癃清片对慢性盆腔炎大鼠子宫阴道炎症及其相关因子变化研究

目的 通过建立苯酚胶浆所致的慢性盆腔炎大鼠模型,对癃清片治疗妇科炎症的作用特点和机制进行探讨。方法 将雌性SD大鼠子宫内注射苯酚胶浆造成大鼠慢性盆腔炎模型,造模7 d后分组,随机分为6组：空白对照组、模型对照组及癃清片高、中、低剂量（9.355 2、4.677 6、2.338 8 g生药/kg）组和千金片组,给药14 d。测定各组大鼠子宫肿胀率及肿胀抑制率、对各组动物子宫、阴道组织进行HE病理学观察以评价炎症反应程度。通过细胞凋亡TUNEL染色观察子宫内膜细胞凋亡程度,并采用免疫组化染色检测肿瘤坏死因子α（TNF-α）、白介素4（IL-4）和细胞黏附因子（ICAM-1）的表达。结果 与空白对照组相比,模型对照组子宫肿胀明显;与模型对照组相比,癃清片各剂量组治疗后子宫肿胀率均有所降低,尤以癃清片中剂量组为佳。与空白对照组相比,模型对照组子宫可见明显扩张,内膜充血明显,水肿程度严重,而给药各组中充血水肿现象少见。在炎性浸润方面,模型对照组阴道可见上皮细胞增生,表层出现黏液层,以中性粒细胞为主的炎细胞浸润,给药各组中炎细胞浸润程度较模型组轻。与空白对照组相比,模型对照组子宫细胞凋亡程度明显增加,癃清片能够明显改善子宫内膜细胞的凋亡程度。与空白对照组相比,TNF-α、IL-4及ICAM-1（CD54）蛋白表达均在胞浆及胞核,呈棕黄色,正常对照组大鼠子宫腺体及炎细胞可见弱阳性表达,模型组大鼠子宫腺体及炎细胞可见强阳性表达,其余各组表达均较模型组有不同程度减弱。结论 癃清片通过下调模型大鼠子宫组织中TNF-α、IL-4的表达水平,从而抑制子宫组织中ICAM-1的表达,防止和缓解子宫组织的黏连,达到治疗慢性盆腔炎的作用。     

盆炎坤和汤对苯酚胶浆致慢性盆腔炎大鼠模型的影响

目的 观察盆炎坤和汤对苯酚胶浆致慢性盆腔炎大鼠模型的影响。方法 雌性SD大鼠,子宫内注射苯酚胶浆造成大鼠慢性盆腔炎模型,造模2周后分组,并灌胃给予盆炎坤和汤高、中、低3个剂量（66g/kg、33g/kg、16.5g/kg）,连续14天,观察大鼠体重、子宫脏体比、子宫内膜的病理组织学改变,检测血清中SOD、MDA的含量。结果 造模后大鼠体重明显降低,子宫脏体比明显增加,血清SOD水平显著下降,MDA含量明显升高,盆炎坤和汤各剂量用药后对上述指标改变均有程度不同的对抗作用,病理检查结果也表明盆炎坤和汤各剂量对子宫内膜炎症程度有一定的改善作用。结论 盆炎坤和汤对苯酚胶浆致慢性盆腔炎大鼠模型有一定的治疗作用。     

