盐酸羟考酮氮氧化物的定位鉴别研究

目的 建立盐酸羟考酮及其制剂中主要杂质氮氧化物的鉴别溶液,解决国内缺少该杂质对照品的问题.方法 将盐酸羟考酮溶解,双氧水加热破坏的方法得到氮氧化物的鉴别溶液.结果与结论 经HPLC、UV和LC-MS/MS验证,该鉴别溶液中的羟考酮氮氧化物与对照品结构一致,为同一物质,可用于盐酸羟考酮及其制剂中主要杂质羟考酮氮氧化物的定位鉴别.     

吡喹酮有关杂质测定方法的探讨

对吡喹酮有关杂质的测定方法按中国药典１９９５年版与美国药典第２３版进行了比较。利用紫外分光光度法考察了两国药典中吡喹酮有关杂质限量范围产生差异的原因.     

吡喹酮的红外分光光度测定

吡喹酮为广谱抗寄生虫病药。其含量测定采用紫外分光光度法。由于该药中含有的某些杂质其紫外吸收与吡喹酮的吸收峰重叠,测得的吡喹酮含量有偏高的假像。为     

泊马度胺原料药杂质来源及其合成研究

目的研究泊马度胺原料药的杂质来源与合成方法,为产品质量控制提供依据和杂质对照品。方法通过对泊马度胺原料药生产过程和存储过程的分析推测可能产生的杂质;以3-硝基邻苯二甲酸酐、3-氨基-2,6-哌啶二酮盐酸盐、2-氨基戊二酸等为原料合成有关杂质;根据对泊马度胺的杂质谱分析及合成的主要杂质对照品,建立了泊马度胺原料药杂质检测的高效液相色谱法。结果与结论合成了泊马度胺的7个相关杂质,其中一个为新结构杂质。7个杂质对照品的结构经1H-NMR、MS谱确证;建立了专属性好、灵敏度高的泊马度胺杂质分析的HPLC法,为泊马度胺原料药制备过程中的杂质控制提供帮助。     

氯噻酮对照品中杂质的结构解析

采用离子阱-飞行时间串级质谱仪(LCMS-IT-TOF)定性分析氯噻酮对照品,并预测了其可能的裂解途径,检测到氯噻酮一个未知杂质,并推测了该杂质可能的结构式及裂解途径.     

盐酸博宁霉素研发中有机杂质峰的确认方法探讨

目的 探讨对1.2类新药盐酸博宁霉素研发过程中有关物质分析中杂质峰确认的最佳方法.方法 通过对各国药典中常用的5种杂质峰确认方法的比较,证明系统适用性对照品(混合杂质对照品)法具有明显的优势.通过对盐酸博宁霉素杂质谱的深入研究,建立了系统适用性对照品;该对照品含有盐酸博宁霉素化学半合成工艺和微生物发酵工艺涉及的全部工艺杂质,可用于对盐酸博宁霉素研发过程中有机杂质峰的确认.结果 采用系统适用性对照品结合参考图谱法能快速、准确的确认盐酸博宁霉素中的诸有机杂质.结论 在杂质谱研究的基础上,以系统适用性对照品为主,结合其他峰确认方法能准确确认新药中有机杂质.     

吡喹酮的高效液相色谱分析

吡喹酮是一广谱抗寄生虫药,原用紫外分光法测定含量,薄层色谱法控制杂质,但含量受有紫外吸收的杂质影响,有虚假的成分,且因吡喹酮吸收系数低(E_(1cm)~(1％)11.9),影响显著。本文采用以紫外分光光度计作为检测器的高效液相色谱法,用内标法测定其含量,回收率在99～101％,变异系数小于1.6％(n=4)。本法用峰面积归一化法控制杂质,一般样品含量大于97％,有3～5个杂质峰,各杂质峰面积之和小于3％,个别紫外法测定含量偏高的样品可出现约10个杂质峰,含量显著偏低。本法较原法准确、快速、简便。     

