In-vitro Characterization of YM872, a Selective,Potent and Highly Water-soluble α-Amino-3-hydroxy-5-methylisoxazole-4-propionate Receptor Antagonist

The in-vitro pharmacological properties of (2,3-dioxo-7-(1H-imidazol-***1-yl)-6-nitro-1,2,3,4-tetrahydro-1-quinoxalinyl)-acetic acid monohydrate, YM872, a novel and highly water-soluble α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)-receptor antagonist were investigated. YM872 is highly water soluble (83 mg mL^?1 in Britton-Robinson buffer) compared with 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo(F)quinoxaline (NBQX), 6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione hydrochloride (YM90K) or 6-cyano-7-nitroquinoxa-line-2,3-dione (CNQX). YM872 potently inhibits [³H]AMPA binding with a K_i (apparent equilibrium dissociation constant) value of 0.096 ± 0.0024 μM. However, YM872 had very low affinity for other ionotropic glutamate receptors, as measured by competition with [³H]kainate (high-affinity kainate binding site, concentration resulting in half the maximum inhibition (IC50) = 4.6 ± 0.14 μm), [³H]glutamate (N-methyl-D-aspartate (NMDA) receptor glutamate binding site, IC50 > 100 μM) and [³H]glycine (NMDA receptor glycine-binding site, IC50 > 100 μM). YM872 competitively antagonized kainate-induced currents in Xenopus laevis oocytes which express rat AMPA receptors, with a pA₂ value of 6.97 ± 0.01. In rat hippocampal primary cultures, YM872 blocked a 20-μM AMPA-induced increase of intracellular Ca²⁺ concentration with an IC50 value of 0.82 ± 0.031 μM, and blocked 300-μM kainate-induced neurotoxicity with an IC50 value of 1.02 μM. These results show that YM872 is a potent and highly water-soluble AMPA antagonist with great potential for treatment of neurodegenerative disorders such as stroke.     

Detection of invasive protein profile of Streptococcus pyogenes M1 isolates from pharyngitis patients

Hasegawa T, Okamoto A, Kamimura T, Tatsuno I, Hashikawa S‐N, Yabutani M, Matsumoto M, Yamada K, Isaka M, Minami M, Ohta M. Detection of invasive protein profile of Streptococcus pyogenes M1 isolates from pharyngitis patients. APMIS 2010; 118: 167–78. Streptococcal toxic shock syndrome (STSS) is a re‐emerging infectious disease in Japan and many other developed countries. Epidemiological studies have revealed that the M1 serotype of Streptococcus pyogenes is the most dominant causative isolate of STSS. Recent characterization of M1 isolates revealed that the mutation of covS, one of the two‐component regulatory systems, plays an important role in STSS by altering protein expression. We analyzed the M1 S. pyogenes clinical isolates before or after 1990 in Japan, using two‐dimensional gel electrophoresis (2‐DE) and pulsed‐field gel electrophoresis (PFGE). PFGE profiles were different between the isolates before and after 1990. Markedly different profiles among isolates after 1990 from STSS and pharyngitis patients were detected. Sequence analysis of two‐component regulatory systems showed that covS mutations were detected not only in STSS but also in three pharyngitis isolates, in which proteins from the culture supernatant displayed the invasive type. The mutated CovS detected in the pharyngitis isolates had impaired function on the production of streptococcal pyrogenic exotoxin B (SpeB) analyzed by 2‐DE. These results suggest that several covS mutations that lead to the malfunction of the CovS protein occurred even in pharyngeal infection.     

肠溶性瑞巴派特壳聚糖胶囊的制备及大鼠口服给药吸收评价

目的评价肠溶性瑞巴派特壳聚糖胶囊的释药作用,考察其结肠定位效果。方法将瑞巴派特1 mg装入壳聚糖胶囊中,并用羟丙基甲基纤维素邻苯二甲酸酯(HPMCP)包裹胶囊,观察胶囊的体外释药性能。在乙醚麻醉下通过聚乙烯管大鼠口服给予瑞巴派特壳聚糖胶囊4 mg,对照组口服同剂量的明胶胶囊和羧甲基纤维素溶液。于给定的时间间隔取血,取出结肠组织,分离提取药物,用HPLC法测定大鼠血液及结肠中药物浓度。结果在6 h体外溶出试验中,即人工胃液2 h和人工肠液4 h中,瑞巴派特从壳聚糖胶囊中的释药量的质量分数小于10%。大鼠口服瑞巴派特壳聚糖胶囊时,在结肠黏膜中的药物含量-时间曲线下面积(AUCLI0-9,16.01 mg.h.L-1)分别是明胶胶囊和羧甲基纤维素溶液的2.5倍和4.4倍。口服瑞巴派特壳聚糖胶囊,大鼠血浆药物含量-时间曲线下面积(AUCPL0-9)为1.02 mg.h.L-1,同剂量的明胶胶囊和羧甲基纤维素溶液分别是2.16 mg.h.L-1和1.89 mg.h.L-1,表明在壳聚糖的作用下,与明胶胶囊或羧甲基纤维素溶液比较,瑞巴派特从胃肠道吸收进入血液循环的量较少。结论在HPMCP的保护下,壳聚糖是瑞巴派特在结肠释药的一种有效的载体。     

A case with dicentric translocation between chromosome 9 and 18: Confirmation by fluorescent in situ hybridization on metaphase spread

A female child with dicentric translocation between chromosome 9 and chromosome 18 presented non-specific minor anomalies with laryngomalacia. Chromosomal analyses were performed by the G-banding method and a fluorescence in situ hybridization (FISH) technique with a specific probe for the centromeric region of chromosome 18 and the painting probe for the chromosomes 9 and 18. Her full karyotype was confirmed as 45, XX, tdic (9;18)(p24;p11). This is the first case of dicentric translocation between chromosomes 9 and 18. The FISH technique is an important tool in chromosome diagnostics.     

Inflammatory esophagogastric polyp and fold in an adolescent

The case of a 13 year old boy with an inflammatory esophagogastric polyp and ulcerative colitis is described. Endoscopy revealed a typical polyp and gastric fold complex at the esophagogastric junction and a hiatal hernia. Histology of a biopsy specimen confirmed an inflammatory polyp covered by hyperplastic squamous and gastric foveolar epithelium. Continuous 24 hour esophageal manometry suggested gastroesophageal reflux, which may be related to the pathogenesis of the lesion. Follow-up endoscopy showed marked regression of the polyp with medication for reflux eosphagitis. This clinical entity is rare in childhood and adolescence, and the manifestations may not be readily recognized. Therefore, endoscopic biopsy is important in children with esophageal polyps. However, polypectomy is unnecessary except when malignancy is suspected or when symptoms persist.     

Acute childhood leukemia in a patient with hemophilia: First report in Japan

This study reports an unusual case of acute leukemia which was diagnosed as hemophilia A on initial admission for leukemia. A 3 year old boy was admitted to Kagoshima University Hospital with anemia. He was diagnosed as acute lymphoblastic leukemia. At the same time he was revealed to have severe hemophilia A⁻ without any previous episodes of severe bleeding tendency or family history of this disease. The laboratory investigation showed his mother to be a carrier of hemophilia A. Although there are many cases of hemophilia which have developed malignant tumors, most of them were caused by association with human immunodeficiency virus (HIV) infection. Only five cases with coexistence of leukemia and hemophilia without HIV infection have been reported and the present case is the first one in Japan. At this stage, hemophiliacs are not necessarily regarded to be a population at risk for the development of leukemia. Furthermore, no particular subtype of leukemia was characterized among these patients in the literature.