西部那非的合成工艺改进

以丁酰丁酮酸乙酯（2）为原料，经肼解环合，甲基化，水解，硝化，酰化，还原，酰胺化，氯磺化，环合制得西地那非，总收率为28%。改进了重要中间体4-氨基-1-甲基-3-正丙基吡唑-5-酰胺（6）的合成工艺。     

4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰胺基）嘧啶-5-羧酸甲酯的合成

目的 合成罗苏伐他汀的关键中间体4-（4-氟苯基）-6-异丙基-2-（N-甲基-N-甲磺酰胺基）嘧啶-5-羧酸甲酯。方法 以异丁酰乙酸甲酯为起始原料，经与对氟苯甲醛缩合、S-甲基异硫脲硫酸盐环合、高锰酸钾氧化，再经甲胺基、甲磺酰基取代全盛的目标化合物。结果 5步反应总收率为25.0%。结论 改进了合成路线，有助于罗苏伐他汀的合成。     

一锅法制备抗肿瘤药对甲苯磺酸索拉非尼

目的 研究分子靶向抗肿瘤药对甲苯磺酸索拉非尼（1）的简便合成工艺。方法 以3-三氟甲基-4-氯苯胺（2）为起始原料,首先在三光气的二氯甲烷或2-甲基四氢呋喃溶液中,在二异丙基乙基胺存在下,制得相应的异氰酸酯（2′）;然后在二异丙基乙基胺存在下,与4-(4-氨基苯氧基)-N-甲基-2-吡啶甲酰胺（3）成脲,一锅法合成索拉非尼（4）;最后与对甲苯磺酸成盐得到目标化合物。结果 以二氯甲烷为溶剂,使用安全易得的三光气,制得索拉非尼的收率为84%,目标物的收率为91%;以绿色溶剂2-甲基四氢呋喃替代二氯甲烷,制得索拉非尼的收率为85%,目标物的收率为96%。结论 该工艺路线操作简便,反应时间短,无需分离高反应活性的中间体,收率较高,绿色环保。     

抗肿瘤新药伊立替康的合成研究

本文报道了抗肿瘤新药伊立替康的合成工艺,以喜树碱为原料合成了关键中间体7-乙基-10-羟基喜树碱（5）,再以苄胺为原料经7步反应合成哌啶基哌啶甲酰氯（7）,最后将两部分连接,制得伊立替康,总收率为21.7%。     

瑞舒伐他汀钙的合成

目的合成瑞舒伐他汀钙（Rosuvastatin Calcium），并进行工艺优化。方法以4-（4-氟苯基）-6-异丙基-2-（N-甲基-N-甲磺酰基氨基）嘧啶-5-甲醛为起始原料，经缩合反应、去保护、还原、水解、成钙盐等反应，制得降血脂药瑞舒伐他汀钙。结果合成的目标化合物，总收率为32.2％。结论本工艺简单，成本较低，收率较高。     

1—（4—甲氧基）苯基—2—丙胺的合成

以对羟基苯乙酸为原料,采用了一条新路线合成了平喘药福莫特罗重要中间体1-（4-甲氧基）苯基-2-丙胺,反应总收率38%。方法操作简单、可行,适于实验室合成。     

盐酸美金刚胺的合成工艺改进

目的改进盐酸美金刚胺的合成工艺。方法以1,3-二甲基金刚烷为原料,在叔丁醇、乙腈、浓硫酸存在下,经Ritter反应生成1-乙酰胺基-3,5-二甲基金刚烷,再以聚乙二醇为溶剂,加入氢氧化钠水解得到美金刚胺,然后在异丙醇溶剂中盐酸化得到盐酸美金刚胺。总收率：70%。结果合成了具有良好化学纯度的盐酸美金刚胺（纯度99.9%,总收率70%）。结论改进的工艺明显提高了反应收率,工艺条件温和,合成步骤简洁,适合工业化生产。     

