EGFR TKIs inhibited the transport of other substrates by both wild-type and variant ABCG2 at 0.1 µM concentrations. Accordingly, epidermal growth factor receptor tyrosine kinase inhibitors may induce interactions with other drugs that are substrates of ABCG2, and single-nucleotide polymorphisms of ABCG2 may influence both the pharmacokinetics and efficacy of these anticancer agents.
Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Antineoplásicos/farmacología , Proteínas de Neoplasias , Inhibidores de Proteínas Quinasas/farmacología , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Transporte Biológico , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Receptores ErbB/antagonistas & inhibidores , Células HEK293 , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Polimorfismo de Nucleótido SimpleRESUMEN
We herein describe the results of further evolution of glycogen synthase kinase (GSK)-3ß inhibitors from our promising compounds containing a 3-methylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3ß inhibitors. SAR studies focused on the nitrogen atom of the piperazine moiety revealed that a phenyl group afforded potent inhibitory activity toward GSK-3ß. Docking studies indicated that the phenyl group on the piperazine nitrogen atom and the methyl group on the piperazine make cation-π and CH-π interactions with GSK-3ß respectively. 4-Methoxyphenyl analogue 29 showed most potent inhibitory activity toward GSK-3ß with good in vitro and in vivo pharmacokinetic profiles, and 29 demonstrated a significant decrease in tau phosphorylation after oral administration in mice.
Asunto(s)
Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinonas/farmacología , Relación Dosis-Respuesta a Droga , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirimidinonas/síntesis química , Pirimidinonas/química , Relación Estructura-ActividadRESUMEN
We herein describe the results of further evolution of glycogen synthase kinase (GSK)-3ß inhibitors from our promising compounds containing a 2-phenylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3ß inhibitors. SAR studies focused on the phenyl moiety revealed that a 4-fluoro-2-methoxy group afforded potent inhibitory activity toward GSK-3ß. Based on docking studies, new hydrogen bonding between the nitrogen atom of the piperazine moiety and the oxygen atom of the main chain of Gln185 has been indicated, which may contribute to increased activity compared with that of the corresponding phenylmorpholine analogues. Effect of the stereochemistry of the phenylpiperazine moiety is also discussed.
Asunto(s)
Descubrimiento de Drogas , Piperazinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinonas/farmacología , Relación Dosis-Respuesta a Droga , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Piperazinas/síntesis química , Piperazinas/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirimidinonas/síntesis química , Pirimidinonas/química , Relación Estructura-ActividadRESUMEN
BACKGROUND/AIM: To investigate bioequivalence among generic and brand-name irinotecan products. MATERIALS AND METHODS: Products of Yakult and Daiichi-Sankyo (brand-name products), Sandoz, Nippon Kayaku, Taiho, and Sawai were compared with respect to their composition and antitumor activity. RESULTS: High-performance liquid chromatography demonstrated that related substances were within the acceptable range. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay revealed significant differences in cytotoxicity for four cancer cell lines among the products. The concentration of the active compound SN-38 was highest in Yakult's product (23.82 ng/ml) and lowest in Daiichi-Sankyo's product (8.96 ng/ml). MTT assay data were correlated with the SN-38 concentration, suggesting that it influenced differences in cytocidal activity among products. However, the SN-38 concentration was far lower than that of irinotecan (20 mg/ml), suggesting a negligible clinical effect. Metabolism of irinotecan to SN-38 or open-ring forms did not differ significantly among the products. CONCLUSION: The generic products showed equivalent efficacy and safety to the brand-name products.
Asunto(s)
Antineoplásicos Fitogénicos/farmacocinética , Camptotecina/análogos & derivados , Medicamentos Genéricos/farmacocinética , Camptotecina/farmacocinética , Línea Celular Tumoral , Cromatografía Líquida de Alta Presión , Humanos , Irinotecán , Equivalencia TerapéuticaRESUMEN
We herein describe the results of further evolution of GSK-3ß inhibitors for Alzheimer's disease from our promising compounds with in vivo tau phosphorylation inhibitory activity by oral administration. Introduction of a low alkyl group instead of the phenyl group at the 3-position of the morpholine moiety aiming to improve pharmacokinetic profiles resulted in potent low molecular weight GSK-3ß inhibitors with good in vitro pharmacokinetic profiles, which also showed in vivo tau phosphorylation inhibitory activity by oral administration. Effect of the stereochemistry of the alkyl moiety is also discussed using docking models.