宁泌泰胶囊对大鼠大肠杆菌感染性盆腔炎的改善作用研究

目的 探究宁泌泰胶囊对盆腔炎病症的改善作用。方法 选用大鼠大肠杆菌感染性盆腔炎模型,苯酚胶浆引起大鼠化学性盆腔炎模型,用妇科千金片(1.0 g/kg)及宁泌泰胶囊高、中、低剂量(2.0、1.0、0.5 g/kg)连续ig 7 d,每天2 次。以动物体质量变化、白细胞计数、病理学检查评价宁泌泰胶囊对盆腔炎的治疗作用。结果 宁泌泰胶囊3 个剂量组对大肠杆菌引起的感染性盆腔炎大鼠子宫肉眼可见的炎性症状有一定的改善作用,可不同程度地抑制炎症引起的血中白细胞的数量升高,并且能改善炎症引起的体质量下降。宁泌泰胶囊高、中(2.0、1.0 g/kg)剂量组可显著减轻子宫的质量,提示抑制炎症引起的肿胀。子宫组织病理学检查结果表明,宁泌泰胶囊可改善大肠杆菌感染引起的大鼠子宫组织学病变,且有一定的剂量相关性。对于苯酚胶浆引起的大鼠盆腔炎,宁泌泰胶囊3 个剂量组均能改善炎症引起的体质量下降。宁泌泰胶囊高剂量组(2.0g/kg)可显著抑制炎症引起的血中白细胞的数量升高,并且可显著减轻子宫的质量,提示抑制炎症引起的肿胀。子宫组织病理学检查结果表明,宁泌泰胶囊可改善苯酚胶浆引起的大鼠子宫组织学病变,且有一定的剂量相关性。结论 宁泌泰胶囊对于化学性和细菌性等多种因素引起的盆腔炎动物模型的相关症状具有明显的改善作用。     

旱莲地茶颗粒对大鼠慢性细菌性盆腔组织炎性病理的影响

目的探讨旱莲地茶颗粒对大鼠慢性细菌性盆腔炎组织炎性病理的影响。方法雌性SD大鼠50只,子宫内注射混合细菌(0.2 mL)建立慢性细菌性盆腔炎大鼠模型。造模7 d后随机分为5组,即模型对照组,妇科千金片组(0.518 g·kg-1),旱莲地茶颗粒低(10.08 g生药·kg-1)、中(20.16 g生药·kg-1)、高(40.32 g生药·kg-1)剂量组。另取20只雌性大鼠,其中10只作为假手术组,除不注射混合细菌外,其他操作均与模型组相同,另外10只雌性大鼠不作处理,作为正常对照组。各组大鼠每周称重1次,按15 mL·kg-1灌胃给药,1次·d-1,连续治疗28 d,正常对照组、假手术组、模型对照组给予等体积蒸馏水灌胃。末次给药后次日,各组大鼠均腹腔注射10%水合氯醛300 mg·kg-1麻醉,取双侧子宫进行子宫脏器系数与病理分析。结果与正常组比较,模型对照组大鼠子宫脏器系数显著升高(P <0.01),大鼠子宫病理评分等级显著升高,子宫内膜等部位炎症细胞浸润、充血扩张的程度显著升高且子宫病变动物数显著增多(P <0.01)。与模型组比较,旱莲地茶颗粒高剂量组大鼠子宫脏器系数显著降低(P <0.01);旱莲地茶颗粒中剂量组大鼠子宫病理学评分等级显著下降,子宫内膜等部位炎症细胞浸润、充血扩张的程度显著降低,子宫病变动物数显著减少(P <0.05)。结论旱莲地茶颗粒能降低盆腔炎大鼠子宫脏器系数,改善盆腔炎大鼠盆腔组织炎性病理。     

肝性脑病大鼠肠道菌群变化的实验研究

目的 制备大鼠肝性脑病/轻微型肝性脑病模型,了解HE/MHE大鼠肠道菌群变化情况.方法 48只大鼠随机分为对照组和3个模型组,3个模型组分别以200,250,350mg/kg体质量/d剂量的TAA隔日行腹腔注射,共2次,建立不同剂量TAA致大鼠HE/MHE动物模型,1d后检测脑十听觉诱发电位和进行胃、空肠、回肠的细菌培养计数及结肠内双歧杆菌和大肠杆菌的培养计数.结果 3个HE/MHE模型组大鼠,胃、空肠、回肠细菌总数显著增多,与对照组比较,增至10～100倍不等(P<0.05),高中低TAA剂量组之间的菌落计数呈量效关系;3个模型组大鼠双歧杆菌数量显著下降而大肠杆菌数量明显增加(P<0.05).B/E比值均小于1.结论 大鼠HE/MHE模型肠道菌群大量上移和过度生长,肠道菌群比例严重失调,肠道定植抗力显著下降,这与HE/MHE发生发展密切相关.     