N-（三氘代甲氧羰基）-L-缬氨酸的合成*

N-（ 三氘代甲氧羰基)-L-缬氨酸（1）是氘代达卡他韦的关键中间体。以N-叔丁氧羰基-L-缬氨酸（3）为起始物料,4步合成目标产物（1）,总收率58%（以氘代甲醇计,收率26%）。以L-缬氨酸甲酯（5’）为起始物料,2步合成化合物（1）,总收率68%（以氘代甲醇计,收率30%）。该路线成本降低了约40%,同时大大降低了对环境的污染,适合工业化生产。     

1-（2m硝基-1-咪唑基）-2-O-四氢吡喃基-3-O-甲苯磺酰基丙二醇的合成

且的合成乏氧显像剂FMISO的前体1-（2-硝基-1-咪唑基）-2-O-四氢吡喃基-3-O-甲苯磺酰基丙二醇（NITTP）。方法以甘油为原料，通过酯化、羟基保护以及亲核取代反应合成目标化合物。结果与结论目标化合物的总收率为29％，结构经^1H-NMR、^13C-NMR、MS确证，本法生产成本低，收率较高。     

正交实验设计优化光敏剂紫红素-18的合成工艺

目的优化光敏剂紫红素-18（1）的合成工艺。方法以脱镁叶绿酸a（2）为原料,经空气氧化及碱开环制得化合物1;选择影响其合成产率的反应时间（A）、氢氧化钾溶液浓度（B）、反应溶剂（C）和化合物2与氢氧化钾的质量投料比（D）为考察因素,每个因素各取三个水平,采用L9（34）正交试验法优化目标物1的最佳合成工艺。结果合成目标物1的最优反应条件为B1C2A2D2,反应工艺收率从34.4%提高到45.6%。结论新工艺提高了收率、缩短了反应时间、消除了毒性溶剂,适合工业化生产     

Fundamental study on ceftizoxime suppositories in adults and children

The pharmacokinetics of newly developed ceftizoxime suppository (CZX-S) was studied in healthy volunteers and in children, compared with that of intramuscular CZX and intravenous CZX: In 8 volunteers (aged 19 to 24 years), each of 500 mg (potency) CZX-S containing 3%, 4% and 5% sodium caprate was compared with 500 mg intramuscular CZX and 500 mg intravenous CZX as a single administration in the cross-over method. In addition each of 500 mg CZX-S containing 4% and 5% sodium caprate was studied in 2 groups of 8 volunteers (aged 22 to 24 years) and of 8 volunteers (aged 19 to 27 years); each CZX-S was given 3 times a day successively for 5 days. The pharmacokinetics of 125 mg and 250 mg CZX-S, which contained 3% sodium caprate, were also evaluated as a single administration in 9 children (aged 6 years 4 months to 12 years 0 month) and in 11 children (aged 7 years 8 months to 12 years 4 months), respectively. The irritabilities of CZX-S were studied in all subjects who participated in this trial. The feeling of foreign body, the feeling of defecation, the burning sensation and the pain were evaluated in volunteers; the feeling of defecation and the pain were evaluated in children. The results were as follows: I. Pharmacokinetics in healthy volunteers 1. Given as a single administration The mean peak concentrations of serum CZX were occurred 30 minutes after 500 mg CZX-S containing 3%, 4% and 5% sodium caprate, which were 10.5 mcg/ml, 12.3 mcg/ml and 12.4 mcg/ml, respectively. These values were 1.35 mcg/ml, 1.60 mcg/ml and 1.69 mcg/ml at the conversion unit of 1 mg dose per 1 kg body weight. The mean peak serum CZX concentration of CZX-S containing 3% sodium caprate was slightly lower than that of CZX-S containing 4% or 5% sodium caprate, but was 1.9 times higher than that of the ABPC suppository. There was no marked difference among 3 preparations of CZX-S in mean Tmax and T1/2. Cmax of CZX-S containing 3% sodium caprate was 1.40 mcg/ml at the conversion unit of 1 mg/kg. AUC of CZX-S containing 3% sodium caprate was slightly smaller than that of CZX-S containing 4% or 5% sodium caprate, but 3.1 times that of the ABPC suppository in healthy volunteers. When 500 mg CZX was intramuscularly administered by one shot to 8 volunteers, Tmax was same as that of CZX-S or was slightly later.(ABSTRACT TRUNCATED AT 400 WORDS)     

Inhaled sodium metabisulphite induced bronchoconstriction: inhibition by nedocromil sodium and sodium cromoglycate.

