大鼠血浆中利培酮及9-羟基利培酮的LC-MS/MS法测定

建立了LC-MS/MS法测定大鼠血浆中的利培酮和9-羟基利培酮.用蛋白沉淀法处理血样,采用C_(18)色谱柱,以0.1%甲酸溶液-甲醇(40:60)为流动相,盐酸苯海拉明为内标,使用多反应监测,检测离子对分别为m/z 411.3→191.4(利培酮)、m/z 427.2→207.1(9-羟基利培酮)和m/z 256.2→167.3(苯海拉明).利培酮和9一羟基利培酮在0.5～1 000 ng/ml范围内线性关系良好,批内、批间RSD均小于5%,回收率为90%～110%.     

利培酮、奥氮平治疗老年性精神障碍效价比研究

目的:探究使用利培酮、奥氮平治疗老年性精神障碍的效价比.方法:从2015年3月~2016年1月,我院收治的老年性精神障碍患者中选取80例并随机分成两组,每组40例,一组给予利培酮治疗,为利培酮组,另一组给予奥氮平治疗,为奥氮平组.经过治疗,比较两组的临床疗效和成本、效果.结果:治疗结束后,利培酮组总有效率为92.5%,奥氮平组总有效率为95.0%,两组差异无统计学意义(P>0.05).经过治疗,两组效果都比治疗前好,但利培酮组不良反应发生率为47.35%,奥氮平组为23.27%.利培酮组药物治疗费用及平均成本/效果明显低于奥氮平组.结论:临床上治疗老年性精神障碍,利培酮和奥氮平均有疗效,奥氮平起较为迅速,不良反应相对较少,但是利培酮价格较低,更容易被广大消费者认可,更适合患者,值得临床推广.     

利培酮与氯氮平治疗精神分裂症比较

目的 :比较利培酮和氯氮平治疗精神分裂症的疗效和安全性。方法 :利培酮组 30例 (男性 12例 ,女性 18例 ,年龄 34a±s 10a ,BPRS评分 5 4分± 5分 )用利培酮 1～ 8mg/d ,po ,bid ;氯氮平组 30例 (男性 14例 ,女性 16例 ,年龄 33a± 11a ,BPRS评分 5 5分± 5分 )用氯氮平 5 0～ 40 0mg/d ,po ,bid ;均以BPRS ,TESS评定观察 8wk。结果 :利培酮组有效率为 83% ,氯氮平组为 80 % (P >0 .0 5 )。利培酮组对阴性症状起效较早 ,对兴奋躁动控制较差。利培酮组较多见副作用为锥体外系症状 ( 2 7% ) ,与氯氮平组 ( 3% )比较差异有显著意义 (P <0 .0 5 ) ,其他副作用较少而轻。结论 :利培酮与氯氮平疗效相似 ,适宜剂量 (≤ 4mg/d)的利培酮是一种安全有效的抗精神病药。     

LC-MS/MS法测定人血浆中利培酮及9-羟基利培酮的浓度

目的:建立同时测定人血浆中利培酮及9-羟基利培酮浓度的方法。方法:血浆样品经液-液萃取后,以AF2672为内标,采用液相色谱-串联质谱(LC-MS/MS)法测定。色谱柱为Xtimate~(TM) C_(18),流动相为乙腈-10 mmol/L乙酸铵溶液(含0.1%甲酸)(37∶63,V/V,pH=3.2),流速为0.25 mL/min,柱温为40℃,进样量为6μL。采用电喷雾电离源,以多反应离子监测进行正离子扫描,用于定量分析的离子对分别为m/z 411.26→191.02(利培酮)、m/z 427.21→206.91(9-羟基利培酮)、m/z 418.00→175.95(内标)。结果:利培酮、9-羟基利培酮血药浓度分别在0.2~50.0、1.0~200.0 ng/mL范围内线性关系良好(r分别为0.999 7、0.998 7);日内、日间RSD<15%,方法回收率分别为92.42%~104.81%、94.51%~100.57%,基质效应分别为98.33%~107.09%、91.05%~105.80%,提取回收率分别为78.11%~92.62%、76.32%~85.09%。采用该法测得78例精神分裂症患者体内利培酮和9-羟基利培酮的血药浓度分别为(13.58±8.31)、(25.62±15.52)ng/mL。结论:该方法操作简便、专属性强、灵敏度高,可用于口服利培酮患者的常规治疗药物监测和急性中毒分析。     

