海洋真菌Aspergillus sp.的二肽类代谢产物的研究

目的对海洋真菌Aspergillussp.发酵液的乙酸乙酯萃取物进行化学成分的研究。方法采用硅胶柱色谱、凝胶柱色谱、高效液相色谱等手段,利用理化和波谱分析方法,对海洋真菌Aspergillussp.发酵液的乙酸乙酯萃取物的化学成分进行分离鉴定。结果与结论从该真菌发酵液的乙酸乙酯萃取物中分离得到8个二肽类化合物,经光谱数据分析,鉴定它们的结构分别为3-苯甲基-6-异丙基哌嗪-2,5-二酮(1)、3-苯甲基-6-异丁基哌嗪-2,5-二酮(2)、3-苯甲基-6-另丁基哌嗪-2,5-二酮(3)、3,6-二苯甲基哌嗪-2,5-二酮(4)、3-异丁基-6-异丙基哌嗪-2,5-二酮(5)、3-另丁基-6-异丁基哌嗪-2,5-二酮(6)、3-另丁基-6-异丙基哌嗪-2,5-二酮(7)、3-异丁基-吡咯并哌嗪-1,4-二酮(8)。这些化合物均是首次从该真菌代谢物中分离得到。     

N-(4,4''''-二氟苯甲基)哌嗪的合成

N-(4,4′-二氟苯甲基)哌嗪(1)是偏头痛治疗药盐酸洛美利嗪(1omerizine hydrochloride)的合成原料[1].可用4,4′-二氟苯基氯甲烷(4)与无水哌嗪反应得到[2],同时生成副产物哌嗪-盐酸盐(2).     

桂利嗪顺式杂质的合成

目的采用新的方法合成桂利嗪的顺式杂质(Z)-1-二苯甲基-4-(3-苯基-2-丙烯基)哌嗪。方法以3-苯基-2-丙炔-1-醇为原料,经过H_2/林德拉催化剂还原、甲磺酰氯氯代,最后与二苯甲基哌嗪发生缩合反应得到目标化合物。结果与结论目标化合物的结构经ESI-MS和~1H-NMR谱确证,3步总收率为41.6%。该合成路线收率较高,操作简便。     

海洋细菌Bacillus sp．次生代谢产物的研究

目的对海洋细菌Bacillus sp．发酵液的乙酸乙酯萃取物进行化学成分的研究。方法采用硅胶柱色谱、凝胶柱色谱、高效液相色谱等手段，利用理化和波谱分析方法，对海洋细菌Bacillus sp、发酵液的乙酸乙酯萃取物的化学成分进行分离鉴定。结果从该细菌发酵液的乙酸乙酯萃取物中分离得到9个化合物，经光谱数据分析，鉴定它们的结构分别为苯丙氨酸（1）、对羟基苯乙胺（2）、3-另丁基-吡咯并哌嗪-1，4-二酮（3）、3-异丁基-吡咯并哌嗪-1，4-二酮（4）、3-苯甲基-7-羟基-吡咯并哌嗪-1，4-二酮（5）、3-苯甲基-吡咯并哌嗪-1，4-二酮（6）、3-异丙基-吡咯并哌嗪-1，4-二酮（7）、胸腺嘧啶（8）、尿嘧啶（9）。结论9个化合物均是首次从该细菌代谢产物中分离得到。     

抗组胺药Cetirizine

寻找研究无镇静作用的H_1受体拮抗药在制药工业已获成效,已有几个无镇静作用的H_1受体抗组胺药用于临床,其余尚在研究中,其中包括cetirizine,为一羟嗪的人体代谢物。是一个作用强而持久,且具选择性的抗H_1受体特性,而无镇静副作用的新的抗过敏药。合成 1-(4-氯二苯甲基)哌嗪(Ⅰ)与2-(2-氯乙氧基)醋酸甲酯(Ⅱ)经加碳酸钠在二甲苯中回流缩合,生成2-〔2-〔4-(4-氯二苯甲基)-1-哌嗪基〕乙氧基〕醋酸甲酯(Ⅲ),然后Ⅲ在乙醇内回流,经氢氧化钾水解而得     

