硝基咪唑类放射增敏剂研究进展及其化学合成方法

放射增敏剂是一类能选择性地增加肿瘤乏氧细胞对放射敏感性的药物。它的开发和应用将大大提高肿瘤放疗的治愈率,自六十年代初以来,这类药物已取得很大进展。硝基咪唑类增敏剂发展概况 1963年Adams等提出化合物的放射增敏作用与其电子亲合性有关的论点,推动了亲电子性增敏剂的发展。其后,系统地研究了多种类型的化合物,如醌类、硝基苯类、硝基呋喃类和硝基咪唑类等,其中以硝基咪唑类作用最好。两只原为抗滴虫药的硝基咪唑类化合物,即甲硝唑(1)和米索硝唑     

卟啉硝基咪唑类衍生物的合成及放射增敏作用

目的设计合成卟啉硝基咪唑类化合物,评价其体外肿瘤放射增敏活性,寻找新的肿瘤放射增敏剂。方法以吡咯、苯甲醛、硝基咪唑为原料,经环合、溴代、取代、络合等反应合成卟啉硝基咪唑类化合物及其金属配合物。采用MTT法考查该系列衍生物对人宫颈癌Helo细胞株的放射增敏活性。结果合成了12个未见文献报道的新化合物,其结构经紫外光谱、ESI质谱、红外光谱和核磁共振氢谱确证。在4Gy照射剂量下,化合物15、16、18、19对人宫颈癌Helo细胞株显示出很好的放射增敏活性,对肿瘤细胞的抑制率达到95%左右。结论金属卟啉结构单元的引入,极大地提高了硝基咪唑类的放射增敏活性。     

硝基(芳亚胺基)二乙基硫代硫酸钠和硝基苯丙氮酸衍生物的合成和放射增敏作用

乏氧细胞对射线所具有的较大抗性是对某些人类肿瘤进行放疗失效的主要原因。放射增敏剂的研究目的是为了提高射线在正常组织可耐受剂量下对肿瘤细胞的杀伤率,从而提高放疗效果。目前试用于临床的放射增散剂misoniizole(MISO)是一种硝基咪唑类化合物,由于其较强的神经毒性,限制了这种药物的推广和使用。为寻找新的低毒有效的放射增敏剂,我们设计并合成了一系列化合物,试验了它们对离体Hela-S_3细胞的放射增敏作用。     

2—硝基咪唑类乏氧细胞放射线增敏剂的合成及其抑制血管增生作用

设计并合成了２－氯代乙酰氨甲酰基－１（２－硝基咪唑基）－３－叔丁氧基丙烷,２－溴代乙酰氨甲酰基－１－（２－硝基咪唑基）－３－（４－叔丁基）酚基丙烷及结构类似的光学异构体,测定了卤代乙酰氨甲酰基－２－硝基咪唑类化合物体外乏氧细胞放射增敏活性和体内抑制血管增生活性。结果表明：２－硝基咪唑侧链上引入卤代乙酰氨甲酰基可明显增大体外乏氧细胞放射增敏活性,而且表现出较强的体内抑制血管增生活性。     

放射增敏剂的研究进展

过去的20年间,乏氧细胞放射增敏剂的研究一直引起人们相当大的兴趣,它的发展将有助于解决肿瘤乏氧细胞对射线的抗性而致肿瘤放疗治愈率低的难题,也可以用于化疗增敏。已发现一些类型化合物有放射增敏作用,但是研究较多、最有希望发展成为临床使用药物的目前有三类,即硝基杂环类,有机-N-氧化物类和醌类。一、硝基杂环类 20年前发现硝基杂环类具有选择性乏氧细胞增敏作用。最初对对硝基苯乙酮类化合物的研究表明,对乏氧细胞的增敏活性为硝基芳环类化合物所特有。其后,对多种硝     

有效的放射增敏剂:二硝基咪唑衍生物的合成及其生物活性

对多种芳香硝基化合物的放射增敏作用研究发现,1-(2-羟基-3-甲氧丙基)-2-硝基味唑(Misonidazole)是一有效的放射增敏剂,但因其神经毒性和诱变性,妨碍其临床应用。为寻找低毒和有效的放射增敏剂,考虑到分子的亲电性的重要作用以及芳环上引入吸电子基可增大活性,合成了一系列2,4-二硝基咪唑衍生物(2～4),并采用中国仓鼠低氧细胞(V-79),进行放射增敏体外试验。     