齐拉西酮片与利培酮治疗精神分裂症对照研究

目的 探讨国产齐拉西酮治疗精神分裂症的疗效及不良反应.方法 将60例精神分裂症患者随机分为齐拉西酮组(30例)和利培酮组(30例),进行临床对照试验.两组药物治疗剂量分别为80～160mg/d和3～6mg/d,疗程8周.疗效指标包括阳性和阴性症状量表(PANSS)及临床总体印象量表(CGI),不良反应指标为不良反应症状量表(TESS)及有关实验室检查.结果 治疗结束时,两组PANSS评分较入组时均显著减低(P＜0.01).PANSS总减分率:齐拉西酮组为(52.6±10.2)%,利培酮组为(71.8±11.6)%;临床总有效率:齐拉西酮组73.3%,利培酮组91.7%,两组间疗效有显著性差异(P＜0.05).齐拉西酮组和利培酮组的总体不良反应无明显差异,但不良反应表现存在异同.结论 国产齐拉西酮治疗精神分裂症是一种有效、安全药物,虽然疗效稍逊于利培酮,但不良反应与利培酮表现方面有不同,对患者选择用药及个体化治疗有指导作用.     

利培酮与氯氯平治疗精神分裂症的对照研究

目的比较利培酮、氯氮平治疗精神分裂症患者的疗效及不良反应.方法将精神分裂症患者41例随机分成2组,21例予利培酮4～6mg/d治疗,20例予氯氮平250～500mg/d治疗.结果2组治疗总有效率分别为73.3%,80%,无显著差异(P＞0.05),利培酮不良反应少(P＜0.05).结论两药对精神分裂症阳性、阴性症状均有效.利培酮不良反应少,安全性好.     

反相高效液相色谱法测定人血中利培酮及9—羟利培酮及其临床应用

目的测定人血中利培酮及其活性代谢物9-羟利培酮浓度,探讨其临床意义。方法采用HypersilODS-C18色谱柱(250mm×4.6mmID,粒度5mm),以甲醇水三乙胺(7326.50.5v/v,冰醋酸调pH=8)为流动相,流速1ml.min-1,在UV280nm处测定了16例口服利培酮精神病患者血中利培酮及其活性代谢物9-羟利培酮浓度。结果利培酮及9-羟利培酮在10~100mg.l-1范围内有良好线性关系(r=0.9950及r=0.9935)。方法回收率为98.3%~102.1%,日内及日间变异系数小于6.71%。在每日2~6mg剂量范围内,16例患者利培酮及9-羟利培酮血液浓度分别为10.9~38.8mg.l-1及11.59~49.7mg.l-1。结论测定方法简便、准确、专一性强,可用于临床治疗药物监测及人体内药代动力学研究。在每日2~5mg剂量范围内,利培酮及9-羟利培酮血浓度随服药剂量的增加而升高。     

利用群体药代动力学方法预测剂量调整对利培酮血药浓度的影响

目的利用群体药代动力学研究方法,寻求预测口服利培酮患者剂量调整后利培酮和9-羟基利培酮血药浓度的方法,实现个体化治疗。方法收集40例精神分裂症患者2个不同时间点时的血浆样品以测定利培酮和9-羟基利培酮血药浓度,应用已经建立的利培酮和9-羟基利培酮的非线性混和效应模型（NONMEM）,通过模型外推预测此后血药浓度数据,并与实测浓度进行比对,验证模型的可预测性。结果模型预测95%置信区间下利培酮预测误差为0.1（-16.47-16.89 nmol/L,相当于-6.8-6.9 ng/mL）,平均预测误差和平均绝对预测误差分别为-1.0和6.1 nmol/L,9-羟基利培酮的预测误差和平均预测误差分别为与1.8（-30.44-47.69nmol/L,相当于-13.0-20.3 ng/mL）,平均预测误差和平均绝对预测误差分别为1.2和14.6 nmol/L。若合并计算利培酮与9-羟基利培酮浓度,95%置信区间下利培酮＋9-羟基利培酮的平均预测误差为1.3（-43.87-56.48 nmol/L）,平均预测误差和平均绝对预测误差分别为0.2和19.0 nmol/L,模型预测的可靠度较高。结论研究结果显示,该方法通过测定利培酮和9-羟基利培酮的血药浓度,可实现患者给药剂量个体化。     