抗高血压药Manidipine

化学名 (±)-1,4-氢-2,6二甲基-4-间硝基苯基-3,5-吡啶二羧酸甲酯2-(4-二苯甲基-1-哌嗪基)-乙酯二盐酸盐药效分类降血压药开发单位武田药品工业株式会社(日) 上市厂商武田药品工业株式会社     

2-[4-[(4-氯苯基)苯甲基]-1-哌嗪基]乙醇的合成

目的制备2-[4-[(4-氯苯基)苯甲基]-1-哌嗪基]乙醇。方法以氯苯和苯甲酰氯为起始原料,经付克反应、还原、氯化,再分别与哌嗪、氯乙醇、氯乙酸钠缩合,得到最终产物。结果合成目标产物的总收率为49.1%,中间体4-氯双苯酮,4-氯双苯甲醇,4-氯双苯氯甲烷,1-[(4-氯苯基)苯甲基]哌嗪为鲁南贝特制药有限公司生产确证。结论通过对合成路线的优化,使生产收率提高,降低成本,工艺更适于工业化的生产。     

头孢拉宗的合成

4-乙基-2,3-二氧代哌嗪经三光气氯代、与D-苏氨酸缩合、甲酸氧化及草酰氯酰氯化制得2-[(4-乙基-2,3-二氧代-1-哌嗪基)甲酰胺基]-3-甲酰氧基丁酰氯(6),6再与7β-氨基-7α-甲氧基-3-(1-甲基-1H-四唑-5-基硫甲基)-8氧代-5-硫-1-氮杂二环[4.2.0]辛-2-烯-2-甲酸二苯甲酯(7-MAC)经缩合、脱二苯甲基保护基和脱甲酰基等反应得到抗菌剂头孢拉宗,总收率约5%.     

盐酸左西替利嗪

[通用名称] levocetirizine hydrochloride，盐酸左西替利嗪 [化学名称R-(-)-2-[2-[4-[(4-氯苯基)苯甲基]-1-哌嗪基]乙氧基]乙酸二盐酸盐,分子式C21H25ClN2O3·2HCl,相对分子质量461.81.     

抗组织胺药吗嗪的合成

吗嗪(Cyclizine hydrochloride),化学名1-二苯甲基-4-甲基哌嗪盐酸盐。本品具有抗组胺和镇静作用,临床上主要用于防治晕动病,可预防头晕、恶心、呕吐及妊娠呕吐等。合成吗嗪大致有三种方法,起始原料均为二苯基甲醇。     

Third-generation antiepileptic drugs: mechanisms of action,pharmacokinetics and interactions

This review briefly summarizes the information on the molecular mechanisms of action, pharmacokinetic profiles and drug interactions of novel (third-generation) antiepileptic drugs, including brivaracetam, carabersat, carisbamate, DP-valproic acid, eslicarbazepine, fluorofelbamate, fosphenytoin, ganaxolone, lacosamide, losigamone, pregabalin, remacemide, retigabine, rufinamide, safinamide, seletracetam, soretolide, stiripentol, talampanel, and valrocemide. These novel antiepileptic drugs undergo intensive clinical investigations to assess their efficacy and usefulness in the treatment of patients with refractory epilepsy.     

消风止痒颗粒中毛蕊花糖苷、焦地黄苯乙醇苷B1、升麻素苷、升麻素、5-O-甲基维斯阿米醇苷、亥茅酚苷、苍术素醇、白术内酯Ⅱ和苍术素的HPLC法测定及其化学计量学综合评价