1. The effects of nedocromil sodium and sodium cromoglycate on bronchoconstriction induced by inhaled sodium metabisulphite have been studied in eight atopic subjects, three of whom had mild asthma. 2. Nedocromil sodium (4 mg, 7.8 X 10(-6) M), sodium cromoglycate (10 mg, 24.1 X 10(-6) M) and matched placebo were administered by identical metered dose inhalers 30 min before a dose-response to sodium metabisulphite (5-100 mg ml-1) was performed. 3. Maximum fall in sGaw after placebo pre-treatment was -43.9 +/- 3.3% baseline (mean +/- s.e. mean). At the same metabisulphite concentration maximum fall in sGaw after sodium cromoglycate was -13.0 +/- 3.6% and after nedocromil sodium was +4.3 +/- 6.8%. Nedocromil sodium prevented any significant fall in sGaw even after higher concentrations of metabisulphite. 4. Both nedocromil sodium, 4 mg, and sodium cromoglycate, 10 mg, inhibited sodium metabisulphite induced bronchoconstriction but nedocromil sodium was significantly more effective. Relative in vivo potency of the two drugs is broadly in line with other in vivo and in vitro studies.     

Compatibility of ondansetron hydrochloride and methylprednisolone sodium succinate in multilayer polyolefin containers.

PURPOSE: The compatibility of ondansetron hydrochloride and methylprednisolone sodium succinate in 5% dextrose injection and 0.9% sodium chloride injection was studied. METHODS: Test solutions of ondansetron hydrochloride 0.16 mg/mL and methylprednisolone sodium succinate 2.4 mg/mL were prepared in triplicate and tested in duplicate. Total volumes of 4 and 2 mL of ondansetron hydrochloride solution and methylprednisolone sodium succinate solution, respectively, were added to 50-mL multilayer polyolefin bags containing 5% dextrose injection or 0.9% sodium chloride injection. Bags were stored for 24 hours at 20-25 degrees C and for 48 hours at 4-8 degrees C. Chemical compatibility was measured with high-performance liquid chromatography, and physical compatibility was determined visually. RESULTS: Ondansetron hydrochloride was stable for up to 24 hours at 20-25 degrees C and up to 48 hours at 4-8 degrees C. Methylprednisolone sodium succinate was stable for up to 48 hours at 4-8 degrees C. When stored at 20-25 degrees C, methylprednisolone sodium succinate was stable for up to 7 hours in 5% dextrose injection and up to 24 hours in 0.9% sodium chloride injection. Compatibility data for solutions containing ondansetron hydrochloride plus methylprednisolone sodium succinate revealed that each drug was stable for up to 24 hours at 20-25 degrees C and up to 48 hours at 4-8 degrees C. CONCLUSION: Ondansetron 0.16 mg/mL (as the hydrochloride) and methylprednisolone 2.4 mg/mL (as the sodium succinate) mixed in 50-mL multilayer polyolefin bags were stable in both 5% dextrose injection and 0.9% sodium chloride injection for up to 24 hours at 20-25 degrees C and up to 48 hours at 4-8 degrees C.     