利培酮缓释片的体外释放度及其在家兔体内的药动学研究

目的:研究利培酮缓释片的体外释药行为及其在家兔体内的药动学。方法:以介孔二氧化硅为骨架制备利培酮缓释片。采用篮法考察市售利培酮片、利培酮缓释片及其物理混合物在0.1 mol/L盐酸中12 h内的体外释放度(Q_(12h)),并对利培酮缓释片释药模型进行拟合。以氯氮平为内标,采用高效液相色谱法测定家兔灌胃市售利培酮片和利培酮缓释片各2 mg后48 h内利培酮和9-羟基利培酮的血药浓度(n=6),并用Kinetica 4.4软件的非房室模型分析,计算药动学参数。结果:与市售利培酮片(Q_(12h)=97%)和物理混合物(Q_(12h)=95%)比较,利培酮缓释片的释放速率明显减慢(Q_(12h)=83.7%),利培酮缓释片在0.1 mol/L盐酸中的释放更接近于一级释放(R2=0.998 9),以扩散为主、溶蚀为辅。市售利培酮片和利培酮缓释片在家兔体内的药动学参数:以利培酮计t_(1/2)为(4.64±0.93)、(6.65±0.92)h,c_(max)为(34.46±7.75)、(8.57±6.91)ng/mL,MRT为(11.48±1.23)、(17.46±2.10)h,AUC_(0-48h)为(314.39±10.33)、(192.98±49.14)ng·h/mL;以9-羟基利培酮计t_(1/2)为(7.08±0.93)、(10.45±0.78)h,c_(max)为(98.08±5.43)、(54.55±4.88)ng/mL,MRT为(11.48±1.23)、(17.46±2.10)h,AUC_(0-48h)为(894.71±131.15)、(1 227.99±112.12)ng·h/mL(n=6)。与市售利培酮片比较,利培酮缓释片的t_(1/2)和MRT明显延长,c_(max)明显降低(P<0.05)。结论:利培酮经介孔二氧化硅负载后具有缓释作用,可延长药效发挥的时间。     

利培酮在健康人体的生物等效性

目的　评价单剂口服试验与参比制剂利培酮片的生物等效性。方法　用随机交叉试验设计,20名健康志愿者单剂口服利培酮试验与参比制剂6mg,RP-HPLC测定利培酮血浆浓度。结果　利培酮试验和参比制剂消除半衰期t1/2β为(4.28±0.46)和(4.36±0.41) h,达峰时间tmax为(0.94±0.14)和(0.98±0.11) h,达峰浓度Cmax 为(49.37±14.41)和(47.05±11.64) ng.mL-1,药-时曲线下面积AUC0-12为(239.26±56.28)和(239.59.83±53.49) ng.h.mL-1,AUC0-∞为(281.31±58.68)和(282.89±56.49) ng.h.mL-1。利培酮片相对生物利用度为(99.28±6.54)%。结论　试验与参比制剂利培酮片具有生物等效性。利培酮人体代谢有较大个体差异。     

D-对羟基苯甘氨酸生产过程的高效毛细管电泳法分析

建立了高效毛细管电泳法测定酶法反应体系中D-对羟基苯甘氨酸、DL-对羟基苯海因、N-氨甲酰基-D-对羟基苯甘氨酸的含量。采用未涂层石英毛细管柱，运行缓冲液为20mmol/L硼砂缓冲液（pH9．0），检测波长230nm。分离电压30kV，进样压力0．5psi，进样时间5s，采用苯酚为内标。三成分均在0．01％～0．1％范围内线性关系良好。     

毛细管电泳分析7-氨基头孢霉烷酸生产过程

建立了高效毛细管电泳分析法检测7-氨基头孢霉烷酸生产过程.采用未涂层石英毛细管柱,缓冲液为0.01mol/L磷酸盐缓冲液(pH 8.0),运行电压30kV,检测波长254nm.7-氨基头孢霉烷酸、头孢菌素C和戊二酰基-7-氨基头孢霉烷酸的线性范围(mg/ml)分别为0.05～3(r=0.998)、0.1～3.5 (r=0.992)和0.1～5 (r=0.996),迁移时间和峰面积的RSD分别为0.5%、1.0%、0.6%和2.2%、3.0%、2.4%.     