Asunto(s)
Enfermedad de Alzheimer/enzimología , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Morfolinas/química , Morfolinas/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Administración Oral , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Animales , Descubrimiento de Drogas , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Humanos , Ratones , Simulación del Acoplamiento Molecular , Morfolinas/administración & dosificación , Morfolinas/farmacocinética , Fosforilación/efectos de los fármacos , Pirimidinas/administración & dosificación , Pirimidinas/farmacocinética , Proteínas tau/metabolismoRESUMEN
A series of 2-(2-phenylmorpholin-4-yl)pyrimidin-4(3H)-ones was synthesized and examined for their inhibitory activity against glycogen synthase kinase-3ß (GSK-3ß). We found 21, 29 and 30 to possess potent in vitro GSK-3ß inhibitory activity with good in vitro PK profiles. 21 demonstrated significant decrease of tau phosphorylation after oral administration in mice and excellent PK profiles.
Asunto(s)
Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Morfolinas/síntesis química , Morfolinas/farmacología , Pirimidinonas/química , Pirimidinonas/farmacología , Administración Oral , Animales , Sitios de Unión , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/metabolismo , Activación Enzimática/efectos de los fármacos , Femenino , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Semivida , Humanos , Masculino , Ratones , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Morfolinas/farmacocinética , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacología , Estructura Terciaria de Proteína , Pirimidinonas/síntesis química , Pirimidinonas/farmacocinética , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Proteínas tau/metabolismoRESUMEN
The discovery of a series of 6-(4-pyridyl)pyrimidin-4(3H)-ones derived from a hit compound with low molecular weight and sufficient chemical space is reported. Transformation of substituents led to subnanomolar potent inhibitors with in vivo tau phoshorylation lowering activity.
Asunto(s)
Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Pirimidinonas/química , Sitios de Unión , Activación Enzimática , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Simulación del Acoplamiento Molecular , Unión Proteica/efectos de los fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Estructura Terciaria de Proteína , Pirimidinonas/síntesis química , Pirimidinonas/metabolismo , Pirimidinonas/farmacología , Relación Estructura-ActividadRESUMEN
OBJECTIVE: Vascular malformations may appear anywhere in the body; 14-65% are in the head and neck. There are several treatments (sclerotherapy, surgery, laser treatment, and embolization, etc.), but standardized guidelines for these treatments are lacking. We conducted a retrospective review of venous or capillary malformations of the head and neck, and analyzed the epidemiology, pathology and treatment. METHODS: We retrospectively reviewed 67 patients with pathologically diagnosed venous or capillary malformations of the head and neck; we analyzed the location, pathology and treatment, as well as recurrent/residual cases. RESULTS: The oral cavity (59%) and nasal cavity (35%) were the most common locations. The frequency of each pathological type depended upon location. Surgery was undertaken in 65 cases, and sclerotherapy done in one patient. Sixty-one cases (92%) had resectable lesions. However polycystic masses (≥3 cysts) and large masses (diameter, ≥5cm) were significantly difficult to cure by single treatment. CONCLUSIONS: Surgery is indicated for localized small vascular malformations. However if the lesions ≥5cm or polycystic lesions were more likely to recur after surgery alone in our study population.