川芎嗪联合乙酰半胱氨酸对慢性应激大鼠外周促炎细胞因子和肠道微生态的影响

目的:考察川芎嗪联合乙酰半胱氨酸(NAC)对慢性应激大鼠外周促炎细胞因子和肠道微生态的影响。方法:将正常大鼠作为正常对照组,将慢性应激大鼠分为模型组、NAC组(60 mg/kg)和川芎嗪+NAC组(15 mg/kg+60 mg/kg),每组20只,ig相应药物15 d。记录各组大鼠一般检查情况,检测血清中白细胞介素6(IL)-6、IL-1β、肿瘤坏死因子α(TNF-α)、干扰素γ(INF-γ)水平,检测肠道菌群。结果:与正常对照组比较,模型组大鼠呈现慢性应激症状,血清中IL-6、IL-1β、TNF-α、INF-γ水平均增强;肠道中的大肠埃希菌和肠球菌增加,乳杆菌和双歧杆菌减少(P<0.05)。与模型组比较,NAC组和川芎嗪+NAC组大鼠慢性应激症状减轻,上述指标均改善(P<0.05),其中川芎嗪+NAC组效果优于NAC组(P<0.05)。结论:川芎嗪联合NAC可通过降低促炎细胞因子水平和改善肠道微生态来改善大鼠慢性应激状态。     

牛蒡根水提物对高血压大鼠血管内皮损伤的保护作用

目的探讨牛蒡根水提物对高血压大鼠血管内皮损伤的保护作用及机制。方法用N-硝基-L-精氨酸(L-NNA)复制高血压大鼠模型,随机分为正常对照组、模型对照组、阳性对照组(卡托普利15 mg/kg)、牛蒡根水提物低剂量组(0.5 g/kg)、牛蒡根水提物中剂量组(1.0 g/kg)及牛蒡根水提物高剂量组(2.0 g/kg),连续灌胃6周,测定大鼠用药后1、4、7、10、13、16、19、22、29、36、42 d的收缩压;6周后,检测大鼠血清C-反应蛋白(CRP)、白介素-6(IL-6)水平,取大鼠胸主动脉,测细胞间黏附分子-1(ICAM-1)水平。结果 (1)牛蒡根水提物组的大鼠尾动脉收缩压低于模型对照组(P<0.05)。(2)牛蒡根水提物可显著改善血管的内皮损伤程度,抑制内膜内皮细胞脱落及血细胞黏附,并抑制中膜平滑肌细胞、胶原纤维增殖等。(3)牛蒡根水提物组的血清IL-6、CRP炎症因子及血管内皮ICAM-1表达水平低于模型对照组(P<0.05)。结论牛蒡根水提物对高血压大鼠血管内皮损伤具有明显改善作用,其机制可能与其抑制炎症因子IL-6、CRP及ICAM-1的表达,改善高血压大鼠血管内皮慢性炎症反应有关。     

菝葜总黄酮对慢性盆腔炎大鼠的保护作用研究

目的 探讨菝葜总黄酮对慢性盆腔炎(CPID)模型大鼠的治疗作用。方法 建立CPID大鼠模型(苯酚胶浆化学烧伤法),将造模成功的SD大鼠按随机数字表法分为模型对照组、菝葜总黄酮高[32.4 g/(kg·d)]、中[16.2 g/(kg·d)]、低[8.1 g/(kg·d)]剂量组,金刚藤胶囊组,地塞米松组,各10只。假手术处理大鼠按随机数字表法分为假手术组与本底对照组,各10只。另外设立空白对照组(10只)不作任何处理。给药14 d后检测各组大鼠血液流变学及血常规指标;观察大鼠左右侧子宫的形态变化,计算子宫肿胀率及肿胀抑制率,苏木精-伊红(HE)染色及Masson染色观察大鼠子宫病理改变。采用酶联免疫吸附试验(ELISA)检测大鼠子宫组织炎症因子白细胞介素1β(IL-1β)、IL-4、IL-6和IL-10的表达。结果 与模型对照组及金刚藤胶囊组比较,菝葜总黄酮各剂量组均能显著降低CPID模型大鼠血液中白细胞、淋巴细胞、中性粒细胞数及各项血液流变学指标,降低大鼠子宫肿胀率,抑制大鼠子宫组织IL-1β及IL-6的表达,促进IL-4及IL-10的表达,并能显著减轻子宫充血、水肿症状,减少炎症细...     