小柴胡颗粒中柴胡皂苷a和柴胡皂苷d的毛细管电泳法测定

建立了毛细管电泳法测定小柴胡颗粒中的柴胡皂苷a和柴胡皂苷d.以苯甲酸为内标,采用未涂层弹性融硅石英毛细管柱,以20 mmol/L Tris+20 mmol/L磺丁基-β-环糊精+25 mmol/L β-环糊精(pH 9.93)为运行缓冲液,分离电压12 kV,重力进样10 s(高度15 cm),检测波长210 nm.柴胡皂苷a和柴胡皂苷d在10～100和8～80 μg/ml浓度范围内线性关系良好.平均回收率为97.1％和98.1％,RSD为1.57％和1.98％.     

磺丁基醚-β-环糊精的高效毛细管电泳-间接UV法分析

建立了高效毛细管电泳-间接UV法测定药用辅料磺丁基醚-B-环糊精(SBE-β-CD).采用未涂层熔融石英毛细管柱,以30 mmol/L苯甲酸-三羟甲基氨基甲烷(Tris)(pH 7.5)为运行缓冲液,分离电压30 kV,检测波长214 nm.考察了缓冲液类型与pH、检测波长、电压、温度和样品浓度对测定的影响,并评价了不同批次的SBE-β-CD.     

Simultaneous determination of risperidone and 9-hydroxyrisperidone enantiomers in human blood plasma by liquid chromatography with electrochemical detection

Risperidone is a commonly prescribed antipsychotic drug. An enantioselective HPLC method with electrochemical detection was developed and validated for simultaneous determination of plasma concentrations of risperidone and its active metabolites, 9-hydroxyrisperidone enantiomers. Following solid phase extraction of 1.0 mL blood plasma, a baseline separation of the analytes was achieved on an AGP (α₁ acid glycoprotein) column using isocratic mobile phase consisting of methanol–phosphate buffer (pH 6.2; 0.1 M) (15:85, v/v). Total analysis run time was 11 min. For the detection of the analytes analytical cell potentials were set at 500, 650, 950, and 950 mV. The method linearity was attained in the range from 1.0 to 100 ng/mL for risperidone and both 9-hydroxyrisperidone enantiomers. The limit of detection was 0.5 ng/mL for all three analytes. The method was precise and accurate and was successfully applied in a clinical study investigating the stereoselectivity of risperidone 9-hydroxylation.     

An open study of risperidone liquid in the acute phase of schizophrenia

An open-label study was performed to investigate the clinical efficacy and mechanisms of risperidone liquid in ameliorating positive symptoms in the acute phase of schizophrenia. Eighty-eight patients (M/F: 50/38; age: 18-74 years;, mean +/- SD =32 +/- 16 years) meeting DSM-IV criteria for schizophrenia and treated with risperidone liquid (14 patients also used lorazepam) were evaluated with regard to their clinical improvement and extrapyramidal side effects using the positive and negative syndrome scale (PANSS) and the Simpson and Angus scale (SAS), while plasma concentrations of HVA and MHPG were analysed by HPLC-ECD before and 4 weeks after risperidone liquid administration. Patients showing a 50% or greater improvement in PANSS scores were defined as responders. An improvement in the PANSS scores related to excitement, hostility and poor impulse control was seen within 7 days after administration of risperidone liquid, and an improvement with regard to hallucinatory behaviour and uncooperativeness was seen within 14 days after its administration. Finally, 68% of patients were classified as responders 4 weeks after risperidone liquid administration. The scores of SAS were not changed after risperidone liquid administration. Pretreatment plasma homovanillic acid (HVA) levels in the responders (8.1 +/- 2.9 ng/ml) were higher than those in nonresponders (5.9 +/- 1.9 ng/ml). In addition, a negative correlation was seen between the changes in plasma HVA levels and the percentage of improvement in PANSS scores. On the other hand, there were no differences between pretreatment plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) levels and those of nonresponders. These results suggest that risperidone liquid is effective and well tolerated for the treatment of acute phase schizophrenic patients, and that efficacy is related to its affects on dopaminergic activity, not noradrenergic activity.     