Induction of DNA synthesis by sodium phenobarbital, uracil, and sodium saccharin in urinary bladder of the F344 rat

DNA synthesis in urothelial cells was determined 2, 4, 6, 10, and 16 weeks following dietary administration of promoters of bladder tumors to weanling male F344 rats. The experimental groups were fed AIN-76A diet or this diet containing 0.15% sodium phenobarbital, 3% uracil, 5% sodium saccharin, 2% sodium bicarbonate, or a combination of 5% sodium saccharin and 2% sodium bicarbonate. Two other groups were given Wayne rodent chow alone or in combination with 5% sodium saccharin. A group of rats given a drinking water containing 0.01% N-butyl-N-(4-hydroxybutyl)nitrosamine served as a positive control. With the exception of phenobarbital which increased the labeling index but did not induce hyperplasia, all other compounds increased the labeling index and induced hyperplasia. The combination of sodium saccharin and sodium bicarbonate was more effective than either compound alone in increasing the labeling index. Sodium saccharin was equally active when incorporated in either the AIN diet or the Wayne rodent chow. The present results suggest that a fundamental mechanism of bladder tumor promotion may be due to an increased DNA synthesis which leads to an increased turnover rate of urothelial cells rather than hyperplasia. However, since sodium saccharin is a promoter when incorporated into the Wayne diet but not into the AIN diet, the ability to stimulate DNA synthesis may be an important but insufficient condition for promotion by saccharin.     

放置时间对两种青霉素类抗菌药物微粒数的影响

目的 研究放置时间对我院静脉用药调配中心(简称PIVAS)配制的注射用哌拉西林钠/三唑巴坦钠和注射用美洛西林钠/舒巴坦钠稳定性及不溶性微粒数的影响。方法 跟踪并记录我院PIVAS 2018年6月18日-24日上午长期医嘱抗菌药物放置时间,通过整理和计算得到相关数据。取注射用哌拉西林钠/三唑巴坦钠和注射用美洛西林钠/舒巴坦钠按一定浓度配制后,分别检测于室温下放置0、1、2、3和4h的不溶性微粒数,探讨放置时间对我院PIVAS配制的两种抗菌药物不溶性微粒数的影响。结果 收集抗菌药物医嘱1917例,其中放置时间≤1h的医嘱占2.8%,放置时间1~2h的医嘱占71.1%,放置时间2~3h的医嘱占20.8%,放置时间3~4h的医嘱占3.7%,放置时间＞4h的占1.5%,最大放置时间5.3h。不溶性微粒数检测显示,两种复配后的抗菌药物配伍液中,粒径≥10μm的微粒数在放置时间达到1h时均有所降低,且具有统计学意义(P＜0.05)。随着放置时间增加,两种配伍液中粒径≥25μm和≥10μm微粒数仍呈减少趋势,但无统计学意义(P＞0.05)。≥25μm的微粒数在4h内无统计学差异(P＞0.05)。结论 注射用哌拉西林钠/三唑巴坦钠和注射用美洛西林钠/舒巴坦钠放置时间在4h内不会造成微粒数增加,反而放置1h后微粒数减少,该现象有利于降低静脉炎等不良反应发生的几率。     

注射用利福霉素钠含量测定及配伍稳定性若干指标考察

目的建立高效液相色谱法测定注射用利福霉素钠的含量方法,考察输液配伍稳定性的若干指标。方法采用高效液相色谱法,色谱柱为Agilent Extended C18（250 mm×4.6 mm）,流动相为甲醇-乙腈-0.075 mol·L-1磷酸二氢钾溶液-1.0 mol·L-1枸橼酸溶液（30∶30∶36∶4）,流速为1.0 ml·min-1,检测波长为227 nm。按说明书要求进行注射用利福霉素钠与5%葡萄糖注射液、0.9%氯化钠注射液的配伍稳定性研究。结果利福霉素钠含量在0.041 9～0.293 4 g·L-1的浓度范围内,本法的线性良好,线性回归方程为A=3.36×107 C-3.11×104（n=7,R=0.999 90）;平均回收率为100.46%。结论本法准确、灵敏、可靠;注射用利福霉素钠与5%葡萄糖注射液、0.9%氯化钠注射液配伍后,被观察的几项指标未见异常,建议在5 h内输液完毕。     

注射用加替沙星与头孢曲松钠配伍的稳定性考察

目的:考察注射用加替沙星与头孢曲松钠在5%葡萄糖注射液和0.9%氯化钠注射液中配伍的稳定性.方法:在室温(22 ℃),观察两药配伍后的外观、pH值变化,并用紫外分光光度法测定加替沙星和头孢曲松钠的含量.结果:两药配伍后,4 h内的含量、pH值及外观均无明显变化.结论:两药可配伍使用,但应在4 h内用完.     