Asunto(s)
Malformaciones Arteriovenosas/terapia , Cabeza , Cuello , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Embolización Terapéutica , Endoscopía , Femenino , Cabeza/irrigación sanguínea , Humanos , Lactante , Masculino , Persona de Mediana Edad , Cuello/irrigación sanguínea , Recurrencia , Estudios Retrospectivos , Escleroterapia , Adulto JovenRESUMEN
BACKGROUND: Although third mandibular molar extraction is a widely used and validated model of acute pain for evaluating analgesic efficacy, a large proportion of patients experience moderate or severe pain following this procedure and require analgesia. Current treatment options have been associated with safety concerns and alternative therapies are sought. OBJECTIVE: Our aim was to assess the efficacy and safety of an additional 200-mg dose of celecoxib, administered 5 to 12 hours after an initial 400-mg dose of the drug for the treatment of moderate or severe acute pain following extraction of an impacted third mandibular molar. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, Phase II study. Patients experiencing moderate or severe pain within 1 to 2 hours following extraction of an impacted third mandibular molar received an initial 400-mg dose of celecoxib. Patients requiring additional analgesia were subsequently randomized to receive either an additional 200-mg dose of celecoxib or placebo 5 to 12 hours after the initial dose. The study was designed and conducted by Pfizer Inc. for approval of celecoxib in Japan for the indication of acute pain. The primary end point was the patient's impression of efficacy (4-category global evaluation scale). Secondary efficacy end points included pain intensity on a 4-category pain intensity scale, pain intensity on a 100-mm visual analog scale (VAS), and the pain intensity difference (100-mm VAS). In an exploratory analysis, use of rescue medication was evaluated. Primary and secondary end points were analyzed using the full analysis set. Assessment of the safety profile included a physical examination, measurement of pulse rate and blood pressure, standard 12-lead ECG, and laboratory tests. RESULTS: A total of 69 patients (celecoxib, 42/64 [65.6%]; placebo, 27/58 [46.6%]) received the additional dose of study medication; all completed the study without the need for rescue medication. A significantly higher proportion of patients in the celecoxib 200 mg group (41/64 [64.1%]) compared with the placebo group (15/58 [25.9%]) rated the study medication as "good" or "excellent" ≥ 2 hours after the additional dose (P < 0.0001). Pain intensity (VAS) 2 hours after the additional dose was significantly higher in the placebo group than in the celecoxib 200 mg group (P = 0.0003). The reduction in pain intensity from baseline to 2 hours after the additional dose of study medication was also significantly greater in the celecoxib 200 mg group than in the placebo group (P < 0.0001). The incidence of treatment-related, all-cause adverse events was slightly lower in patients receiving celecoxib 200 mg (20.3%) compared with placebo (31.0%). CONCLUSIONS: Overall, an additional 200-mg dose of celecoxib was well tolerated and efficacious in reducing the pain associated with extraction of an impacted third mandibular molar in the study population. ClinicalTrials.gov identifier: NCT01062113.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Tercer Molar/cirugía , Dolor Postoperatorio/tratamiento farmacológico , Pirazoles/uso terapéutico , Sulfonamidas/uso terapéutico , Extracción Dental , Diente Impactado/cirugía , Adulto , Celecoxib , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Pirazoles/efectos adversos , Sulfonamidas/efectos adversosRESUMEN
We investigated the prevalence, risk factors, and optimal timing of treatment for advanced periodontitis in patients undergoing elective heart valve surgery. Dental examinations were given to 209 patients (aged 65 ± 10 years) scheduled for valve surgery. Patients with no or mild periodontitis were assigned as controls (n = 105). Patients with advanced periodontitis underwent tooth extraction and curettage (n = 104), 68 of whom underwent tooth extraction within two weeks (short wait) and 36 of whom underwent extraction longer than two weeks, before surgery. The three groups (control, short, and long wait) were similar in age, gender, diseased valve, and type of surgery received. The average number of teeth extracted was 2.3 ± 2.3. In both univariate and multivariate analysis, risk factors for advanced periodontitis were history of smoking and heart failure. No complications arose from the extractions. Length of postoperative hospital stay, intrafebrile days, white blood cell count and serum C-reactive protein (assessed at postoperative days 1, 3 and 7) were similar among the three groups. During the mean follow-up period of 60 ± 16 months, no patient developed prosthetic valve endocarditis, and there were no postoperative deaths. In conclusion, we found no evidence that receipt and timing of dental treatment affected surgical success rates and postoperative course.
