氧哌嗪青霉素钠的合成

本实验采用毒性小的氯甲酸三氯甲酯代替毒性较强的光气做为氯甲酰化试剂，摸索出以６－ＡＰＡ为卢始原料合成氧哌嗪青霉素的工艺路线。     

三嗪青霉素的合成研究

三嗪青霉素是对绿脓肝菌有优异抗苗活性的广谱半合成青霉素。本文采用水合氧代丙二酸酯代替氧代丙二酸酯,并将其与氨基硫脲缩合,再经环合水解和氧化制成三嗪酸的四步反应改进为“一勺烩”的连续操作法,提高收率27.3%。三嗪酸与羟氨苄青霉素的缩合反应用价廉的氯甲酸乙酯代替氯甲酸异丁酯,提高了收率。又采用三嗪酸的琥珀酰亚胺活性酯对羟氨苄青霉素进行的酰化反应也获成功。     

氧哌嗪青霉素体外抗菌活性及其胆汁浓度测定方法的研究

本文应用琼脂平板稀释法测定氧哌嗪青霉素对40株常见致病菌的最低抑菌浓度(MI-C),并应用AVANTAGE分析仪对胆道感染致病菌对氧哌嗪青霉素的敏感性进行测定。结果表明,氧哌嗪青霉素对G~ 球菌的MIC为0.5～32μg/ml,对G~-杆菌的MIC为<0.0625～64μg/ml,对胆道常见致病菌的敏感率为75～100%。同时应用AVANTAGE分析仪自动化比浊法探讨了氧哌嗪青霉素胆汁浓度的测定方法。以吸收度(y)对浓度(x)回归,得回归方程为y=0.1878-0.002776x,R=-0.9975。表明在标准浓度2.5～40μg/ml范围内,氧哌嗪青霉素胆汁浓度与吸收度具有良好的线性关系。在三个浓度水平上回收率分别为98.4%、101.3%和105.0%。管间变异<5.7%、日内变异<5.6%、日间变异<6.2%,表明该测定方法较为精确,可以接受并进一步用于临床研究。     

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%.     

氧哌嗪青霉素给药方案讨论

本文根据药物代谢动力学原理，分析了氧哌嗪青霉素在体内的代谢规律，按药动学一室模型计算氧哌嗪青霉素在体内血药浓度，使血药浓度维持有效抗菌浓度，讨论其最佳给药方案，并根据病人维持滴注时间和输液量，控制静滴速度，以达到最佳治疗效果。     

皮试阴性氧哌嗪青霉素过敏1例

患者61岁,长期身体欠佳,近期患急性肾炎,遵医嘱,皮试青霉素(-)后,在家自行静滴氧哌嗪青霉素5g/d(氯化钠注射液500ml)40～60滴/min.当滴注不到70ml时,患者诉说皮肤发痒,家属忙而未作处置.     

氧哌嗪青霉素导致过敏性休克护理体会

氧哌嗪青霉素(piperacillin，哌拉西林)为半合成的氨脲苄类抗假单胞菌青霉素，是临床上常用抗生素之一。在我科以往的临床治疗工作中，青霉素并用氧哌嗪青霉素时发生过敏性休克的病例少见。2004年我科收治1例银屑病(点滴型)患，因输注青霉素无不良反应且同时输注氧哌嗪青霉素而致急性过敏性休克，经积极抢救成功。现报告如下。     

氧哌嗪青霉素致药物热1例

患者,男,67岁。因右上腹部胀痛3d,于1997年7月13日入院。住院后经B超检查确诊为急性胆囊炎、胆石症,给予氧哌嗪青霉素抗感染治疗。患者既往无青霉素类药物过敏史,做氧哌嗪青霉素皮试,结果阴性。遵医嘱予氧哌嗪青霉素3.0g,ⅳ,bid。用药第1次,几分钟后患者开始出现畏寒,继而寒战,体温上升。查体:体温39.5℃,血压15/9kPa,神清,全身皮肤粘膜未见皮疹及出血点,呼吸急促,口唇紫绀,四肢抖动,心率130次·min~(-1),律齐,两肺听诊正常,右上腹部压痛,肝脾未及。初起,怀疑寒战发热可能系胆道感染所致,未予重视,给予物理降温,半小时后寒战止,4h后体温恢复正常,患者一般情况     