目的建立HPLC法同时测定消风止痒颗粒中毛蕊花糖苷、焦地黄苯乙醇苷B1、升麻素苷、升麻素、5-O-甲基维斯阿米醇苷、亥茅酚苷、苍术素醇、白术内酯Ⅱ和苍术素,并采用化学计量学方法对检测结果进行综合评价。方法采用Agilent Zorbax SB-C18色谱柱(250 mm×4.6 mm,5μm);以乙腈-0.2%磷酸溶液为流动相,梯度洗脱;检测波长:330 nm(0~14 min检测毛蕊花糖苷和焦地黄苯乙醇苷B1)、254 nm(14~31 min检测升麻素苷、升麻素、5-O-甲基维斯阿米醇苷和亥茅酚苷)、270 nm(31~55 min检测苍术素醇、白术内酯Ⅱ和苍术素);体积流量0.9 mL/min;柱温25℃;进样量10μL。采用SPSS26.0统计软件对消风止痒颗粒中9种成分进行聚类分析和主成分分析。结果毛蕊花糖苷、焦地黄苯乙醇苷B1、升麻素苷、升麻素、5-O-甲基维斯阿米醇苷、亥茅酚苷、苍术素醇、白术内酯Ⅱ和苍术素分别在2.53~63.25、1.09~27.25、8.17~204.25、2.38~59.50、4.07~101.75、1.74~43.50、0.66~16.50、1.47~36.75、2.86~71.50μg/m L线性关系良好;平均回收率分别为99.01%、98.17%、100.13%、97.63%、98.72%、97.22%、96.93%、99.24%、100.01%,RSD值分别为1.42%、1.26%、0.72%、1.55%、0.84%、1.06%、1.18%、0.67%、0.95%;11批样品聚类分析为3类,主成分1~3是影响消风止痒颗粒质量评价的主要因子。结论该方法操作简便、重复性好,可作为消风止痒颗粒中多指标成分质量评价模式。     

Pediatric Obesity: Pharmacokinetic Alterations and Effects on Antimicrobial Dosing

Limited data exist for appropriate drug dosing in obese children. This comprehensive review summarizes pharmacokinetic (PK) alterations that occur with age and obesity, and these effects on antimicrobial dosing. A thorough comparison of different measures of body weight and specific antimicrobial agents including cefazolin, cefepime, ceftazidime, daptomycin, doripenem, gentamicin, linezolid, meropenem, piperacillin‐tazobactam, tobramycin, vancomycin, and voriconazole is presented. PubMed (1966–July 2015) and Cochrane Library searches were performed using these key terms: children, pharmacokinetic, obesity, overweight, body mass index, ideal body weight, lean body weight, body composition, and specific antimicrobial drugs. PK studies in obese children and, if necessary, data from adult studies were summarized. Knowledge of PK alterations stemming from physiologic changes that occur with age from the neonate to adolescent, as well as those that result from increased body fat, become an essential first step toward optimizing drug dosing in obese children. Excessive amounts of adipose tissue contribute significantly to body size, total body water content, and organ size and function that may modify drug distribution and clearance. PK studies that evaluated antimicrobial dosing primarily used total (or actual) body weight (TBW) for loading doses and TBW or adjusted body weight for maintenance doses, depending on the drugs’ properties and dosing units. PK studies in obese children are imperative to elucidate drug distribution, clearance, and, consequently, the dose required for effective therapy in these children. Future studies should evaluate the effects of both age and obesity on drug dosing because the incidence of obesity is increasing in pediatric patients.     

国内对头孢克肟的临床研究与评价

头孢克肟是第1种第3代口服头孢菌素类抗生素,由日本藤泽制药株式会社于1987年研制成功并首先在日本上市应用于临床,1989年在美国上市。1999年已在80多个国家得到广泛的临床使用。头孢克肟的制剂剂型的研究已发展有胶囊剂、颗粒剂、混悬剂、片剂(普通片剂、咀嚼片、分散片)等。笔者综述了国产头孢克肟与日本产头孢克肟在胶囊剂、颗粒剂、混悬剂、片剂(普通片剂、咀嚼片、分散片)等的药动学比较,以及头孢克肟与头孢泊肟、头孢克洛、头孢呋辛、头孢美他酯、头孢噻肟、头孢地尼、头孢特仑、头孢妥仑匹酯等体外抗菌活性及临床药效学比较。     