Asunto(s)
Enfermedades de las Válvulas Cardíacas/cirugía , Implantación de Prótesis de Válvulas Cardíacas , Periodontitis/cirugía , Curetaje Subgingival , Extracción Dental , Anciano , Análisis de Varianza , Distribución de Chi-Cuadrado , Procedimientos Quirúrgicos Electivos , Endocarditis/etiología , Endocarditis/prevención & control , Femenino , Enfermedades de las Válvulas Cardíacas/epidemiología , Prótesis Valvulares Cardíacas/efectos adversos , Implantación de Prótesis de Válvulas Cardíacas/efectos adversos , Implantación de Prótesis de Válvulas Cardíacas/instrumentación , Humanos , Japón , Tiempo de Internación , Modelos Logísticos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Periodontitis/diagnóstico , Periodontitis/epidemiología , Cuidados Preoperatorios , Prevalencia , Infecciones Relacionadas con Prótesis/etiología , Infecciones Relacionadas con Prótesis/prevención & control , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Índice de Severidad de la Enfermedad , Curetaje Subgingival/efectos adversos , Factores de Tiempo , Extracción Dental/efectos adversos , Resultado del TratamientoRESUMEN
The recent clinical results are reviewed of stereotactic radiosurgery/radiotherapy for the treatment of pituitary adenomas. The outcomes of pituitary adenomas treated by stereotactic radiosurgery/radiotherapy with gamma knife, CyberKnife, or linear accelerator (LINAC) radiosurgery were evaluated from articles published after 2004. Each study was evaluated for the number of patients, radiosurgical parameter (marginal dose), length of follow up, tumor growth control, rate of hormonal normalization in secretary adenomas, and adverse events. After gamma knife radiosurgery, the tumor reduction rates varied from 42.3% to 89% in non-secreting adenomas. However, the tumor control rates in non-secreting adenomas were more than 90% in most studies. In growth hormone-secreting adenomas, the rates of insulin-like growth factor-1 normalization ranged from 36.9% to 82%. In adrenocorticotropin-secreting adenomas, the rates for 24-hour urine free cortisol normalization ranged from 27.9% to 54%. In prolactin-secreting adenomas, the prolactin normalization ranged from 17.4% to 50%. New hormonal deficits ranged from 0% to 34%. New visual deficits were relatively low. The number of patients treated with CyberKnife and LINAC radiosurgery/radiotherapy was small and follow-up periods were relatively short compared to those with gamma knife treatment, but the clinical outcomes after these therapies were similar to those after gamma knife therapy. Image-guided stereotactic radiosurgery/radiotherapy with the gamma knife, CyberKnife, or LINAC system is effective and safe against pituitary adenomas. Careful long-term follow up of the patients is necessary because of long-term anti-tumor effects and delayed adverse events.
Asunto(s)
Adenoma/cirugía , Evaluación de Resultado en la Atención de Salud/métodos , Neoplasias Hipofisarias/cirugía , Radiocirugia/métodos , Adenoma/patología , Adenoma/fisiopatología , Humanos , Neoplasias Hipofisarias/patología , Neoplasias Hipofisarias/fisiopatología , Radiocirugia/tendencias , Resultado del TratamientoRESUMEN
The effect of MKC-231 on acetylcholine (ACh) synthesis and release was studied in the hippocampus of normal and AF64A-treated rats. AF64A (3 nmol/brain, i.c.v.) produced significant reduction of high-affinity choline uptake (HACU) and high K+-induced ACh release in hippocampal synaptosomes. Treatments with MKC-231 (10(-8) and 10(-7) M) showed significant reverse of the decrease in both HACU and ACh release. In hippocampal slices superfused with choline-containing artificial cerebro-spinal fluid (ACSF), high K+-induced ACh release was gradually decreased by repeated alteration of resting and high K+ stimulations in AF64A-treated rats. However, addition of MKC-231 (10(-8) to 10(-7) M) in the superfusate reduces this decrease. In vivo microdialysis studies indicate MKC-231 (10 mg/kg, p.o.) significantly reversed reduction of basal ACh concentrations in AF64A-treated rats, measured by radioimmunoassay without a cholinesterase inhibitor in the perfusate. These results indicate MKC-231 improves AF64A-induced cholinergic hypofunction by enhancing HACU, subsequently facilitating ACh synthesis and release in vitro and in vivo.