氧哌嗪青霉素工艺条件的研究

氧哌嗪青霉素是广谱半合成β-内酰胺类抗生素,从它的临床应用来看,对革兰氏阴性菌抗菌作用强,明显优于氨苄青霉素和呋苄青霉素,对革兰氏阳性和阴性的需氧和厌氧菌有广泛的抗菌活性。氧哌嗪青霉素在体内吸收快,药效作用时间长,在体外具有与硫苯咪唑青霉素和苯咪唑青霉素相似的抗菌活性,并对耐药倾向显著的菌种有特强的抗菌作用。因此,氧哌嗪青霉素是一种有发展的新     

氧哌嗪青霉素钠同六种常用药物配伍的稳定性

本文报道用紫外分光光度法对氧哌嗪青霉素钠含量进行测定,在波长326nm 处有最大吸收.本法操作较简便、灵敏度高、重现性良好、结果可靠.并与常用6种药物配伍,结果表明除与10%GS Vitc 配伍24h,温度为37℃时含量下降10%以下外,其余各组配伍均稳定.     

Cyclisierende Carbonylierung von Glykolohydroximsäure-estern zu 3-Alkoxy-4H-1,5,2-dioxazin-6-onen

Cyclic Carbonylation of Glycolohydroximic Esters to 3-Alkoxy-4H-1,5,2-dioxazine-6-ones Reactions of the (E)-2-hydroxy carbohydroximic esters 3 with trichloromethyl chloroformate produce the 3-alkoxy-4H-1,5,2-dioxazine-6-ones 4 . Treatment of 4c with benzylamine gives compound 5 , and methanolysis of 4c affords the carbonate 7 .     

Acute nose-only inhalation exposure of rats to di- and triphosgene relative to phosgene

Groups of young adult Wistar rats were acutely exposed to trichloromethyl chloroformate (diphosgene) and bis(trichloromethyl) carbonate (triphosgene) vapor atmospheres using a directed-flow nose-only mode of exposure. The exposure duration used was 240 min. The median lethal concentration (LC50) of diphosgene and triphosgene was 13.9 and 41.5 mg/m3, respectively. Based on the molar exposure concentrations, the LC50s of phosgene (previously published), diphosgene, and triphosgene were 0.07, 0.07, and 0.14 mmol/m3, respectively. Although the principal toxic mode of action of the volatile diphosgene was similar to phosgene gas, the vapor phase of triphosgene appeared to be different to that of phosgene and diphosgene based on a more persistent occurrence of signs of respiratory distress and a biphasic onset of mortality. While all substances caused mortality within 1 day postexposure, triphosgene induced a second phase of mortality 11?14 days postexposure. The vapor saturation concentration of triphosgene at ambient temperature is ?100 times its LC50. In summary, triphosgene-induced lung injury patterns are different from that of phosgene and diphosgene. More research is needed to close the substantial data gaps of triphosgene.     

Acute nose-only inhalation exposure of rats to di- and triphosgene relative to phosgene

Groups of young adult Wistar rats were acutely exposed to trichloromethyl chloroformate (diphosgene) and bis(trichloromethyl) carbonate (triphosgene) vapor atmospheres using a directed-flow nose-only mode of exposure. The exposure duration used was 240?min. The median lethal concentration (LC₅₀) of diphosgene and triphosgene was 13.9 and 41.5?mg/m³, respectively. Based on the molar exposure concentrations, the LC₅₀s of phosgene (previously published), diphosgene, and triphosgene were 0.07, 0.07, and 0.14 mmol/m³, respectively. Although the principal toxic mode of action of the volatile diphosgene was similar to phosgene gas, the vapor phase of triphosgene appeared to be different to that of phosgene and diphosgene based on a more persistent occurrence of signs of respiratory distress and a biphasic onset of mortality. While all substances caused mortality within 1 day postexposure, triphosgene induced a second phase of mortality 11–14 days postexposure. The vapor saturation concentration of triphosgene at ambient temperature is ≈100 times its LC₅₀. In summary, triphosgene-induced lung injury patterns are different from that of phosgene and diphosgene. More research is needed to close the substantial data gaps of triphosgene.     

