阿糖腺苷毫微囊的化学稳定性研究

本文应用反相HPLC建立了阿糖腺苷毫微囊(Ara-A-NC)混悬型注射剂中Ara-A的含量测定方法,并以此法研究了Ara-A-NC的化学稳定性。结果表明,Ara-A-NC注射剂中Ara-A受热作用,按一级动力学降解,降解反应的活化能为46.49kJ/mol,初步预测Ara-A-NC有效期为10.47个月(25℃).     

阿糖腺苷毫微囊的研究

以α-氰基丙烯酸正丁酯(BCA)为囊材采用均匀设计方案,筛选了阿糖腺苷毫微囊(Ara-A-Nc)的制备工艺,制品稳定性较好。Ara-A-NC 荷负电,加入电解质后荷正电,包封率为43.6%。药理结果表明,脑内 HSV-Ⅰ型病毒感染的小鼠,ip Ara-A-NC 50～100mg/kg,与 Ara-A 溶液对照组比较,更能延长存活时间。     

阿糖腺苷2′,5′-环磷酸酯和阿糖腺苷5′-亚磷酸酯的合成

为提高抗病毒药阿糖腺苷(Ara-A)的水溶性,合成了阿糖腺甘2′,5′-环磷酸酯,阿糖腺苷5′亚磷酸酯以及相应的酰基衍生物。抗病毒筛选结果表明,阿糖腺苷2′,5′-环磷酸酯在1μg/ml 浓度时对Ⅰ型单纯疱疹病毒有明显抑制作用。     

阿糖腺苷眼膏的研制

本文介绍了抗病毒药阿糖腺苷眼膏的配制方法、质量控制、药理实验。表明阿糖腺苷眼膏可用于Ⅰ型单纯疱疹病毒性角膜炎的治疗。     

正交实验法优选注射用单磷酸阿糖腺苷的配伍条件

目的 考察多因素对注射用单磷酸阿糖腺苷与不同溶媒配伍后稳定性的影响。方法 选择温度、光照、放置时间、溶媒、溶媒用量5个影响因素,采用L₁₈(3⁵)正交试验表,以单磷酸阿糖腺苷含量、配伍液的pH值变化及不溶性微粒数为检测指标,采用高效液相色谱法测定配伍液中单磷酸阿糖腺苷的含量,pHs-2C型精密酸度计测定配伍前后pH值的变化,GWJ-4型智能微粒检测仪测定溶液中微粒数。结果 配伍液的外观、性状在考察时间内均无明显变化。温度、放置时间对配伍液中单磷酸阿糖腺苷的含量有显著性影响;光照对溶液中微粒的含量有显著性影响;溶媒及溶媒用量对所有考察指标均无显著性影响。结论 注射用单磷酸阿糖腺苷合理配伍条件为25 ℃、白炽灯光照下与100 mL 0.9%氯化钠注射配伍放置4 h。     

苦参素联合单磷酸阿糖腺苷治疗慢性乙型肝炎HBVDNA定量变化

目的为探讨慢性乙型病毒型肝炎的抗病毒治疗效果,本文将苦参素联合单磷酸阿糖腺苷（Ara-AMp）（治疗组）与单用（Ara-AMp）抗病毒治疗慢性乙型病毒性肝炎（对照组）HBVDNA定量变化对比观察。方法治疗组（50例）采用苦参素联合单磷酸阿糖腺苷抗病毒治疗,对照组（56例）采用单磷酸阿糖腺苷抗病毒治疗。两组治疗结果采用χ2检验。结果治疗组HBVDNA阴转率64.0%,HBeAg阴转率58.0%,对照组HBVDNA阴转率39.3%,HBeAg阴转率37.5%。结论苦参素联合单磷酸阿糖腺苷抗病毒治疗优于单用单磷酸阿糖腺苷抗病毒治疗。     