辐射化学修饰剂沙纳唑研究进展

沙纳唑是硝基三氮唑类乏氧细胞辐射化学修饰剂,其不良反应小、放射增敏作用强。本文综述其药动学特点、免疫调节作用、放射增敏作用、化学增敏作用、及其在临床肿瘤治疗中的研究结果。     

3-硝基-1,2,4-三唑类乏氧细胞放射增敏剂的构效关系

为了寻找毒性低、增敏作用强的乏氧细胞放射增敏剂,设计并合成了一系列5-溴-,5-甲基-,和5-未取代的3-硝基-1,2,4-三唑-1-乙酰胺类化合物,用HeLaS3细胞进行了体外试验。结果表明5-溴取代衍生物的增敏作用强于相应的5-甲基-或5-未取代的硝基三唑衍生物,但是它们的毒性亦增大。修饰1位乙酰胺侧链也可以改变化合物的增敏作用和亲脂性。在所测定的化合物中TA-101[2-(3-硝基-1-三唑基)乙酰胺]由于有高的增敏作用和低亲脂性,可能是一个有希望的放射增敏剂。     

3－硝基－1，2，4－三唑类乏氧细胞放射增敏剂的构效关系

为了寻找毒性低、增敏作用强的乏氧细胞放射增敏剂，设计并合成了一系列５－溴－，５－甲基－，和５－未取代的３－硝基－１，２，４－三唑－１－乙酰胺类化合物，用ＨｅＬａＳ３细胞进行了体外试验。结果表明５－溴取代衍生物的增敏作用强于相应的５－甲基－或５－未取代的硝基三唑衍生物，但是它们的毒性亦增大。修饰１位乙酰胺侧链也可以改变化合物的增敏作用和亲脂性。在所测定的化合物中ＴＡ－１０１［２－（３－硝基－１－三唑基）乙酰胺］由于有高的增敏作用和低亲脂性，可能是一个有希望的放射增敏剂。     

一种新型放射增敏剂PR-350对二氢嘧啶脱氢酶活性和5-氟尿嘧啶的药代动力学的作用

众所周知 ,在应用放疗局部控制癌症方面 ,实体瘤中乏氧细胞的放射不敏感性是限制因素之一。尽管已经证明米索硝唑 (ｍｉｓｏｎｉｄａｚｏｌｅ)对实体瘤中乏氧细胞有放射增敏效应 ,但其神经毒性限制了其应用。为有效提供低毒和 (或 )高效放射增敏剂 ,依他硝唑(ｅｔａｎｉｄａｚｏｌｅ)、哌莫硝唑 (ｐｉｍｏｎｉｄａｚｏｌｅ)和其他增敏剂已相继被开发出来。ＰＲ 35 0化学名为 (± ) (2ＲＳ ,3ＳＲ) 〔3 (2 硝基咪唑基 1)甲氧基〕 1,2 ,4丁三醇 ,由ＰＯＬＡ化工企业 (日本横滨 )开发研制的一种放射增敏剂。前期研究证实 ,它具有与依他硝唑…     

Physiological response of carp,Cyprinus carpio,exposed to raw sewage containing fish processing wastewater

Physiological changes of carp exposed to raw sewage were investigated by the use of clinical examination methods. All carp exposed to raw sewage died within 6 h. On hour 48, 10, 40, and 90% of exposed carp survived in 60, 20, and 10% sewage, respectively. Carp exposed to 50 and 20% sewage increased ammonia, glucose, Mg, Cu, and Br, and decreased Fe and Zn in plasma. Even in 10% sewage, ammonia, glucose, and Br in plasma increased. Forty-eight hours of exposure to 50 and 20% sewage caused severe pathological changes in the gills. In the kidney, light abnormalities were observed at this time. When exposed to 50 and 20% sewage, atrioventricular conduction time and duration of electrical systole measured by electrocardiogram shortened briefly, and then extended gradually. In 50 and 20% sewage, heart rate and respiratory frequency increased briefly, and then decreased gradually. Cough reaction increased with the exposure. © 1997 by John Wiley & Sons, Inc. Environ Toxicol Water Qual 12: 1–9, 1997     