Asunto(s)
Acetilcolina/metabolismo , Aziridinas/farmacología , Colina/análogos & derivados , Bloqueantes Neuromusculares/farmacología , Quinolinas/farmacología , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismo , Análisis de Varianza , Animales , Colina/metabolismo , Colina/farmacología , Inhibidores de la Colinesterasa/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Hipocampo/ultraestructura , Técnicas In Vitro , Masculino , Microdiálisis , Potasio/farmacología , Ratas , Ratas Wistar , Tacrina/farmacología , Tritio/metabolismoRESUMEN
MKC-231, a putative cholinergic activity, is reported to improve learning and memory impaired in AF64A-treated animals. MKC-231 enhances high-affinity choline uptake (HACU) known as the rate-limiting step of acetylcholine (ACh) synthesis. We investigated the mode of action (MOA) of HACU enhancement by MKC-231. Intracerebroventricular (i.c.v.) injections of AF64A (3 nmol/brain) resulted in significant HACU reduction in hippocampal synaptosomes. Treatment with MKC-231 increased Vmax of HACU and Bmax of [3H]-HC-3 binding 1.6 and 1.7-fold, respectively. In studies of [3H]-MKC-231 binding and Biacore analysis, MKC-231 showed noticeable affinity for cloned high-affinity choline transporters (CHT1). The present study suggests that MKC-231 directly affects trafficking of CHT1 and increases the numbers of transporter, working for HACU, at the synaptic membrane.
Asunto(s)
Colina/metabolismo , Quinolinas/farmacología , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismo , Animales , Aziridinas/farmacología , Células COS , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Chlorocebus aethiops , Colina/análogos & derivados , Colina/farmacología , Interacciones Farmacológicas , Hemicolinio 3/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/ultraestructura , Masculino , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Inhibidores de la Captación de Neurotransmisores/farmacología , Unión Proteica/efectos de los fármacos , Ensayo de Unión Radioligante , Ratas , Ratas Wistar , Transfección , Tritio/metabolismoRESUMEN
MKC-231 is reported to increase high-affinity choline uptake (HACU) in vitro and improve learning impairment on a single oral administration in AF64A-treated rats. In this study, we investigated the effects of repeated administration of MKC-231 (1 and 3 mg/kg, p.o., 8 days) on learning impairment in the water-maze task in AF64A-treated rats 1, 24, 48, and 72 h after the last dose. Significant cognitive improvement was observed for 24 h, however, concentration measurement studies indicated MKC-231 was not detected in the brain by this time. We also studied the effects of 8-days repeated administration of MKC-231 on HACU 1, 24, 48, and 72 h after the last dose and observed an increase of HACU similar in time course with cognitive improvement. From these results, we discussed the possibility that MKC-231 could induce long-lasting procognitive effects by changing the choline transporter regulation system.
Asunto(s)
Aziridinas , Colina/análogos & derivados , Discapacidades para el Aprendizaje/inducido químicamente , Discapacidades para el Aprendizaje/tratamiento farmacológico , Quinolinas/uso terapéutico , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Isótopos de Carbono/farmacocinética , Colina/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Interacciones Farmacológicas , Hipocampo/patología , Hipocampo/ultraestructura , Discapacidades para el Aprendizaje/patología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Quinolinas/química , Quinolinas/farmacocinética , Ratas , Ratas Wistar , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismo , Factores de TiempoRESUMEN
Biological substances with neurotrophic activities, such as nerve growth factor (NGF) and monosialoganglioside GM1, have been considered as agents for diabetic peripheral neuropathy. Because recent studies have suggested that decreased availability of these substances might contribute to the pathogenesis of diabetic peripheral neuropathy, some clinical trials of NGF for diabetic peripheral neuropathy have been conducted and have led to mixed conclusions. The major reasons were its limited delivery to the nervous system and adverse effects induced by subcutaneous injection, which was necessary because NGF is a polypeptide. The current study investigates whether an orally active sialic acid derivative, MCC-257, has neuroprotective properties in diabetic peripheral nerves. MCC-257 augmented NGF activity in cultured dorsal root ganglia and PC12 (pheochromocytoma 12) cells. Treatment with MCC-257 elevated NGF levels in the sciatic nerve, accompanied by improvement in nerve conduction velocity in streptozotocin-induced diabetic animals. More importantly, MCC-257 ameliorated small fiber dysfunctions, including thermal hypoalgesia, substance P content, and histopathological innervation in the plantar skin of diabetic animals. Thus, the orally active neurotrophin enhancer provides a new option for the clinical treatment of diabetic peripheral neuropathy.