溶菌酶对聚酯毫微粒稳定性的影响

近２０年来，可生物降解的聚合物毫微球（毫微囊、毫微粒）作为静注、口服、眼部给药载体，已进行了广泛的研究。但有关该新型给药系统与体液中的蛋白、酶之间的相互作用以及在体液中的稳定性研究很少有报道。为此本研究选用在粘膜表面浓度较高且为泪液中主要蛋白成分的溶菌酶（ＬＺＭ），以评价聚己内酯（ＰＥＣＬ）毫微囊、毫微粒在ＬＺＭ中的稳定性，并由此设法阻止Ｉ－ＺＭ对聚酯毫微球的去稳定效应。采用表面聚合物沉降法和毫微粒沉淀法分别制备了ＰＥＣＬ毫微囊及毫微粒。毫微粒是由ＰＥＣＩ。聚合物单位缠结而成的基质型系统，而毫微…     

阿克拉霉素癌微囊的研究(英文)

研究工作阐述了毫微囊的制备及冻干条件，并进行了毫微囊的再分散性实验，测定了毫微囊的粒度分布和药物包封率。家兔静脉注射阿克拉霉素Ａ毫微囊后，血药浓度表明其符合二室开放模型，与阿克拉霉素Ａ注射液相比，阿克拉霉素Ａ毫微囊在家兔体内的消除半衰期较长，（前者ｔ１／２（β）＝１０．２５ｈ，Ａｕｃ＝８１．８８ｍｇ／Ｌ·ｈ；后者ｔ１／２（β）＝１７．０４ｈ，Ａｕｃ＝１０６．７４ｍｇ／Ｌ·ｈ），而且阿克拉霉素Ａ包于聚氰基丙烯酸正丁酯毫微囊后改变了其在大鼠体内的组织分布。结果表明：阿克拉霉素Ａ在肺、胸腺、脾和小肠中浓度较高，而在心、肾、肝和大肠中浓度较低。     

注射用单磷酸阿糖腺苷与小儿电解质补给注射液的配伍稳定性考察

目的:考察注射用单磷酸阿糖腺苷与小儿电解质补给注射液配伍后的稳定性。方法:采用高效液相色谱法,测定在5、25、35℃避光和光照条件下24 h内配伍液中单磷酸阿糖腺苷的含量变化,并考察配伍前后配伍液外观、pH值及不溶性微粒的变化。结果:注射用单磷酸阿糖腺苷与小儿电解质补给注射液配伍后,在避光条件下,24 h内配伍液的外观、pH值均无明显变化,不溶性微粒均符合《中国药典》(2010年版)规定,单磷酸阿糖腺苷百分含量在99%以上(相对于0 h);而在光照条件下,随着温度的升高,放置时间的延长,配伍液中单磷酸阿糖腺苷的含量有所下降,pH值及不溶性微粒则无变化。结论:注射用单磷酸阿糖腺苷与小儿电解质补给注射液配伍后,24h内于避光条件下可稳定共存,光照是影响其稳定性的主要因素。     

单磷酸阿糖腺苷在小儿电解质补给注射液中的稳定性考察

目的考察注射用单磷酸阿糖腺苷在小儿电解质补给注射液中的稳定性。方法采用高效液相色谱法,测定在5,25,35℃避光和光照条件下24 h内小儿电解质补给注射液中单磷酸阿糖腺苷的含量变化,并考察配伍前后配伍液外观、p H值及不溶性微粒的变化。结果注射用单磷酸阿糖腺苷与小儿电解质补给注射液配伍后,在避光条件下,24 h内配伍液的外观、p H值均无明显变化,不溶性微粒均符合中国药典2010年版规定,单磷酸阿糖腺苷百分含量>99%(相对于0 h);而在光照条件下,随着温度的升高,放置时间的延长,配伍液中单磷酸阿糖腺苷的含量有所下降,p H值及不溶性微粒则无变化。结论注射用单磷酸阿糖腺苷与小儿电解质补给注射液配伍,24 h内于避光条件下可稳定共存,而光照是影响其稳定性的主要因素。     