Formation and reversibility of S-linked conjugates of N-(1-methyl-3,3-diphenylpropyl)isocyanate, an in vivo metabolite of N-(1-methyl-3,3-diphenylpropyl)formamaide, in rats

The metabolic disposition of N-(1-methyl-3,3-diphenylpropyl) formamide was studied in rats. The water-soluble metabolites, N-acetyl-S-[N-(1-methyl-3,3-diphenylpropylcarbamoyl)]cysteine and S-[N-(1-methyl-3,3-diphenylpropylcarbamoyl)]glutathione, were identified in urine and bile, respectively, of rats doses with the secondary formamide. The structures of these metabolites were confirmed by comparison with synthetic standards and by using liquid chromatography mass spectrometry and fast atom bombardment mass spectrometry. Synthetic standards of these metabolites were obtained by reacting the N-(1-methyl-3,3-diphenylpropyl)isocyanate with glutathione or N-acetylcysteine in methanolic solutions. The isocyanate was obtained in high yield by reacting 1-methyl-3,3-diphenylpropylamine with trichloromethyl chloroformate. The S-linked conjugates released the isocyanate in mild alkali, but were stable under acidic conditions. The released isocyanate was characterized by comparison with the synthetic standard using GC/MS and HPLC. A mechanism is proposed for the base-catalyzed elimination of the isocyanate from the thiol conjugates.     

Studies on the disproportionation of mixed anhydrides of N-alkoxycarbonylamino acids

Mixed anhydrides from Z-valine and ethyl, isobutyl, isopropyl and isopropenyl chloroformate, and from N-tert-butoxycarbonyl- (Boc) and N-benzyloxycarbonyl- (Z) leucine and phenylalanine and Boc- and N-9-fluorenylmethoxycarbonyl-valine and ethyl chloroformate were purified and left in dichloromethane at 23°C. The symmetrical anhydride (SyAn) generated after 24 h was determined by normal phase high-performance chromatography. No SyAn was produced from the anhyrides of Z- and Boc-valine; SyAn was produced from the other anhydrides. Anhydrides examined without isolation generally produced more SyAn than the pure compounds. More SyAn was generated in dimethylformamide and tetrahydrofuran than in dichloromethane, or in the presence of an excess of N-methylmorpholine or triethylamine. The anhydride from isobutyl chloroformate was much more stable than the anhydride from ethyl chloroformate. It is suggested that disproportionation of pure mixed carboxylic acid – carbonic acid anhydrides occurs by a bimolecular mechanism.     

Antimalarial activity of 2-(substituted amino)-4,6-bis(trichloromethyl)-1,3,5-triazines and N-(chlorophenyl)-N'-[4-(substituted amino)-6-(trichloromethyl)-1,3,5-triazin-2-yl]guanidines

A series of 2-[[(dialkylamino)alkyl]amino]-4,6-bis(trichloromethyl)-1,3,5-triazines (III) and N-(4-chlorophenyl)-N'-[4-[[(dialkylamino)alkyl]amino]-6- (trichloromethyl)-1,3,5-triazin-2-yl]guanidines (IV) were prepared from 2,4,6-tris(trichloromethyl)-1,3,5-triazine and 2-chloro-4,6-bis(trichloromethyl)-1,3,5-triazine. Compounds of type III showed modest antimalarial activity while XIa with the camoquin side chain was more potent. Analogues of type IV broadly exhibited modest antimalarial activity.     