Asunto(s)
Diabetes Mellitus Experimental/complicaciones , Neuropatías Diabéticas/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Ácidos Siálicos/uso terapéutico , Administración Oral , Animales , Ganglios Espinales/efectos de los fármacos , Masculino , Factor de Crecimiento Nervioso/análisis , Factor de Crecimiento Nervioso/farmacología , Conducción Nerviosa/efectos de los fármacos , Células PC12 , Fosforilación , Ratas , Ratas Wistar , Receptor trkA/metabolismo , Piel/inervación , Estreptozocina , Sustancia P/análisis , Ubiquitina Tiolesterasa/análisisRESUMEN
Hange-shashin-to (HST) has been used as an herbal formula to treat inflammatory ulcerative gut diseases complicated with psychoneurosis in Japanese traditional Kampo medicine. The aim of the present study is to clarify anti-colitic effect of HST using a model of colitis induced by intracolonic instillation of 2,4,6-trinitrobenzene sulfonic acid (TNBS) in rats, and to evaluate the pharmaceutical properties of its herbal components. The colonic damage was elucidated by macroscopic damage scores, colon wet weight and area of mucosal necrosis. Orally administered HST significantly reduced the colonic damage. Other rats were orally treated with single-component berberine (BE), baicalin (BA), glycyrrhizin (GL) or saponin fraction of ginsenosides (GS), or with the mixture (TL) of BA, BE, GL and GS, or with the combinations of BA plus BE (BA-BE), or that of GL plus GS (GL-GS). Oral treatment of TL ameliorated colitis observations. However, no effects were found in the treatment of single-component BA, BE, GL or GS, whereas the GL-GS combination ameliorated the colitis. These results suggest that HST might suppress inflammatory bowel disease (IBD) and imply that there will be a potential benefit in the traditionally derived herbal combination.
Asunto(s)
Antiulcerosos/uso terapéutico , Colitis/tratamiento farmacológico , Medicamentos Herbarios Chinos/uso terapéutico , Fitoterapia , Administración Oral , Animales , Antiulcerosos/química , Colitis/inducido químicamente , Colitis/patología , Colon/efectos de los fármacos , Colon/patología , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/química , Masculino , Úlcera Péptica/tratamiento farmacológico , Úlcera Péptica/patología , Ratas , Ratas Wistar , Ácido TrinitrobencenosulfónicoRESUMEN
3,4,5-trimethoxycinnamic acid (TMCA) is one of the constituents in Onji (roots of Polygala tenuifolia WILLD), an herbal medicine used for sedative in Japanese traditional Kampo medicine. Our previous study revealed that oral administration of this compound prolongs sleeping time induced by hexobarbital in mice to exhibit sedative action. In the present study, we investigate the effects of TMCA on the stress induced with repeated cold exposure or intracerebroventricular injection of corticotrophin-releasing hormone (CRH). Both types of stress significantly reduced the sleeping time induced with pentobarbital in rat, which was significantly prolonged by intraperitoneal injection of TMCA. The intracerebroventricular injection of CRH significantly augmented the content of norepinephrine (NE) in locus coeruleus (LC) of rats, which was significantly suppressed by the intracerebroventricular injection of TMCA. These findings suggest that TMCA would exhibit sedative effects by suppressing NE content in LC.