A new method for the measurement of nitrosoureas in plasma: an h.p.l.c. procedure for the measurement of fotemustine kinetics

1. An analytical method for a novel nitrosourea, fotemustine, has been developed using solid-phase extraction and h.p.l.c. with u.v. detection. As part of the development, different methods for stabilising fotemustine after sample collection have been investigated. The method has been successfully applied to pharmacokinetic studies in monkeys and man. 2. Providing plasma was separated immediately from blood and frozen within 3 min of collection, negligible degradation of fotemustine occurred. The samples could then be stored at -20 degrees C in the dark for up to six days particularly if thawing prior to analysis was accelerated using a 50 degrees C water-bath so that it was complete within 3 min. Equivalent results were also obtained with samples stabilised with 0.1 M citric acid immediately after the preparation of plasma. 3. The analytical method showed good precision with a within-day variation ranging between +/- 10.7% at the lowest concentration investigated (0.1 micrograms ml-1) to 2.0% at 50.0 micrograms ml-1. The accuracy of measurement was from 108.9% to 97.6% at 0.1 and 50.0 micrograms ml-1 respectively and the response was linear up to 50 micrograms ml-1. The minimum level of quantitation was 20 ng ml-1. 4. After a single intravenous bolus dose of [14C]fotemustine (100 mg m-2) to Cynomolgus monkeys, intact drug levels rapidly declined (t1/2 12.6 +/- 0.5 min) although the half-life of radioactivity (approx 100 h) was much longer. The plasma clearance of fotemustine was 225 +/- 63 ml min-1 with a volume of distribution based on area of 4.1 +/- 1.2 litres. 5. As with monkey, plasma levels of intact fotemustine in a patient given [14C]-drug as a 1 h constant rate intravenous infusion (approx. 100 mg m-2), declined rapidly but with a half-life of 23.2 min. Again, the half-life for total radioactivity was considerably longer (30.8 h). The plasma clearance was 1426 ml min-1 and the volume of distribution based on area was 47.71.     

Plasma concentrations and pharmacokinetics of midazolam during anaesthesia

Midazolam and 1-hydroxymidazolam plasma concentrations have been monitored and pharmacokinetic parameters of midazolam estimated during anaesthesia induced and maintained by its repeated injection according to two protocols (3 X 0.3 mg kg-1 at 45 min intervals or an induction dose of 0.3 mg kg-1 with maintenance doses of 0.15 mg kg-1 at 30 min intervals). Minimum plasma concentrations of midazolam measured just before each injection were 258.8 +/- 108.4 ng ml-1 for the first protocol and 353.1 +/- 55.2 ng ml-1 for the second protocol; maximum midazolam concentrations, measured 5 min after the last administration, were 1103.1 +/- 237.9 ng ml-1 and 743.0 +/- 103.2 ng ml-1, respectively, suggesting that a continuous infusion of midazolam after a loading dose should be better than repeated injections at keeping the concentration close to the sedative level of 400 ng ml-1. The estimated pharmacokinetic parameters were similar to those already published, except for the beta elimination half-life of midazolam (3.24 +/- 0.90 h for protocol 1 and 3.34 +/- 1.47 h for protocol 2) which was slightly longer than that reported for single dose studies. The comparison of plasma determinations, obtained either by gas-liquid chromatography or by a radioreceptor assay technique, clearly showed that 1-hydroxymidazolam, even after repeated midazolam administration, was not present at a concentration sufficient to affect the overall pharmacological activity of the parent drug.     

Sensitive method for the determination of phenytoin in plasma, and phenytoin and 5-(4-hydroxyphenyl)-5-phenylhydantoin in urine by high-performance liquid chromatography.

