N-丁基-1-脱氧野尻霉素的合成新方法

以2,3,4,6-四-O-苄基-α-D-葡萄糖为原料,经4步反应制得中间体2,3,4,6-四-O-苄基-D-葡萄糖酸-δ-内酰胺(6);在碱性条件下6与正溴丁烷进行氮原子上的烃基化反应得N-丁基-2,3,4,6-四-O-苄基-D-葡萄糖酸-δ-内酰胺(7);用氢化铝锂将7的羰基还原为亚甲基得N-丁基-2,3,4,6-四-O-苄基-1-脱氧野尻霉素(8);8经催化氢解脱去苄基合成了N-丁基-1-脱氧野尻霉素,其结构经1H NMR,13C NMR和MS确证。

Relation between Gastrointestinal Adverse Effects in Gaucher Disease Patients and Intestinal Disaccharidases Activity Evaluated by Methane Hydrogen Breath Test

The aim of this paper is to study the disaccharidase profile in GD （Gaucher disease） patients treated or not with miglustat and compare it with a healthy control group. Miglustat is an iminosugar used as substrate inhibitor in the therapy of some lysosomal disorders, its main side effects resembling carbohydrate maldigestion symptoms and cause more than 50% of medication discontinuation among GD patients. In-vitro studies have revealed that miglustat can act as an inhibitor of some digestive enzymes. An exploratory non-interventional study was designed to compare the disaccharidase profile assessed by MHBT （methane hydrogen breath test） and to analyze the correlation with the reported gastrointestinal symptoms in GD patients （40） and healthy subjects （20）. MHBT was performed following the ingestion of lactose, sucrose and maltose on different days. Each participant completed two detailed surveys about dietary habits, medications and gastrointestinal symptoms previous and during the test. Twenty-one GD were receiving miglustat, 10 （47.6%） of them reported gastrointestinal side effects, and 7/10 （70%） recorded a positive MHBT （lactose 5, maltose 2, and sucrose 1）. In 6/19 （31.6%） patients that never been exposed to miglustat and 7/20 （35%） controls a positive MHBT were detected. The comparison of the malabsorption phenotype between GD patients exposed and not exposed to miglustat （p = 0.028） and control group （p 〈 0.04） showed high statistical significance for the group of patients treated with miglustat. These results suggest that miglustat therapy induces persistent changes in digestive enzyme activity in GD patients.

尼曼-匹克病C型诊治进展

尼曼-匹克病C型(Niemann-Pick disease type C,NPC)是由NPC1或NPC2基因突变引起的一种常染色体隐性遗传性疾病,发病率约为(1~9)/10万。NPC1/NPC2基因突变导致细胞胆固醇转运障碍,游离的胆固醇和其他脂质在溶酶体内贮积而致病。NPC发病年龄和临床表现差异很大,其中神经系统开始受累的年龄和临床表现决定了疾病的严重程度和患者的预后。生物标志物筛查、皮肤活检成纤维细胞Filipin染色、基因检测有助于NPC诊断。NPC的治疗主要以支持治疗为主,使用美格鲁特可延缓神经系统症状进展。该文通过对NPC的流行病学、发病机制、临床表现、诊断、鉴别诊断、治疗、预后等研究进展进行综述,希望有助于提高临床医生对NPC的认识和诊治水平。

尼曼匹克病C型诊疗新进展

尼曼匹克病C型(NPC)是一种常染色体隐性遗传的溶酶体脂质贮积病,主要累及内脏器官和神经系统,自婴幼儿至成人均可发病,儿童期多见。新生儿期持续存在的胆汁淤积性黄疸、脾脏肿大、猝倒发作和垂直性核上性眼肌麻痹为该病的特征性表现,因发病年龄不同,首发的神经系统症状不一致,临床有明显的异质性。NPC基因缺陷导致游离胆固醇转运障碍,在细胞内大量沉积是疾病的始发因素,细胞的自噬功能障碍、钙稳态失平衡、氧化应激等均参与疾病的病理生理过程。通过皮肤成纤维细胞培养发现异常沉积的游离胆固醇或行基因检查发现NPC的致病性突变可确诊该病。美格鲁特是唯一被批准上市的特效药物,早期应用可以改善神经系统症状和延缓疾病的进展。

Possible FDA-approved drugs to treat Ebola virus infection

There is currently no effective treatment for the Ebola virus(EBOV)thus far.Most drugs and vaccines developed to date have not yet been approved for human trials.Two FDA-approved c-AbI1 tyrosine kinase inhibitors Gleevec and Tasigna block the release of viral particles;however,their clinical dosages are much lower than the dosages required for effective EBOV suppression.Anα-1,2-glucosidase inhibitor Miglustat has been shown to inhibit EBOV particle assembly and secretion.Additionally,the estrogen receptor modulators Clomiphene and Toremifene prevent membrane fusion of EBOV and 50-90%of treated mice survived after Clomiphene/Toremifene treatments.However,the uptake efficiency of Clomiphene by oral administration is very low.Thus,I propose a hypothetical treatment protocol to treat Ebola virus infection with a cumulative use of both Miglustat and Toremifene to inhibit the virus effectively and synergistically.EBOV infection induces massive apoptosis of peripheral lymphocytes.Also,cytolysis of endothelial cells triggers disseminated intravascular coagulation(DIC)and subsequent multiple organ failures.Therefore,blood transfusions and active treatments with FDA-approved drugs to treat DIC are also recommended.

尼曼匹克病C型研究进展

尼曼匹克病C型是一种胆固醇转运障碍引起的脂质贮积病,为NPC1或NPC2基因突变所致。因发病年龄不同,分为5型,分别为新生儿型、早期婴幼儿型、晚期婴幼儿型、青少年型和成人型。不同类型的临床表现及预后均有差异。特征性的临床表现为肝脾肿大、肺浸润、垂直性核上性凝视麻痹和痴笑猝倒。该病确诊依赖于发现NPC1或NPC2基因致病性突变和(或)皮肤成纤维细胞培养菲律宾菌素染色显示胆固醇异常分布。目前该病仍缺乏有效的治疗手段,整体上预后仍较差。麦格司他可延缓神经系统症状的出现时间,改善部分患者的生存期。

HPLC-ELSD法测定美格鲁特胶囊的含量

目的：建立测定美格鲁特胶囊含量的方法。方法：采用高效液相色谱-蒸发光散射检测器法。色谱柱为MN Nucleosil100-5 C6H5苯基柱,流动相为乙腈-水（0.1%三氟醋酸）（5∶95,V/V）,流速为1.0 ml/min,柱温为30℃;蒸发光散射检测器漂移管温度为40℃,载气（空气）流速为2.8 L/min。结果：美格鲁特检测质量浓度线性范围为0.100 2~1.002 0 mg/m（lr=0.999 1）,平均回收率为98.95%,RSD=1.40%（n=9）。结论：该方法灵敏、准确,可用于美格鲁特胶囊的含量测定。