Alpinia zerumbet,a ginger plant with a multitude of medicinal properties: An update on its research findings

In this review, the botany and uses of Alpinia zerumbet (yan shan jiang) are described, and the current knowledge of its phytochemistry, pharmacological properties, and clinical trials is summarized. An important ginger crop in East Asia, A. zerumbet has many uses, both medicinal and non-medicinal. Leaves are used to produce essential oils and herbal teas. Rhizomes are consumed as spices, and stem fibers are made into paper, fabrics, and handicrafts. In Brazil, tea from A. zerumbet leaves is believed to have hypotensive, diuretic, and anti-ulcerogenic properties. This species possesses many medicinal properties due to its chemical constituents, including flavonoids, phenolic acids, phenylpropanoids, kava pyrones, sterols, and terpenoids. Extracts of A. zerumbet display antioxidant, antimicrobial, insecticidal, anthelmintic, tyrosinase and melanogenesis inhibitory, anti-atherogenic, anti-aging, anti-glycation, integrase and neuraminidase inhibitory, lifespan prolongation, hair growth promotion, anticancer, antidepressant, anxiolytic, anti-obesity, analgesic, anti-inflammatory, hypolipidemic, anti-ulcerogenic, anti-platelet, osteoblastic, osteogenic, thrombolytic, and cardiacarrhythmogenic activities. Essential oils of A. zerumbet leaves have antimicrobial, larvicidal, antinociceptive, hypotensive, vasorelaxant, myorelaxant, antispasmodic, antidepressant, anxiolytic, anti-neuraminidase, anti-atherogenic, anti-aging, anti-melanogenic, anti-tyrosinase, cytoprotective, cardiodepressive, antipsychotic, analgesic, anti-inflammatory, and tissue healing activities.Clinical trials conducted in Brazil showed that extracts of A. zerumbet have hypotensive and diuretic effects whereas topical application of the essential oil has positive therapeutic effects on patients with fibromyalgia. Spanning two continents of Asia and South America, A. zerumbetis truly a multi-purpose ginger plant with promising medicinal properties.     

Effects of typical and atypical antipsychotics on glucose–insulin homeostasis and lipid metabolism in first-episode schizophrenia

Rationale Glucose and lipid metabolism dysfunction is a significant side effect associated with antipsychotics. Although there are many studies about the linkages between drugs and metabolic dysfunction, most of these studies have compared the effects of two antipsychotics on only one metabolic measure: either glucose or lipid metabolism.Objectives The present study aimed to investigate the effects of clozapine, olanzapine, risperidone, and sulpiride on glucose and lipid metabolism in first-episode schizophrenia.Materials and methods One hundred twelve schizophrenics were assigned randomly to receive clozapine, olanzapine, risperidone, or sulpiride for 8 weeks. Planned assessments included body mass index (BMI), waist-to-hip ratio, fasting glucose, insulin, C-peptide, insulin resistance index (IRI), cholesterol, and triglyceride. All measures were collected at baseline and at the end of the 8-week treatment.Results After treatment, insulin, C-peptide, and IRI were significantly increased in the four groups, but not fasting glucose levels. Cholesterol and triglyceride levels were significantly increased in the clozapine and olanzapine groups. Patients treated with clozapine and olanzapine had higher fasting insulin, C-peptide, and IRI levels than those treated with risperidone and sulpiride. Among the four antipsychotics, the increases of mean BMI from high to low were as follows: clozapine, olanzapine, sulpiride, and risperidone.Conclusions This study confirmed that the four antipsychotic drugs were associated with an increase of insulin, C-peptide, and IRI. It was found that clozapine and olanzapine were associated with an increase in cholesterol and triglyceride levels. The effects of clozapine and olanzapine on the glucose and lipid metabolism outweighed those of risperidone and sulpiride.     

