2-(3-噻吩基)丙二酸的合成

3-甲基噻吩经溴代、氰基取代制得3-噻吩乙腈，再经醇解、与碳酸二乙酯反应和碱性水解制得合成青霉素类抗生素的中间体2-（3-噻吩基）丙二酸，总收率36％。     

替卡西林钠的合成新工艺

目的:制备替卡西林钠。方法:以3-噻吩丙二酸为起始原料,经过酰氯化、酰胺化、成盐反应制得替卡西林单钠。替卡西林单钠与碳酸氢钠在水溶液中反应后,真空冷冻干燥制得替卡西林钠。结果:总收率62.8%,含量>98.0%。结论:该方法制备的替卡西林钠收率高,质量好,易于实现工业化。     

氟哌酸中间体—3-氯-4-氟苯胺亚甲基丙二酸二乙酯的合成工艺改进

3-氯-4-氟苯胺在适当的Lewis酸存在下,与原甲酸三乙酯及丙二酸二乙酯缩合,一步制得了3-氯-4-氟苯胺亚甲基丙二酸二乙酯(Ⅲ),反应收率几乎为100％,本方法可在氟哌酸的生产巾完全代替乙氧_亚甲基丙二酸二乙酯工艺。     

禹州漏芦中噻吩类的化学成分

目的研究禹州漏芦(Echinops latifoliusTausch)噻吩类化学成分。方法采用反复硅胶柱层析分离纯化,通过理化常数测定和光谱分析鉴定其化学结构。结果从禹州漏芦中分离得到6个噻吩类化合物,即5-(丁烯-3--炔1)-2,2′-联噻吩[5-(but3-en-1-ynyl)-2,2-′bithiophene,1]、α-三联噻吩(-αterthienyl,2)、卡多帕亭(cardopatine,3)、5-乙酰-基2,2′-联噻吩(5-acetyl-2,2-′bithiophene,4)、5-(3-乙酰氧基-4-异戊酰氧基丁炔-1)-2,2′-联噻吩[5-(3-acetoxy-4-isovaleroyloxybut-1-ynyl)-2,2-′bithio-phene,5]、5-(4-羟基丁炔-1)-2,2′-联噻吩[5-(4-hydroxybut-1-ynyl)-2,2-′bithiophene,6]。结论化合物4-6为首次从该植物中分离得到。     

3-氯-4-氟苯胺基亚甲丙二酸二乙酯制备的改进

3-氯-4-氟苯胺在 Lewis 酸存在下直接同原甲酸三乙酯、丙二酸二乙酯反应,除得到60～70%收率的主产物3-氯-4-氟苯胺基亚甲丙二酸二乙酯(1)外,还分离到三个产物,经 IR、MS、~1HNMR 及元素分析,证明其结构分别是甲脒3的盐酸盐、4和5。可用本法代替原用乙氧亚甲丙二酸二乙酯制备1的工艺。     

《中国医药工业杂志》2006年(第37卷)年度索引

主题索引1抗微生物感染药物1A抗生素1A1β-内酰胺类1A1A青霉素类氨苄西林Ampicillin复方～-氟氯西林胶囊及有关物质的HPLC测定37:633比阿培南Biapenem合成37:793多尼培南Doripenem合成37:361氟氯西林Floxacillin复方氨苄西林-～胶囊及有关物质的HPLC测定37:633青霉素Penicillin玉米浆对～发酵生产的影响37:528替卡西林Ticarcillin替莫西林Temocillin2-(3-噻吩基)丙二酸的合成37:5201A1B头孢菌素类氨噻肟酸乙酯的合成37:2297β-氨基-3-氯甲基-7α-甲氧基-1-氧化-3-头孢烯-4-羧酸二苯甲酯的合成路线图解37:2147-ACA7-ADAC利用粘红…     

取代噻吩高选择性溴代反应

N -溴代琥珀酰亚胺 (NBS)于室温加至 3-烷基噻吩的冰醋酸溶液中 ,反应自行升温达 6 0～ 70℃ ,全过程 6～ 5 0 m in,得 2 -溴 -3-烷基噻吩 ,4例收率 91.7～ 97.9% ,纯度 97～ 99%。2 .2′-二噻吩基甲烷同法得到 5 ,5′-二溴代物。本法选择性高 ,收率高 ,可扩大制备取代噻吩高选择性溴代反应@马霞     

2-(3-羟基-1-金刚烷基)-2-乙醛酸的合成

金刚烷经相继甲酸化、酰氯化后与丙二酸二乙酯乙氧基镁反应,得到1-金刚烷甲酰基丙二酸二乙酯,再经水解脱羧、高锰酸钾氧化得到沙克列汀中间体2-(3-羟基-1-金刚烷基)-2-乙醛酸,总收率约28%。     