Separation and determination of strychnine and brucine in Strychnos nux-vomica L. and its preparation by nonaqueous capillary electrophoresis

An easy, rapid method for simultaneous determination of strychnine and brucine in Strychnos nux-vomica L. and its preparation was developed by nonaqueous capillary electrophoresis (NACE) without pretreatment for the first time. Optimum separation was achieved with a fused-silica capillary column (50 cmx75 microm i.d.) and a running buffer containing 30 mM ammonium acetate, 1.0% acetic acid and 15% acetonitrile (ACN) in methanol medium. The applied voltage was 30.0 kV. The analytes were detected by UV at 214 nm. The effects of concentration of ammonium acetate, acetic acid and organic modifier on electrophoretic behavior of the analytes were studied. The established method with sophoridine as internal standard was linear in the range of 5-1000 mg/mL for both strychnine and brucine. The extracts of Strychnos nux-vomica and its preparation could be directly injected for determination with recoveries ranging from 94.5 to 104%.     

Sucrose acetate isobutyrate as an in situ forming system for sustained risperidone release

The objective of this study was to develop sustained-release sucrose acetate isobutyrate (SAIB) in situ formulations of risperidone for parenteral delivery. The formulations contained SAIB, solvent (anhydrous ethanol, ethyl lactate, or N-methyl-2-pyrrolidone), and additives such as polylactic acid (PLA). In vitro release profiles of risperidone from the SAIB formulations, which followed the Higuchii square root law, were obtained. An increase in SAIB content from 75% to 85% resulted in a reduction in the initial burst and the rate of risperidone release. The initial drug release could be increased by reducing the pH of the release medium and the release rate could be increased by an increase in drug loading. The burst release fell significantly from 20.0% to 3.5% following the inclusion of 10% (w/w) PLA in the formulations. In the case of this high viscosity depot system containing SAIB, anhydrous ethanol, PLA, and 25 mg/g risperidone, the in vivo biocompatible test results obtained support the use of SAIB as an injectable risperidone sustained-release formulation.     

Enantioseparation of vesamicol in human serum by capillary electrophoresis with solid phase extraction and sulfated-beta-cyclodextrin

An enantioseparation of racemic vesamicol in human serum by capillary electrophoresis with solid phase extraction and sulfated B-cyclodextrin (S-B-CD) is presented The separation was achieved on an uncoated 72 cm x 50 microm id fused silica capillary maintained at 30 degrees C and + 15 kV applied voltage using a run buffer of 128 micro-B-CD in 50 mM phosphate buffer at pH 5. The detection wavelength was 260 nm. Bond Elut C18 solid phase extraction cartridges were used in the sample preparation of the vesamicol samples from serum. Among the CDs studied, the migration order of the enantiomers was reversed in CM-B-CD compared to S-B-CD. Increases in migration time and differences in time between enantiomers was observed with increasing concentrations of S-B-CD. Baseline separation was achieved in the 2-20 microg/ml range of enantiomer concentration (r > .996). A sample stacking technique was used to improve peak shape and LOD. LODs were 0.5 microg/ml for each enantiomer. Studies of various factors and CE conditions showed the effect of CD type, CD concentration, buffer type, buffer concentration and pH on stability and resolution.     

Quantitative determination of alginic acid in pharmaceutical formulations using capillary electrophoresis

A capillary electrophoresis (CE) method has been developed and validated for the quantitative determination of alginic acid, which is used as a rafting agent in complex antacid formulations. The method involves a preliminary separation of the alginic acid from the formulation by washing the sample matrix with methanol, diluted HCl and water. This is followed by electrophoresis within a fused silica capillary using borate/boric acid buffer as the electrolyte, and the quantification is performed by a UV detector monitoring at 200 nm, where the intrinsic absorption of alginic acid is measured. An assay precision of better than 3% was achieved in intra- and interday determinations. No interference was found from the matrix of the antacid formulations.