过量奥卡西平致定向力障碍及共济失调

1例6岁男性癫痫患儿,曾先后口服苯妥英钠、拉莫三嗪、丙戊酸钠、苯巴比妥治疗,因不能规律服药致使癫痫反复发作且进行性加重,家属自行给予其口服奥卡西平300 mg、3次/d,上述症状未再发作。但40 d后出现行走不稳、反应迟钝,且癫痫症状也加重。入院诊断为癫痫,全身强直-阵挛发作,奥卡西平致定向力障碍及共济失调。停用奥卡西平,给予丙戊酸钠、还原性谷胱甘肽、维生素C,次日癫痫得到控制。第8天定向力障碍及共济失调消失,癫痫未再发作,遂出院。出院后规律服用丙戊酸钠和氯硝西泮。随访1个月,未再出现癫痫发作、定向力障碍和共济失调。     

A review of anti-inflammatory,antioxidant, and immunomodulatory effects of Allium cepa and its main constituents

ContextAllium cepa L. (Liliaceae), known as onion, is consumed throughout the world. Onion and its derivatives including saponins, aglycones, quercetin, cepaenes, flavonoids, organosulfurs, and phenolic compounds, showed various pharmacological properties and therapeutic effects.ObjectiveAnti-inflammatory, antioxidant, and immunomodulatory effects of A. cepa and its main constituents, along with the underlying molecular mechanisms are presented.MethodsDatabases including, Web of Knowledge, Medline/PubMed, Scopus, and Google Scholar were checked for articles published between 1996 and the end of July 2020, using the key-words Allium cepa, quercetin, anti-inflammatory, antioxidant and immunomodulatory.ResultsA. cepa and its constituents mainly quercetin showed anti-inflammatory effects mediated via reduction of total and differential WBC counts, inhibition of chemotaxis of polymorphonuclear leukocytes, COX, and LOX pathways and prevented formation of leukotrienes and thromboxanes, prostaglandin E2 (PGE2) as onVCAM-1, NF-κB, MARK,d STAT-1, JNK, p38 and osteoclastogenesis. A. cepa and its derivatives showed antioxidant effect by decreasing lipid peroxidation, NAD(P)H, MDA, NO, LPO and eNOS but enhancing antioxidants such as SOD, CAT, GSH, GPx, GSPO, TrxR, SDH, GST and GR activities and thiol level. Immunomodulatory effects of the plant and quercetin was also shown by reduction of Th2 cytokines, IL-4, IL-5, and IL-13 as well as IL-6, IL-8, IL-10, IL-1β and TNF-α and IgE levels, but increased CD4 cells, IFN-γ level and IFN-γ/IL4 ratio (Th1/Th2 balance).ConclusionsThe effect of onion and its constituents on oxidative stress, inflammatory and immune system were shown indicating their therapeutic value in treatment of various diseases associated with oxidative stress, inflammation, and immune-dysregulation.     

Comparison of the gastrointestinal anatomy,physiology, and biochemistry of humans and commonly used laboratory animals

In addition to metabolic differences, the anatomical, physiological, and biochemical differences in the gastrointestinal (G.I.) tract of the human and common laboratory animals can cause significant variation in drug absorption from the oral route. Among the physiological factors, pH, bile, pancreatic juice, and mucus and fluid volume and content can modify dissolution rates, solubility, transit times, and membrane transport of drug molecules. The microbial content of the G.I. tract can significantly affect the reductive metabolism and enterohepatic circulation of drugs and colonic delivery of formulations. The transit time of dosage forms can be significantly different between species due to different dimensions and propulsive activities of the G.I. tract. The lipid/protein composition of the enterocyte membrane along the G.I. tract can alter binding and passive, active, and carrier-mediated transport of drugs. The location and number of Peyer's patches can also be important in the absorption of large molecules and particulate matter. While small animals, rats, mice, guinea pigs, and rabbits, are most suitable for determining the mechanism of drug absorption and bioavailability values from powder or solution formulations, larger animals, dogs, pigs, and monkeys, are used to assess absorption from formulations. The understanding of physiological, anatomical, and biochemical differences between the G.I. tracts of different animal species can lead to the selection of the correct animal model to mimic the bioavailability of compounds in the human. This article reviews the anatomical, physiological, and biochemical differences between the G.I. tracts of humans and commonly used laboratory animals.     