青连宁心胶囊在缺血性心律失常模型大鼠体内的药效学与药动学研究

目的 研究青连宁心胶囊在缺血性心律失常大鼠体内的药效学与药动学.方法 将30只雄性SD大鼠随机分为空白对照组、模型对照组、青连宁心胶囊组(4.00 g/kg)、青蒿组(1.43 g/kg)和黄连组(0.42 g/kg),每组6只.各药物组大鼠分别连续灌胃相应药液,模型对照组和空白对照组大鼠灌胃生理盐水,每天1次,连续7...     

仙方活命饮加减方减轻脓毒症致大鼠肝损伤的机制研究

目的 从肠道菌群与代谢组学的角度探究仙方活命饮加减方防治脓毒症致肝损伤的作用机制。方法 采用体质量均衡分配法将60只SD大鼠分为空白组（生理盐水）、模型组（生理盐水）、阳性对照药组（地塞米松片，5.0 mg/kg）和仙方活命饮加减方高、中、低剂量组（以生药计分别为6.0、3.0、1.5 g/kg），每组10只。灌胃相应药物/生理盐水，灌胃体积均为10 mL/kg；每天给药1次，连续14 d。末次给药后，除空白组外，其余各组大鼠均腹腔注射脂多糖10 mg/kg建立脓毒症模型。造模12 h后，检测大鼠血清中炎症指标[白细胞介素1β(IL-1β)、IL-6、肿瘤坏死因子α(TNF-α)]和肝功能指标[总胆固醇（TC）、甘油三酯（TG）、天冬氨酸转氨酶（AST）、丙氨酸转氨酶（ALT）]水平；采用16S rRNA技术联合肝脏代谢组学分析大鼠肠道菌群及肝脏代谢产物的变化。结果 仙方活命饮加减方可显著改善脓毒症致肝损伤大鼠血清中炎症指标与肝功能指标（P<0.05或P<0.01），对5种优势菌门中11种菌属（如阿克曼氏菌属、乳杆菌属、沃氏嗜胆菌属等）的相对丰度有显著回调作用（P<0...     

明目蒺藜丸联合聚乙烯醇滴眼液治疗干眼症的临床研究

目的 制备他达拉非片并考察其体内外释药特性。方法 以溶出度为评价指标,筛选他达拉非片各辅料用量及包衣增重。用相似因子（f₂）法比较自制制剂与参比制剂在0.5% SDS溶液、含0.5% SDS的0.1 mol/L的盐酸溶液、含0.5% SDS的pH 4.5醋酸钠缓冲液、含0.5% SDS的pH 6.8磷酸盐缓冲液中溶出曲线的相似性。比较二者在Beagle犬体内的药动学特征。结果 他达拉非片处方为他达拉非20 mg、乳糖50M 227.625 mg、羟丙基纤维素L 10.5 mg、交联羧甲基纤维素钠19.6 mg、SDS 0.525 mg、微晶纤维素M102 70 mg、硬脂酸镁1.75 mg,包衣增质量范围2%～4%。自制与参比制剂在4种溶出介质中的f₂均大于65,二者体外溶出行为相似。2种制剂在Beagle体内的药动学参数AUC_0~t、C_max、t_max均无显著性差异,自制他达拉非片的相对生物利用度为（101.67±8.99）%。结论 成功制备他达拉非片,其体外溶出和体内药动学行为与参比制剂相似。     

Human plasma concentrations of cytochrome P450 probes extrapolated from pharmacokinetics in cynomolgus monkeys using physiologically based pharmacokinetic modeling

Abstract

1.?Cynomolgus monkeys are widely used in preclinical studies as non-human primate species. Pharmacokinetics of human cytochrome P450 probes determined in cynomolgus monkeys after single oral or intravenous administrations were extrapolated to give human plasma concentrations.

2.?Plasma concentrations of slowly eliminated caffeine and R-/S-warfarin and rapidly eliminated omeprazole and midazolam previously observed in cynomolgus monkeys were scaled to human oral biomonitoring equivalents using known species allometric scaling factors and in vitro metabolic clearance data with a simple physiologically based pharmacokinetic (PBPK) model. Results of the simplified human PBPK models were consistent with reported experimental PK data in humans or with values simulated by a fully constructed population-based simulator (Simcyp).