An isocratic high-performance liquid chromatographic method is described for the quantitative analysis of phenytoin (PHT) in plasma and both phenytoin and its main metabolite, 5-(4-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) in urine. Following ethyl acetate (plasma) and Extrelut-1 (urine) extraction, samples are analysed by means of a reversed-phase column (Nova-Pak C18), using a mobile phase consisting of methanol-water-tetrahydrofuran (40:60:4, v/v/v) with UV detection at 230 nm. The chromatography is complete in 10 min and the results show good precision (RSD 1.23-4.49%) and sensitivity for a linear range of 0.4-4.0 micrograms ml-1 for PHT in plasma, 0.1-1.0 microgram ml-1 for PHT in urine and 0.1-1.2 microgram ml-1 for p-HPPH in urine. The results indicate the method to be suitable for pharmacokinetic studies.     

Bioavailability of indomethacin after intramuscular injection and rectal administration of solution and suppositories

The pharmacokinetics of indomethacin was studied after intravenous and intramuscular injection of 50 mg and administration of rectal solution and suppositories of 100 mg to 8 volunteers. Peak plasma concentrations of indomethacin occurred 20 min. after administration of the rectal solution (3.7 micrograms X ml-1), 40 min. after intramuscular injection (2.7 micrograms X ml-1), and 60 min. after suppositories (3.7 micrograms X ml-1). The bioavailability after the two rectal forms was found to be almost the same, about 80%. After intramuscular injection the bioavailability was calculated to be complete. These results suggest that indomethacin administered as a rectal solution or as intramuscular injection may be an alternative to intravenous administration when an early plasma peak of the drug is required.     

血浆中葛根素的高效液相色谱测定法及其在狗体内的药代动力学

为阐明葛根素的代谢规律,建立了血浆中葛根素的高效液相色谱荧光检测法。用YWG-C₁₆为固定相,甲醇—水—0.1mol·L^-1磷酸缓冲液(pH7.4)(450∶522.5∶27.5)为流动相,大豆甙元作内标,以峰高比计算含量。葛根素的平均回收率为95.3%,RSD为4.8%;最低检测量为0.04ng,相当于10ng·mL^-1血浆。方法灵敏、特异、简便、快速。狗静注2.25mg·kg^-1葛根素的血药浓度—时间曲线符合开放二室模型,T_1/2α及T_1/2β分别为6.0及57.4min。     

Effect of the hour of administration on the pharmacokinetics of lidocaine in the rat

The aim of the present study was to investigate an eventual influence of the hour of administration on lidocaine kinetics in the rat. 280 Wistar AF-SPF adult male rats were used for this study and maintained under controlled environmental conditions (LD: 06.00-18.00) during the month of October. A single 50 mg X kg-1 dose of lidocaine was given by intramuscular route, at four different fixed time points of a 24 hour period (i.e.: 10.00, 16.00, 22.00 and 04.00) to 70 rats. Blood samples were taken at the following time points: 5, 15, 30 min., 1, 2, 4 and 6 hours after the drug administration. Lidocaine plasma levels (free and bound) were determinated according to a specific gas chromatographic method. The data showed circadian variations of pharmacokinetic parameters:--Elimination half-life: max. 2.12 +/- 0.05 h at 10.00, min. 1.50 +/- 0.03 h at 16. --Initial concentration: max. 5.05 +/- 0.65 micrograms X ml-1 at 16.00; min. 2.97 +/- 0.29 micrograms X ml-1 at 04.00.--Elimination constant rate: max. 0.4618 +/- 0.0094 h-1 at 16.00, min 0.3279 +/- 0.0079 h-1 at 10.00.--Area under curve (experimental): max. 11.11 +/- 1.07 micrograms X kg-1 X h-1 at 16.00, min. 7.45 +/- 0.84 micrograms X kg-1 X h-1 at 04.00.--Apparent volume of distribution: max. 16.67 +/- 1,67 L X kg-1 at 04.00, min. 9.75 +/- 1.04 L X kg-1 at 16.00. The lidocaine-free fraction varied with time and the protein binding of lidocaine showed a circadian variation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Application of a modified colorimetric enzyme assay to monitor plasma paracetamol levels following single oral doses to non-patient volunteers