Asunto(s)
Cinamatos/uso terapéutico , Polygala/química , Estrés Fisiológico/tratamiento farmacológico , Animales , Cinamatos/farmacología , Locus Coeruleus/efectos de los fármacos , Locus Coeruleus/metabolismo , Microdiálisis , Norepinefrina/metabolismo , Raíces de Plantas/química , RatasRESUMEN
The leaves of Perilla frutescens Britton (Labiatae) are one of the most popular garnishes in Japan, used as an antidote for fi sh and crab meat allergy or as a food colorant. The present study was conducted to evaluate its anti-allergic effect and to identify its active constituents using mice ear-passive cutaneous anaphylaxis (PCA)-reaction. 48 h after the cutaneous injection of anti-ovalbumin serum into the ears of mice, ovalbumin and evansblue dye were intravenously injected. Perilla was extracted with boiling water, and intraperitoneally injected 15 min before ovalbumin-treatment. Thirty min after ovalbumin-treatment, the ears were removed and the colorant in the ear was colorimetrically quantitated. Perilla extract significantly suppressed the PCA-reaction, which was brought about by rosmarinic acid with a partial contribution from some macromolecular compounds. The anti-allergic titer of rosmarinic acid was more effective than tranilast, which is a modern anti-allergic drug. Perilla and rosmarinic acid are potentially promising agents for the treatment of allergic diseases.
Asunto(s)
Antialérgicos/uso terapéutico , Hipersensibilidad Inmediata/tratamiento farmacológico , Anafilaxis Cutánea Pasiva/efectos de los fármacos , Perilla frutescens , Fitoterapia , Preparaciones de Plantas/uso terapéutico , Animales , Antialérgicos/administración & dosificación , Antialérgicos/farmacología , Relación Dosis-Respuesta a Droga , Azul de Evans , Femenino , Hipersensibilidad Inmediata/patología , Ratones , Ratones Endogámicos BALB C , Ovalbúmina , Hojas de la Planta , Preparaciones de Plantas/administración & dosificación , Preparaciones de Plantas/farmacologíaRESUMEN
Juvenile nasopharyngeal angiofibroma (JNA) tumors can be locally destructive when they spread submucosally. The purpose of this study was to present an image-guided, robotic radiotherapy (Cyberknife) to successfully treat a 12-year-old boy with Juvenile nasopharyngeal angiofibroma (JNA). He complained of progressive right nasal obstruction, intermittent epistaxis. Computed tomography (CT), and magnetic resonance imaging (MRI) revealed the presence of a tumor in the right nasal cavity and nasopharynx with significant hypervascularization from the right maxillary artery. Pathological findings confirmed the diagnosis of JNA. Surgical treatment was recommended but refused by religious reasons. We initially treated the patient with external-beam radiation therapy (total treatments, 12; total dose, 2400 cGy), which, after 7 months, failed to reduce the size of the tumor or relieve the patient's symptoms. We subsequently treated the patient with Cyberknife therapy (total treatments, 3; total dose, 4512 cGy) and observed almost complete disappearance of the tumor after 7 months. After 2 years of observation, there has been no tumor recurrence. Cyberknife therapy is compared with other therapeutic options for JNA, and its benefits are discussed in the context of the findings in the literature.
Asunto(s)
Angiofibroma/radioterapia , Angiofibroma/cirugía , Neoplasias Nasofaríngeas/radioterapia , Neoplasias Nasofaríngeas/cirugía , Cirugía Asistida por Computador/instrumentación , Angiofibroma/diagnóstico , Niño , Humanos , Imagen por Resonancia Magnética , Masculino , Neoplasias Nasofaríngeas/diagnóstico , Dosis de Radiación , Tomografía Computarizada por Rayos XRESUMEN
There are many important considerations in the interactions among the herbal constituents in a prescription of traditional Chinese medicine (TCM). Ephedra Herb [Chinese characters: see text] (Eph) is described a warm and acrid agent in TCM. The combination of Eph and Gypsum [Chinese characters: see text] (Eph-Gyp) shows specific actions in patients with different body temperatures. Previous reports suggested that Gypsum prevents the thermogenesis effect induced by ephedrine at an ambient temperature of 22 degrees C. In this investigation, the properties of Eph-Gyp in hyperthermal rats were studied in detail. It was shown that Gypsum Extract (GyE) enhanced the thermogenesis of Eph in hyperthermal rats, although not in normal rats. The results support not only the opposite actions of Eph-GyE but also the clinical differences in the symptomatic patterns of body temperature for Makyo-Kanseki-To [Chinese characters: see text] and Dai-Seiryu-To [Chinese characters: see text].