药物中杂质对照品的标定项目与纯度测定方法研究进展

药物中的杂质是否能被全面准确地控制,直接关系到药品的质量可控与安全性。《中国药典》多采用主成分自身对照法规定有关物质的限度,而国外药典中多用到杂质对照品进行检测,这也就要求杂质对照品符合一定的质量标准后方可使用。对照品的标定中常涉及的项目包括纯度测定、结构确证、含量测定等,考虑到杂质对照品的微量性,标定时选择合适的分析方法十分重要,如进行纯度测定可使用高效液相色谱法、差示扫描量热法等试样用量少的分析仪器。     

应用微生物试验法对吡喹酮致突变性的观察

用Ames氏微生物试验法观察了吡喹酮的致突变性。以组氨酸缺陷型鼠伤寒沙门氏菌TA_(100)及TA_(98)为菌株,吡喹酮浓度分别为50、100、250、500、1000μg/皿。平肌内回变菌落数超过自发回变菌落数2倍以上为阳性。结果吡喹酮各种浓度无论加或不加活化系统(肝匀浆微粒休S-9)均为阴性。阳性对照黄曲霉素回变菌落数超过自发回变菌落数2倍以上。     

甘露醇与吡喹酮和地塞米松联合治疗脑囊虫病34例

甘露醇与吡喹酮和地塞米松联合治疗脑囊虫病３４例（河南省郑州市１５３医院４５００６５）胡永兴，彭淑芳为防止因单纯服用吡喹酮后导致颅内高压和病情加重，我们对３４例不同类型的脑囊虫病分别采用甘露醇加吡喹酮（二联法），甘露醇加地塞米松加吡喹酮（三联法）治疗，...     

Effects of liquid and freeze-dried grapefruit juice on the pharmacokinetics of praziquantel and its metabolite 4'-hydroxy praziquantel in beagle dogs.

Grapefruit juice changes the pharmacokinetic parameters of a variety of drugs metabolized primarily by cytochrome P450 3A. In a three-phase crossover study, six male beagle dogs were administered 100 ml of water (control), 100 ml of commercial liquid grapefruit juice, or 10 g of freeze-dried grapefruit juice (equivalent to 100 ml of liquid grapefruit juice) with 100 ml of water, followed after 2 h by single oral dose of praziquantel (30 mg kg(-1)). After treatment, the dogs were sampled at different times. Determination of praziquantel and its metabolite 4'-hydroxy praziquantel (identified by GC/MS) was performed by HPLC. Liquid and freeze-dried grapefruit juice preadministration increased the C(max) of praziquantel about three-fold and the AUC 2.5- and 2.3-fold, respectively. The T(max) (0.75 h) was unaffected by liquid or freeze-dried grapefruit juice, while T(1/2) was 2.3- and 1.7-fold higher compared with controls. The amount of 4'-hydroxy praziquantel was also affected by both liquid and freeze-dried grapefruit juice administration: the AUC and C(max) increased four- and three-fold, respectively and the T(max) was significantly enhanced. These findings demonstrate that both freeze-dried grapefruit juice and commercial liquid grapefruit juice significantly increase plasma concentrations and T(1/2) of praziquantel in dogs.     

Ultrastructural investigations on the effects of praziquantel on human trematodes from Asia: Clonorchis sinensis, Metagonimus yokogawai, Opisthorchis viverrini, Paragonimus westermani and Schistosoma japonicum

The effect of praziquantel (Biltricide) on the ultrastructure of trematodes pathogenic to man in Asia was investigated in: Clonorchis sinensis, Opisthorchis viverrini, Schistosoma japonicum, Metagonimus yokogawai, and Paragonimus westermani. The different parasites were isolated from their respective experimental hosts and uniformly incubated for 5, 15, 30 or 60 min at 37 degrees C in medium TC 199 containing 0, 1, 10 or 100 micrograms praziquantel/ml. All parasites exposed to praziquantel were contracted and displayed tegumental alterations. 1. Clonorchis sinensis, Opisthorchis viverrini and Schistosoma japonicum reacted with severe tegumental vacuolisation within 5 min after exposure to 1 microgram praziquantel/ml. The extent of the damage induced increased with exposure time. 2. In vivo treated Opisthorchis viverrini worms had the same damages as in vitro treated ones. 3. Metagonimus yokogawai displayed the same degree of vacuolisation after exposure to all concentrations of praziquantel. Complete destruction of the tegumental surface was not achieved, however, possibly because of the presence of numerous tegumental hooks. 4. Paragonimus westermani was least sensitive to praziquantel. Only very few vacuoles were formed after incubation in 100 micrograms/ml for 60 min. It is assumed that the very dense texture of the thick tegument is responsible for the relative refractoriness to praziquantel in vitro. However, in vivo the parasite is successfully eliminated by praziquantel.     