DL-色氨酸合成新工艺

DL-色氨酸原工艺系采用吲哚为原料,先制成夹拉明(3-二甲胺基甲基吲哚),再与乙酰氨基丙二酸二乙酯缩合成α-乙酰氨基-α-(吲哚-3)-甲基丙二酸二乙酯,最后经皂化、脱羧、水解、精制得到。由于吲哚价格昂贵,供应紧张,为了降低成本,扩大生产,我们进行了革除吲哚的工艺改革。     

盐酸度洛西汀的合成

以2-乙酰噻吩、N-甲基苄胺和多聚甲醛为原料,经Mannich反应、硼氢化钠还原、与1-氟萘经O-烷基化反应制得(±)-N-苄基-N-甲基-3-(1-萘氧基)-3-(2-噻吩基)-1-丙胺,脱苄基后经L-二苯甲酰酒石酸拆分得到( )-(S)-N-甲基-3-(1-萘氧基)-3-(2-噻吩基)-1-丙胺-L-二苯甲酰酒石酸盐,用氢氧化钠游离后与盐酸成盐得到盐酸度洛西汀,总收率为13.5%。     

Effects of DN-2327, a new anxiolytic,diazepam and buspirone on exploratory activity of the rat in an elevated plus-maze

In the present study, the effects of a new anxiolytic, DN-2327, were compared to those of diazepam and buspirone in rats in the elevated plus-maze test. Two indices of anxiety were obtained in this test: the number of entries into the open arms expressed as a percentage of the total number of arm entries and the percentage of time spent on the open arms. Both a typical anxiolytic, diazepam, at 2.5, 5 and 10 mg/kg, PO and a new anxiolytic, DN-2327, at 2.5 and 5 mg/kg, PO dose-dependently increased the two indices: the percentage of time spent on the open arms and the percentage of open-arm entries. On the other hand, pentylenetetrazol (PTZ) at 10 and 20 mg/kg, IP decreased the two indices dose dependently as did yohimbine at 1.5 and 3 mg/kg, IP. DN-2327 at 2.5 and 5 mg/kg, PO and diazepam at 5 and 10 mg/kg, PO dose dependently and significantly increased the two indices that were suppressed following administration of PTZ at 10 mg/kg, IP. The effects of both DN-2327, 5 mg/kg, PO, and diazepam, 10 mg/kg, PO, on the two indices were significantly antagonized by the benzodiazepine (BZD) receptor antagonist flumazenil, 20 mg/kg, IP. Buspirone (2.5–20 mg/kg, PO) did not affect either of the two responses but dose dependently decreased the number of rearings, although in the Vogel conflict test, the anti-conflict activity of buspirone was equipotent to that of diazepam and DN-2327 at the minimum effective dose (10 mg/kg, PO) of each drug. In conclusion, the present experiment revealed that the anxiolytic effect of DN-2327 in this test was clear, whereas buspirone showed no apparent effect.     

The debate on DDT

The paper reviews the early toxicologic and pharmacologic studies carried out by the author and his associates from 1943 to 1947, which were largely responsible for launching DDT as an agent for the control of typhus, malaria, yellow fever, and related vector-borne diseases. After reviewing recent studies conducted at the University of Miami, which dealt with organochlorine pesticides in human tissues, the tumorigenicity of aldrin, dieldrin and endrin (rat), six-generation mouse and three-generation dog reproduction studies, synergism of DDT and aldrin (dog), and the fate of DDT and aldrin during a period of severe starvation (rat), it is pointed out that it is primarily the overuse and misuse of DDT in pest control that have caused the pollution in our ecology. It is emphasized that the requirements for pest control differ the world over and that it must therefore be left to the national regulatory agencies to legislate the safe use of DDT and related pesticides. It is recommended that future human and animal studies with DDT and its derivatives give consideration to: (a) the balance and metabolism of the various hormones, (b) reproduction (estrus, libido, mammary development, milk production, (c) hepatic microsomal enzyme activities, (d) cancer prevention and cancer production, (e) excessive body weight changes induced by disease, unbalanced diet or starvation, and (f) the effects of DDT and its derivatives when absorbed in combination with other related and even unrelated compounds.Presented at the joint meeting of the Scandinavian and German Pharmacological Societies, Copenhagen, Denmark, July 20–23, 1971.     