A modified enzyme-based colorimetric method has been used to determine plasma paracetamol profiles following single dose (2 x 500 mg) administration of three dosage forms to non-patient volunteers. The assay is linear over the concentration range 0.15-60 micrograms ml-1 with a coefficient of variation of 9.1% at the 1.5 micrograms ml-1 level. It is rapid, requiring small sample volumes; compares favourably with other techniques such as HPLC; and is not subject to interference from paracetamol metabolites and other drugs. Administration of paracetamol as two different dosage forms, as a solid tablet and as a dispersible tablet, resulted in no statistically significant difference in pharmacokinetic parameters between treatments.     

The pharmacokinetics of mecillinam and pivmecillinam in pregnant and non-pregnant women.

1. The pharmacokinetics of parenteral mecillinam (n = 27) and oral pivmecillinam (n = 12) were studied in pregnant (n = 27) and non-pregnant (n = 12) subjects. 2. In early pregnancy (9-14 weeks of gestation) the mean peak plasma drug concentration (Cmax = 19 +/- 9 micrograms ml-1) after an intravenous injection of 200 mg mecillinam was significantly lower (P less than 0.05) and the volume of distribution (V = 49 +/- 20.1) significantly larger (P less than 0.05) than in non-pregnant subjects (Cmax = 35 +/- 18 micrograms ml-1, V = 29 +/- 12.1). In late pregnancy (39-40 weeks of gestation) the plasma mean peak concentration (Cmax = (29 +/- 14 micrograms ml-1) after parenteral administration of 200 mg mecillinam was slightly lower and the volume of distribution (V = 65 +/- 29.1, V = 0.9 +/- 0.4 l kg-1) significantly larger than that in non-pregnant subjects (V = 0.4 +/- 0.3 l kg-1). Also after oral administration of 200 mg pivmecillinam, equimolar to 136.5 mg mecillinam, the mean peak plasma concentration in pregnant subjects (Cmax = 1.8 +/- 1.2 micrograms ml-1) was slightly lower than that in non-pregnant subjects (Cmax = 1.7 +/- 1.2 micrograms ml-1). 3. The mean half-life of elimination after parenteral administration of mecillinam was significantly longer during both early (t1/2,Z = 133 +/- 38 min, P less than 0.05) and late pregnancy (t1/2,Z = 107 +/- 41 min, P less than 0.05) as compared with the non-pregnant state (t1/2,Z = 75 +/- 21 min).(ABSTRACT TRUNCATED AT 250 WORDS)     

Determination of benzylpenicillin in plasma and lymph at the ng ml-1 level by reversed-phase liquid chromatography in combination with digital subtraction chromatography technique

A method for the determination of benzylpenicillin (Pc-G) at very low levels in plasma and lymph is described. Detection at 325 nm of the mercuric mercaptide of benzylpenicillinic acid was made by liquid chromatography via a pre-column derivatization method. By using a digital subtraction chromatography technique, the bioanalytical method could be applied to different kinds of samples whether interfering peaks were present or not. Two different clean-up steps were used for two concentration ranges 0.1-100 micrograms and 1-1000 ng Pc-G ml-1; namely, precipitation of a 100-microliters sample with acetonitrile, or precipitation of a 1- or 2-ml sample followed by concentration via liquid-liquid extraction. The pre-column derivative of Pc-G was achieved using mercury(II)chloride in the presence of imidazole. The blank samples required for the digital subtraction chromatography technique were obtained by penicillinase treatment. Standard curves were made in the two concentration ranges. The relative standard deviation (RSD) at 5 ng Pc-G ml-1 plasma was 4.9% and at 5 micrograms Pc-G ml-1 lymph it was 2.8%. The stability of Pc-G, including the problems with non-sterile samples, was studied.