吡喹酮对神经肌肉接头传递的作用

吡喹酮可使电刺激腓总神经所引起的胫前肌收缩反应明显加强。如给腓总神经施加超强刺激,静脉注射筒箭毒碱可减弱肌肉收缩反应,吡喹酮却能加强筒箭毒碱的抑制作用,使神经肌肉传递迅即完全阻断。采用微电极细胞内记录技术研究吡喹酮对离体大鼠膈神经隔肌的作用,发现吡喹酮不明显影响膈肌细胞的静息膜电位。低浓度吡喹酮(2×10^-4M)可使微终板电位(mepp)频率明显增加。高浓度吡喹酮8×10^-4M则使mepp振幅逐渐变小和消失。吡喹酮在使神经肌肉传递阻滞不断加深的同时,尚能使终板电位的振幅变小,终致完全消失。     

Direct determination of praziquantel in pharmaceutical formulations and human plasma by cathodic adsorptive stripping differential-pulse voltammetry

The polarographic and cyclic voltammetric behaviour of praziquantel was studied in B.R. buffers of different pH values. Contradictory to that mentioned in a previously published work, praziquantel is an electro-active compound. Its polarogram exhibited a single 2-electron irreversible reduction wave in B.R. buffer of pH 5, the wave height decreased on the increase of pH till it disappeared in solution of pH >7. This wave was attributed to the reduction of the Cz.dbnd6;O double bond. The quantitative trace determination of bulk praziquantel was studied at a hanging mercury drop electrode by cathodic adsorptive stripping differential-pulse voltammetry. A fully validated sensitive procedure based on controlled adsorptive accumulation of the drug onto a HMDE was developed for its direct determination without derivatization. Accumulation of praziquantel was found to be optimized in 0.1 M Na(2)SO(4) solution as supporting electrolyte under the following conditions: accumulation potential, -1.2 V (vs. Ag/AgCl/KCl(s)); accumulation time, 30 s; scan rate, 10 mV/s and pulse height 100 mV. The proposed procedure was applied successfully for determination of praziquantel in its pharmaceutical formulations and human plasma. The mean recoveries of the drug were 98.85-99.42% and 99.12-100.47% with RSD of 0.49-0.95% and 0.45-0.52% in pharmaceutical formulations and human plasma, respectively. Limits of detection and quantitation of 1.14x10(-9) and 3.80x10(-9) M praziquantel, respectively, were achieved.     

吡喹酮对日本血吸虫雄虫的Ca2+,Mg2+,K+与Na+的含量及45Ca2+在虫体内分布的影响

日本血吸虫雄虫在4℃或37℃的HBS及无⁴⁵Ca²⁺的HBS中经吡喹酮1或30μg/ml作用0.5～2h后,未见虫的Ca²⁺,Mg²⁺含量有明显变化,但除4℃的HBS组外,余2组虫的K⁺含量明显减少,而虫的Na⁺含量的增加则不明显。在含30 mM Mg²⁺的HBS中,雄虫经吡喹酮作用1h后,虫的Mg²⁺含量明显增加。在37℃的HBS中,血吸虫雄虫经吡喹酮1μg/ml作用5～60min后,虫的皮层胞质中的⁴⁵²⁺含量的百分比较各相应对照组的明显减少,而虫体肌肉的则相反。在4℃的HBS或无⁴⁵Ca²⁺的HBS中,吡喹酮对⁴⁵²⁺在虫体内的分布无明显影响。     