3.?Oral administrations of metoprolol and dextromethorphan (human P450 2D probes) in monkeys reportedly yielded plasma concentrations similar to their quantitative detection limits. Consequently, ratios of in vitro hepatic intrinsic clearances of metoprolol and dextromethorphan determined in monkeys and humans were used with simplified PBPK models to extrapolate intravenous PK in monkeys to oral PK in humans.

4.?These results suggest that cynomolgus monkeys, despite their rapid clearance of some human P450 substrates, could be a suitable model for humans, especially when used in conjunction with simple PBPK models.     

硫酸沙丁胺醇微球缓释片的制备及初步药动学研究

目的 探讨硫酸沙丁胺醇微球缓释片的制备方法,并对微球缓释片在家犬体内的药动学进行初步研究。方法 运用喷雾干燥法制备硫酸沙丁胺醇缓释微球,直接压片得到硫酸沙丁胺醇微球缓释片。对微球缓释片和市售普通片进行家犬体内单剂量给药实验,建立了血药浓度测定的高效液相色谱法。结果 普通片和微球缓释片的药动学参数Cmax分别为（155.1±3.4）和（126.7±1.9）ng·mL^-1;Tmax分别为（1.5±0.6）和（4.1±0.8）h;t1/2分别为（4.12±0.93）和（5.73±0.64）h,相对生物利用度为109.7%。结论 硫酸沙丁胺醇微球缓释片具有缓释效果。     

Are Physiologically Based Pharmacokinetic Models Reporting the Right Cmax? Central Venous Versus Peripheral Sampling Site

Physiologically based pharmacokinetic (PBPK) models can over-predict maximum plasma concentrations (C_max) following intravenous administration. A proposed explanation is that invariably PBPK models report the concentration in the central venous compartment, rather than the site where the samples are drawn. The purpose of this study was to identify and validate potential corrective models based on anatomy and physiology governing the blood supply at the site of sampling and incorporate them into a PBPK platform. Four models were developed and scrutinised for their corrective potential. All assumed the peripheral sampling site concentration could be described by contributions from surrounding tissues and utilised tissue-specific concentration-time profiles reported from the full-PBPK model within the Simcyp Simulator. Predicted concentrations for the peripheral site were compared to the observed C_max. The models results were compared to clinical data for 15 studies over seven compounds (alprazolam, imipramine, metoprolol, midazolam, omeprazole, rosiglitazone and theophylline). The final model utilised tissue concentrations from adipose, skin, muscle and a contribution from artery. Predicted C_max values considering the central venous compartment can over-predict the observed values up to 10-fold whereas the new sampling site predictions were within 2-fold of observed values. The model was particularly relevant for studies where traditional PBPK models over-predict early time point concentrations. A successful corrective model for C_max prediction has been developed, subject to further validation. These models can be enrolled as built-up modules into PBPK platforms and potentially account for factors that may affect the initial mixing of the blood at the site of sampling.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-015-9796-7) contains supplementary material, which is available to authorized users.KEY WORDS: C_max, intravenous, PBPK modelling, pharmacokinetics, physiological model     

Development and Internal Validation of an In Vitro-in Vivo Correlation for a Hydrophilic Metoprolol Tartrate Extended Release Tablet Formulation

Purpose. To develop and validate internally an in vitro-in vivo correlation (IVIVC) for a hydrophilic matrix extended release metoprolol tablet. Methods. In vitro dissolution of the metoprolol tablets was examined using the following methods: Apparatus II, pH 1.2 & 6.8 at 50 rpm and Apparatus I, pH 6.8, at 100 and 150 rpm. Seven healthy subjects received three metoprolol formulations (100 mg): slow, moderate, fast releasing and an oral solution (50 mg). Serial blood samples were collected over 48 hours and analyzed by a validated HPLC assay using fluorescence detection. The f ₂ metric (similarity factor) was used to analyze the dissolution data. Correlation models were developed using pooled fraction dissolved (FRD) and fraction absorbed (FRA) data from various combinations of the formulations. Predicted metoprolol concentrations were obtained by convolution of the in vivo dissolution rates. Prediction errors were estimated for C_max and AUC to determine the validity of the correlation. Results. Apparatus I operated at 150 rpm, and pH of 6.8 was found to be the most discriminating dissolution method. There was a significant linear relationship between FRD and FRA when using either two or three of the formulations. An average percent prediction error for C_max and AUC for all formulations of less than 10% was found for all IVIVC models. Conclusions. The relatively low prediction errors for C_max and AUC observed strongly suggest that the metoprolol IVIVC models are valid. The average percent prediction error of less than 10% indicates that the correlation is predictive and allows the associated dissolution data to be used as a surrogate for bioavailability studies.     