Covalent adduct formation and chloroform production after free radical attack on fatty acids by carbon tetrachloride reactive intermediates

The interactions of fatty acids and the trichloromethyl free radical generated anaerobically by the benzoyl peroxide model system were studied. Chloroform was produced due to the interaction of the trichloromethyl free radical with the unsaturated fatty acid ester methyl oleate, indicating the hydrogen in chloroform may result from abstraction from fatty acids. In addition, chloroform was detected in incubations containing the saturated fatty acid ester methyl stearate, indicating hydrogen abstraction is not limited to allylic hydrogens. Mass spectral analysis identified one adduct resulting from additional reactions to methyl oleate, and an adduct resulting initially from hydrogen abstraction on methyl stearate. These findings describe previously unreported reactions of the trichloromethyl free radical with saturated fatty acid, and inhibition of chloroform production by 3 free radical inhibitors.     

哌拉西林／他唑巴坦（邦达）治疗细菌性感染疗效观察

目的 :观察邦达治疗细菌性感染的临床疗效及安全性。方法 :以中、重度细菌性感染患者为试验对象 ,参照哌拉西林 (对照A组 ) ,特治星 (进口哌拉西林 他唑巴坦 ) (对照B组 )。将符合病例选择标准的 10 7例患者随机地分入试验组 ( 36例 ) ,对照A组( 36例 ) ,对照B组 ( 35例 ) ,并对其进行治疗、观察。结果 :各组临床有效率分别为 88 9%、6 3 9%和 91 4 % ,各种致病菌感染的临床有效率分别为 92 3%、5 7 6 % ,和 94 3% ;纸片法药敏试验高敏感率分别为 92 3%、6 2 6 %和 94 5 % ;细菌阴转率分别为 92 3% ,6 3 6 %和 94 3% ;细菌清除率分别为 87 2 %、5 4 5 %和 91 4 %。经统计学处理 ,试验组与对照A组各对应的参数间比较均有显著性差异 (P <0 0 2 5 ) ,与对照B组比较各对应的参数间均无显著性差异 (P >0 0 5 )。不良反应发生率分别为 5 5 6 %、8 33%和5 71% ,均无统计学显著性差异 (P >0 0 5 )。结论 :邦达的抗菌疗效明显优于哌拉西林 ;与同类进口药近似 ,临床疗效肯定而无差异但价格便宜 ;且不良反应少 ,安全性高 ,耐受性好 ,对于临床上常见的中、重度细菌性感染 ,尤其是产酶菌引起的感染 ,具有较高的临床应用价值和较好的应用前景     

哌拉西林/三唑巴坦对肺炎克雷伯菌和大肠埃希菌的体外敏感性

目的 评价哌拉西林/三唑巴坦对肺炎克雷伯菌和大肠埃希菌的体外敏感性。方法 收集肺炎克雷伯菌和大肠埃希菌426株,用Kirby-Bauer琼脂扩散法作药敏试验;用表型确认试验检测用广谱β-内酰胺酶(ESBLs)。结果 426株肺炎克雷伯菌和大肠埃希菌中,哌拉西林/三唑巴坦的敏感性为99.53％,与亚胺培南(100％)和头孢哌酮/舒巴坦(100％)相当,明显高于青霉素类抗生素哌拉西林(48.83％)和第二代头孢菌素头孢呋新(60.09％),也高于第三代头孢菌素头孢三嗪(62.91％)、头孢噻肟(64.79％)、头孢哌酮(65.73％)和头孢他啶(88.26％),略优于第四代头孢菌素头孢吡肟(94.37％)。142株(33.33％)菌株经表型确认试验证实为产ESBLs菌;哌拉西林/三唑巴坦对产ESBLs菌的体外敏感性为98.59％。结论 哌拉西林/三唑巴坦对肺炎克雷伯菌和大肠埃希菌的体外抗菌活性与亚胺培南和头孢吸酮/舒巴坦相当,高于第三、四代头孢菌素;哌拉西林/三唑巴坦可作为产ESBLs菌感染的治疗选择。