Neuropharmacological studies of phencyclidine (PCP)-induced behavioral stimulation in mice

A variety of drugs were screened to determine which were capable of blocking the behavioral stimulation produced in mice by acute administration of phencyclidine (PCP). Chlorpromazine and clozapine blocked PCP-induced stimulation, while haloperidol, reserpine, and alpha-methyl-p-tyrosine did not. The GABA receptor agonists imidazole acetic acid and muscimol blocked PCP, but other drugs that influence GABA, such as dipropylacetic acid, baclofen, and diazepam, were ineffective. Yohimbine and methysergide also blocked PCP in high dosages, but other drugs with comparable alpha-noradrenergic and serotonergic blocking properties (phentolamine, cyproheptadine, and cinnanserin) were ineffective. Cholinergic and anticholinergic drugs, beta-noradrenergic and opiate antagonists, and nonspecific sedatives and convulsants were also ineffective. These finding suggest that chlorpromazine, clozapine, yohimbine, and methysergide may share a property that is unlike their primary known modes of action on dopaminergic, alphanoradrenergic, and serotonergic neurotransmitter systems, and that this property accounts for their ability to block PCP. However, the effectiveness of GABA agonists appears to be mediated through direct activation of GABA receptors. It is suggested that chlorpromazine and imidazole acetic acid should be considered as possible drug treatments for PCP toxicity.     

聚氯乙烯和聚烯烃热塑性弹性体输液器对4种常用注射液稳定性及吸附性影响

目的：比较聚氯乙烯（PVC）输液器与聚烯烃热塑性弹性体（TPE）输液器对4种常用注射液的稳定性与吸附性的影响。方法：将乳酸环丙沙星氯化钠、左氧氟沙星氯化钠、乳酸左氧氟沙星氯化钠和托烷司琼氯化钠4种常用注射液迅速充满输液器并封存放置或正常流经输液器,采用HPLC法测定环丙沙星、左氧氟沙星和托烷司琼浓度,比较各药标示量变化,评价各药稳定性和输液器吸附性。结果：PVC和TPE输液器乳酸环丙沙星氯化钠注射液、左氧氟沙星氯化钠注射液、乳酸左氧氟沙星氯化钠注射液、托烷司琼氯化钠注射液最终（90 min）各药百分含量分别为94.11%,98.42%,98.02%,100.59%,101.91%,102.73%,99.04%,102.89%,2组含量变化无显著差异（P<0.05）,提示各药稳定。PVC和TPE输液器90 min各药百分含量分别为101.74%,100.21%,101.04%,99.37%和101.64%,103.10%,103.35%,103.27%,2组间含量变化无显著差异（P<0.05）,提示2种输液器吸附性相当。结论：PVC和TPE输液器不影响乳酸环丙沙星氯化钠注射液、左氧氟沙星氯化钠注射液、乳酸左氧氟沙星氯化钠注射液、托烷司琼氯化钠注射液的稳定性,对4种注射液中各药亦无吸附发生,可常规使用。     

Impact of Fusarium-Derived Mycoestrogens on Female Reproduction: A Systematic Review

Contamination of the world’s food supply and animal feed with mycotoxins is a growing concern as global temperatures rise and promote the growth of fungus. Zearalenone (ZEN), an estrogenic mycotoxin produced by Fusarium fungi, is a common contaminant of cereal grains and has also been detected at lower levels in meat, milk, and spices. ZEN’s synthetic derivative, zeranol, is used as a growth promoter in United States (US) and Canadian beef production. Experimental research suggests that ZEN and zeranol disrupt the endocrine and reproductive systems, leading to infertility, polycystic ovarian syndrome-like phenotypes, pregnancy loss, and low birth weight. With widespread human dietary exposure and growing experimental evidence of endocrine-disrupting properties, a comprehensive review of the impact of ZEN, zeranol, and their metabolites on the female reproductive system is warranted. The objective of this systematic review was to summarize the in vitro, in vivo, and epidemiological literature and evaluate the potential impact of ZEN, zeranol, and their metabolites (commonly referred to as mycoestrogens) on female reproductive outcomes. We conducted a systematic review (PROSPERO registration CRD42020166469) of the literature (2000–2020) following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The data sources were primary literature published in English obtained from searching PubMed, Web of Science, and Scopus. The ToxR tool was applied to assess risk of bias. In vitro and in vivo studies (n = 104) were identified and, overall, evidence consistently supported adverse effects of mycoestrogens on physiological processes, organs, and tissues associated with female reproduction. In non-pregnant animals, mycoestrogens alter follicular profiles in the ovary, disrupt estrus cycling, and increase myometrium thickness. Furthermore, during pregnancy, mycoestrogen exposure contributes to placental hemorrhage, stillbirth, and impaired fetal growth. No epidemiological studies fitting the inclusion criteria were identified.