高效液相色谱法同时测定麻仁丸中大黄素、大黄酚、大黄酸、大黄素甲醚、芦荟大黄素的含量

目的建立麻仁丸中大黄素、大黄酚、大黄酸、大黄素甲醚、芦荟大黄素的含量测定方法。方法采用奥泰ALLTIMA-C18色谱柱(4.6 mm×250 mm,5μm),以甲醇(A)-0.1%磷酸溶液(B)为流动相,梯度洗脱[0~9min,60%A;9~20 min,60%→80%A;20~45 min,80%A];流速:1.0 mL.min-1;柱温:30℃;检测波长254 nm。结果大黄素、大黄酸、大黄酚、大黄素甲醚、芦荟大黄素线性范围分别为在9.08~81.72、8.4~75.6、13.42~120.7、7.56~68.04、8.2~73.8μg.mL-1,与峰面积线性关系良好,平均回收率分别为99.1%、99.6%、99.4%、99.8%、99.2%,RSD分别为2.0%、1.8、3.2%、1.1%、1.5%。结论本方法可作为麻仁丸中大黄素、大黄酚、大黄酸、大黄素甲醚、芦荟大黄素含量测定的一种准确、灵敏、可行的方法。     

Neuroscience and Hormesis: Overview and General Findings

This article provides a summary of an assessment of the occurrence and impact of hormesis in the neurosciences, including the areas of neuroprotection, neurite outgrowth, and drugs for Alzheimer's disease, Parkinson's disease, anxiety, pain, seizures, stroke, as well as in the areas of behavioral pharmacology, addictive drugs, stress biology including the Yerkes–Dodson law, and p-glycoprotein efflux activity. The findings indicate that the hormetic dose response has a common, if not dominant, presence in each of these diverse areas of neuroscience and further strengthens the conclusion that hormesis is highly generalizable, being independent of biological model, endpoint, and chemical class.     

Inductively coupled plasma and clinical biology. Toxicological applications

The multi-elementary quantitation method using inductively coupled plasma mass spectrometry has been widely developed for use with biological fluids. Many elements can be quantified simultaneously in biological fluids, including: Li, Be, B, Al, Mn, Co, Ni, Cu, Zn, Ga, Ge, As, Se, Rb, Sr, Mo, Pd, Cd, Sn, Sb, Te, Ba, W, Pt, Hg, Tl, Pb, Bi, U. The validation procedure is described by the French Society of Clinical Biology. Results for urine are corrected after creatinine determination.We report applications in clinical toxicology and forensic toxicology. Advances in inductively coupled plasma mass spectrometry in the field of clinical biology are particularly important for toxicological analysis. This powerful tool is helpful for better patient care and for the search for cause of death.     

A Quantitative Exploration of Attitudes Out of Line with the Prevailing Norms Toward Alcohol,Tobacco, and Cannabis Use Among European Students

The study examines groups of 15–16-year-old students whose attitudes toward drug use are out of line with the prevailing norms. It analyzes data from eight countries from the 2003 European School Survey on Alcohol and Other Drugs (ESPAD): Bulgaria, the Czech Republic, Hungary, France, Malta, Slovenia, Sweden, and the United Kingdom. In those countries, 22,900 15–16-year-old pupils answered the ESPAD questionnaire. Groups of subjects whose responses are far removed from the modal value are sought and studied. The aim is to explore “rare answers” compared to what is perceived by the majority of students. In order to explore what can lead a pupil to an atypical perception of risk, a cluster analysis, based on the risk perceptions of alcohol, tobacco, and cannabis use, was run to isolate the groups in which pupils tend to answer differently. Six clusters were established classifying students into those who failed to respond, deny the risks, do not know about the risks, see any drug use as great risk, see regular use as great risk, and who see a moderate risk for most frequencies of use. The nonresponders, risk deniers, and those ignorant of the risks are infrequent making up, in all, only 16.9% of the total sample. Gender, country, alcohol use, cannabis use, tobacco use, and friends’ consumption were used to describe both the individual risk perceptions and the clusters based on them. Both global context (country) and “micro” context (frequencies of drug use, peers lifestyle, and parental permissiveness) appear to play a major role in the risk perception of drug use.     

［~3H］二氢埃托啡在大鼠脑分布的定量放射自显影

本文用体外定量受体放射自显影分析法观察了［３Ｈ］二氢埃托啡（ＤＨＥ）在大鼠脑中定位分布和结合特点。结果表明，［３Ｈ］ＤＨＥ特异结合较高的部位主要为纹状体，伏隔核，大脑皮质Ⅰ层和Ⅲ层，丘脑，缰核，杏仁核。脚间核和蓝斑，ＤＨＥ主要作用于ｕ－阿片受体．