吡喹酮对感染日本血吸虫小鼠与家兔的疗效和血药浓度的关系

本文报道小鼠与家兔感染日本血吸虫后不同时间用吡喹酮ig或im治疗,其疗效与周用血药浓度无密切的平行关系。在疗效相仿的剂量下,感染4wk鼠给药后的最高血药浓度达20.2μg/ml,而感染 4wk兔的血药浓度仅为0.05μg/ml。从感染兔的十二指肠注人吡喹酮时,则门静脉的血药浓度最高可达15～25μg/ml。结果显示感染宿主ig吡喹酮治疗时,门静脉的血药浓度可能在吡喹酮杀虫过程中具有重要意义。     

Structural characterization and enantioseparation of the chiral compound praziquantel

In this study, we aimed to characterize the chiral compound type of a leading antischistosomal drug, praziquantel. The optically pure praziquantel enantiomers were recovered from the racemic mixture by enantiomeric separation, which was performed on preparative scale chromatography by using a novel beta-cyclodextrin type chiral column. The thermodynamic properties of praziquantel were determined from differential scanning calorimetry and the physical properties were studied by examining Fourier transform infrared spectroscopy and X-ray powder diffraction. Based on the differential scanning calorimetry data, a melting point binary phase diagram was constructed. A ternary solubility phase diagram of praziquantel in methanol was also determined at the temperature of 0 degrees C. All the experimental results support the conclusion that praziquantel is a racemic compound. The characterization of physical properties of praziquantel and the phase diagram are crucial for understanding the rationality for the successful resolution of praziquantel and also provide the basis for designing the strategy of separation and recovery of pure enantiomer.     

Mediation of the schistosomicidal effect of praziquantel through nitric oxide

The effect of praziquantel (CAS 55268-74-1) on serum nitrate/nitrite level (a marker for nitric oxide (NO) synthesis) in S. mansoni infected mice was studied. The effects of the NO precursor (L-arginine) and NO-synthase inhibitor (NG-nitro-L-arginine methyl ester, L-NAME) on the effect of praziquantel on nitrate/nitrite level as well as on its antischistosomal activity were also evaluated. Praziquantel increased nitrate/nitrite level in serum of infected mice in a dose dependent manner. An oral dose of 75 mg/kg praziquantel produces a significant (p < 0.05) increase in serum nitrate/nitrite level by about 3.5 fold. Administration of L-arginine (200 mg/kg orally) induced a significant (p < 0.05) increase in nitrate/nitrite level (to about 5 fold) compared to praziquantel 75 mg/kg alone. Praziquantel-induced increase in nitrate/nitrite level was significantly reduced by administration of L-NAME 100 mg/kg. The antischistosomal activity of praziquantel was evaluated using two models: hepatic shift model and reduction of worm burden. In the hepatic shift model, praziquantel increased the percentage of worms in the liver (from 5% in control to 60%). Praziquantel-induced hepatic shift was not significantly affected by concurrent L-arginine or L-NAME administration. In the second model, praziquantel induced a significant decrease of the worm burden (p < 0.05) and the action of praziquantel was significantly increased by L-arginine and reduced by L-NAME administration. In conclusion, NO is possibly involved in the antibilharzial effect of praziquantel and administration of L-arginine with praziquantel produces beneficial antibilharzial effect.     

吡喹酮聚乳酸纳米粒制备工艺研究

目的探讨改良的自乳化溶剂扩散法制备吡喹酮聚乳酸纳米粒的最佳工艺。方法以包封率为指标，采用正交设计，考察聚乳酸和吡喹酮原料药药物的投料比、PVA浓度、有机相与水相体积比和搅拌速度等影响因素，筛选出比较理想的制备工艺。结果最佳工作条件为：聚乳酸与吡喹酮药物的投料比10：1，水相和有机相比为10：1，PVA浓度选择0．5％，搅拌速度600r·min^-1。所得纳米粒包封率为（46．74％±0．47％），收率为（49．30％±1．85％）。结论改良的自乳化溶剂扩散法可用于吡喹酮纳米粒的制备。