注射用炎琥宁与头孢呋辛钠配伍的稳定性考察

目的:考察注射用炎琥宁与注射用头孢呋辛钠在0.9%氯化钠注射液中的配伍稳定性.方法:采用高效液相色谱法,测定注射用炎琥宁与注射用头孢呋辛钠配伍后在室温下8 h内的含量变化,并观察和检测配伍液的外观及pH值变化.结果:配伍液pH值无明显变化,颜色随时间变化逐渐加深,头孢呋辛钠相对百分含量在5 h后降至95%以下,4 h后降解产物峰面积占总峰面积百分比超过1%.结论:注射用炎琥宁与注射用头孢呋辛钠在0.9%氯化钠注射液可配伍使用,但应在4 h内用完.     

医院内获得性肺炎抗菌药物的疗效和安全性比较

目的:比较头孢唑肟钠/莫西沙星,头孢哌酮钠/舒巴坦钠和头孢唑肟钠治疗医院内获得性肺炎(HAP)的有效性和安全性.方法:203例HAP患者随机分为Ⅰ、Ⅱ、Ⅲ组.Ⅰ组患者给予盐酸莫西沙星注射液400 mg,qd;注射用头孢唑肟钠2~4 g,bid.Ⅱ组患者给予注射用头孢哌酮钠舒巴坦钠(2:1)1~2 g,bid.Ⅲ组患者给予注射用头孢唑肟钠2~4 g,bid.主要疗效指标是在治疗期结束后患者的临床症状,次要观察指标为不良反应和细菌学反应.结果:头孢唑肟钠/莫西沙星、头孢哌酮钠舒巴坦钠、头孢唑肟钠的临床有效率分别为91.9%、89.7%和78.7%.治疗结束后,头孢唑肟钠/莫西沙星和头孢哌酮钠舒巴坦钠对痰液细菌的清除率显著高于头孢唑肟钠.3组药物的不良反应无明显差异.与头孢唑肟钠单独用药相比,头孢菌素联合喹诺酮类或β-内酰胺酶抑制剂的抗菌疗效更佳.结论:头孢菌素联合喹诺酮类药物或β-内酰胺酶抑制剂可作为临床治疗HAP的优选用药方案.     

Effects of cadmium acetate and sodium selenite on mucociliary functions and adenosine triphosphate content in mouse trachea organ cultures

The effects of cadmium acetate and sodium selenite in mouse trachea organ culture have been studied separately and in combination. Ciliary activity, morphology, rate of total protein and glycoconjugate (i.e. glycoprotein and proteoglycan) synthesis/secretion and ATP content were investigated. Exposure to 10 microM cadmium acetate or 2000 microM sodium selenite resulted in a complete cessation of ciliary activity within 5 h. With cadmium acetate also a swelling of epithelial cells was observed. Sodium selenite (250-2000 microM) delayed by 2-3 h the inhibitory effect of cadmium acetate (5-20 microM) on ciliary activity. The rate of protein synthesis, as determined by incorporation of [3H]proline, was reduced by 13% and 44% at exposure for 4 h at 37 degrees C to 250 microM and 500 microM sodium selenite respectively, the effect being partly abolished by cadmium acetate. With 5 microM and 10 microM cadmium acetate the rate of glycoconjugate synthesis, as measured by incorporation of [3H]glucosamine, increased by 50% and 69%, respectively, after incubation for 4 h. This increase was partly reduced by sodium selenite. Neither cadmium acetate nor sodium selenite had any effect on the rate of total protein or glycoconjugate secretion. The ATP content in trachea rings was reduced by 48% and 54% after incubation for 4 h with 250 microM and 500 microM sodium selenite, respectively. No significant effect of cadmium acetate was found on ATP content. An antagonistic effect of sodium selenite and cadmium acetate in mouse trachea organ culture is suggested from the present experiments.