Retinal Delivery of Celecoxib Is Several-Fold Higher Following Subconjunctival Administration Compared to Systemic Administration

PURPOSE: We have previously demonstrated that celecoxib, a selective COX-2 inhibitor, reaches the retina following repeated oral administrations and inhibits diabetes-induced vascular endothelial growth factor (VEGF) mRNA expression and vascular leakage in a rat model. The aim of this study was to quantify the relative retinal bioavailability of celecoxib from the subconjunctival route compared to a systemic route. METHODS: The plasma and ocular tissue distribution of celecoxib was determined in male Sprague-Dawley rats following subconjunctival and intraperitoneal administrations of drug suspension at a dose of 3 mg/rat. The animals were sacrificed at 0.5, 1, 2, 3, 4, 8, and 12 h post-dosing, the blood was collected, and the eyes were enucleated and frozen. The plasma, sclera, retina, vitreous, lens, and the cornea were isolated and celecoxib levels were determined using an HPLC method. The tissue exposure of the drug was measured as the area under the curve (AUC(0-infinity)) of the concentration vs. time profiles. The relative bioavailability was estimated as the AUC(0-infinity) ratio between subconjunctival and intraperitoneal groups. RESULTS: For the subconjunctivally dosed (ipsilateral) eye, the AUC(0-infinity) ratios between subconjunctival and intraperitoneal groups were 0.8 +/- 0.1, 53 +/- 4, 54 +/- 8, 145 +/- 21, 61 +/- 16, and 52 +/- 6 for plasma, sclera, retina, vitreous, lens, and cornea, respectively. For the contralateral ocular tissues, the AUC0-infinity ratios were 1.2 +/- 03, 11 +/- 0.3, 1.1 +/- 0.4, 1.0 +/- 0.3, and 1.2 +/- 0.3 in the sclera, retina, vitreous, lens, and the cornea, respectively, between the subconjunctival and the intraperitoneal groups. Assuming that the drug AUCs in contralateral eye were equal to the systemic pathway contribution to AUCs in the ipsilateral eye, the percent contribution of local pathways as opposed to systemic circulation for celecoxib delivery to the ipsilateral eye tissues was estimated to be 98% or greater. CONCLUSIONS: The retinal delivery of celecoxib was substantially higher following subconjunctival administration compared to the intraperitoneal route. The transscleral pathway almost completely accounts for the retinal celecoxib delivery following subconjunctival administration.     

肠道菌群与健康、疾病和药物作用的影响

肠道菌群作为人体内一个复杂的微生态系统,在维持人体微生态的稳态中,肠道菌群在维持宿主生理功能具有上非常重要的作用,也对许多代谢性疾病、免疫性疾病以及肿瘤都有着密切的关系,且对于药物治疗合理安全有效具有重要意义。本文从正视存在人体的细菌的有益性和有害性、肠道菌群与健康和寿命、肠道菌群与疾病以及药物作用的影响等4方面分析和讨论。肠道菌群与不同类型药物的关系已经成为近些年的热点研究领域,本文分别讨论免疫治疗、化学药物、抗生素和中药的相关问题,希望为认识药物治疗过程、科学合理用药、认识药物作用机制、新药研究开发等研究有所参考。     

The solute carrier transporters and the brain:Physiological and pharmacological implications

Solute carriers(SLCs)are the largest family of transmembrane transporters that determine the exchange of various substances,including nutrients,ions,metabolites,and drugs across biological membranes.To date,the presence of about 287 SLC genes have been identified in the brain,among which mutations or the resultant dysfunctions of 71 SLC genes have been reported to be correlated with human brain disorders.Although increasing interest in SLCs have focused on drug development,SLCs are currently still under-explored as drug targets,especially in the brain.We summarize the main substrates and functions of SLCs that are expressed in the brain,with an emphasis on selected SLCs that are important physiologically,pathologically,and pharmacologically in the blood-brain barrier,astrocytes,and neurons.Evidence suggests that a fraction of SLCs are regulated along with the occurrences of brain disorders,among which epilepsy,neurodegenerative diseases,and autism are representative.Given the review of SLCs involved in the onset and procession of brain disorders,we hope these SLCs will be screened as promising drug targets to improve drug delivery to the brain.     

Behavioral phenotypes of inbred mouse strains: implications and recommendations for molecular studies

 Choosing the best genetic strains of mice for developing a new knockout or transgenic mouse requires extensive knowledge of the endogenous traits of inbred strains. Background genes from the parental strains may interact with the mutated gene, in a manner which could severely compromise the interpretation of the mutant phenotype. The present overview summarizes the literature on a wide variety of behavioral traits for the 129, C57BL/6, DBA/2, and many other inbred strains of mice. Strain distributions are described for open field activity, learning and memory tasks, aggression, sexual and parental behaviors, acoustic startle and prepulse inhibition, and the behavioral actions of ethanol, nicotine, cocaine, opiates, antipsychotics, and anxiolytics. Using the referenced information, molecular geneticists can choose optimal parental strains of mice, and perhaps develop new embryonic stem cell progenitors, for new knockouts and transgenics to investigate gene function, and to serve as animal models in the development of novel therapeutics for human genetic diseases. Received: 8 November 1996 / Final version: 15 March 1997     

COMPARATIVE STUDIES ON THE PHARMACOLOGICAL ACTIONS OF ANTIARRHYTHMIC DRUGS IN ISOLATED RAT PAPILLARY MUSCLE

1. The effects of ajmaline, cocaine, phenytoin, lignocaine, procainamide, propranolol, quinidine and trimetazidine on the contractility and the refractory period of isolated rat papillary muscles were compared. 2. At the higher concentrations used, all drugs suppressed the contractile tension of the rat papillary muscles. 3. The effects of these drugs on the refractory period were compared at concentrations at which the contractile tension was suppressed by 30% of the control. At this point, lignocaine, procainamide, ajmaline and quinidine prolonged the refractory period more than two-fold while the effects of propranolol and phenytoin were slight, cocaine and trimetazidine had little or no effect.     

Hemodialyzer clearances of gentamicin,kanamycin, tobramydn,amikacin, ethambutol. procainamide,and flucytosine,with a technique for planning therapy

Hemodialyzer clearance studies have been undertaken on the following drugs: gentamicin, kanamycin, tobramycin, amikacin, ethambutol, procainamide, and flucytosine. The following hemodialyzers were tested: Dow model 4, Kiil, Travenol UF II, and the Extracorporeal EX-03. The studies were predominantly undertaken in vitro,permitting direct comparison between drug clearances on the same dialyzer. Protein binding studies for gentamicin, kanamycin, procainamide, and ethambutol are also reported. Nomograms to facilitate the prediction of drug dosage regimens in dialysis patients are included.This work was supported in part by a grant from the General Clinical Research Centers Program (RR-133) of the Division of Research Resources, National Institutes of Health, and by a research contract (2-2219) from the Artificial Kidney-Chronic Uremia Program of the National Institute of Arthritis, Metabolism, and Digestive Diseases, National Institutes of Health.This paper was presented in part at the American Society of Nephrology meeting, 1974.     

Novel agents and strategies to treat herpes simplex virus infections

The quiet pandemic of herpes simplex virus (HSV) infection has plagued humanity since ancient times, causing mucocutaneous infection, such as herpes labialis and herpes genitalis. Disease symptoms often interfere with everyday activities and occasionally HSV infections are the cause of life-threatening or sight-impairing disease, especially in neonates and the immunocompromised patient population. After primary or initial infection the virus persists for life in a latent form in neurons of the host, periodically reactivating and often resulting in significant psychosocial distress for the patient. Currently, no cure is available. In the mid-1950s the first antiviral, idoxuridine, was developed for topical treatment of herpes disease and, in 1978, vidarabine was licensed for systemic use to treat HSV encephalitis. Acyclovir (Zovirax^®), a potent, specific and tolerable nucleosidic inhibitor of the herpes DNA polymerase, was a milestone in the development of antiviral drugs in the late 1970s. In the mid-1990s, when acyclovir became a generic drug, valacyclovir (Valtrex^®) and famciclovir (Famvir^®), prodrugs of the gold standard and penciclovir (Denavir^®, Vectavir^®), a close analogue, were launched. Though numerous approaches and strategies were tested and considerable effort was expended in the search of the next generation of an antiherpetic therapy, it proved difficult to outperform acyclovir. Notable in this regard was the award of a Nobel Prize in 1988 for the elucidation of mechanistic principles which resulted in the development of new drugs such as acyclovir. Vaccines, interleukins, interferons, therapeutic proteins, antibodies, immunomodulators and small-molecule drugs with specific or nonspecific modes of action lacked either efficacy or the required safety profile to replace the nucleosidic drugs acyclovir, valacyclovir, penciclovir and famciclovir as the first choice of treatment. Recently though, new inhibitors of the HSV helicase-primase with potent in vitro antiherpes activity, novel mechanisms of action, low resistance rates and superior efficacy against HSV in animal models have been discovered. This review summarises the current therapeutic options, discusses the potential of preclinical or investigational drugs and provides an up-to-date interpretation of the challenge to establish novel treatments for herpes simplex disease.