基于化合物结构预测人体ADME/PK性质的效能评价

目的：整合定量结构性质关系（QSPR）模型预测化合物在人体的吸收、分布、代谢、排泄 （ADME）性质参数和基于生理药代动力学（PBPK）模型预测人体药代动力学（PK）曲线的方法,并评价该方法的预测能力。方法：以文献报道的具有体外实测理化、生物药剂学性质和临床观测PK性质的 14个化合物作为模型药物。采用ADMET Predictor软件的QSPR模型预测各个化合物的理化与生物药剂学参数,将上述预测的参数加载到GastroPlus软件的PBPK模型中预测各个化合物经口服给药后在人体的PK 曲线以及主要PK参数。对比预测与实测ADME/PK参数间的差异,以评估所用模型的预测效能。结果： QSPR模型预测的理化与生物药剂学性质参数与观测值间的绝对值较为接近,两者具有较好的线性关系（大部分参数的相关系数均接近或超过0.7）;14个化合物中,有6个化合物（43%）的最大血药浓度 （C_max）预测值落在观测值的2倍误差范围内,9个化合物（64%）的C_max落在观测值的3倍误差范围内; 有7个化合物（50%）的血药浓度-时间曲线下的面积（AUC）预测值落在观测值的2倍误差范围内,8个化合物（57%）的AUC落在观测值的3倍误差范围内。结论：联合QSPR和PBPK模型可用于评估化合物的ADME性质并进一步预测人体PK特征。经过当前工作的验证,表明该方法具有较高的预测能力。     

注射用酒石酸长春瑞滨胶束及注射用长春瑞滨在比格犬体内的毒动学比较

目的 测定连续给予注射用酒石酸长春瑞滨胶束的毒动学参数，并与注射用酒石酸长春瑞滨进行比较。方法 选取16只比格犬随机分为4组，雌雄各半，分别连续iv给予注射用酒石酸长春瑞滨胶束低、中、高剂量（0.29、0.58、1.174 mg/kg）与注射用酒石酸长春瑞滨1.174 mg/kg，建立测定比格犬血浆中酒石酸长春瑞滨浓度的液相色谱-串联质谱（LC-MS/MS）法，测定血药浓度，采用DAS3.1.4药动学软件计算动力学参数。结果 比格犬iv给予注射用酒石酸长春瑞滨胶束低、中、高3个剂量，血药浓度、AUC_（0-t）、C_max随给药剂量的增加而增大；连续iv给药，低、中、高剂量组动物血药浓度、AUC_（0-t）、C_max在给药第1、29、71天时均变化不大，无明显蓄积倾向。而注射用长春瑞滨胶连续iv给药后随给药时间延长，动物血药浓度、AUC_（0-t）、C_max有上升趋势，AUC_（0-t）蓄积因子分别为2.08、1.80，C_max蓄积因子分别为2.58、2.32，均有蓄积倾向。结论 注射用酒石酸长春瑞滨胶束与普通注射用酒石酸长春瑞滨毒动学参数比较，无明显的蓄积倾向，可降低长期服药的毒性风险。     

Intra- and Inter-Subject Variabilities of CGP 33101 after Replicate Single Oral Doses of Two 200-mg Tablets and 400-mg Suspension

Purpose. The purpose of this study was to use a replicate designed trial to assess the overall, intra- and inter-subject variabilities in pharmacokinetic parameters of CGP 33101 after oral administration of tablets relative to that of powder suspended in water, and to determine the relative proportion of the intra-subject variance to the overall variability. Methods. Sixteen healthy subjects were randomly assigned to four groups to receive tablets and suspension twice in four different treatment sequences. The plasma concentration-time profile of CGP 33101 was characterized in terms of C_max, T_max, and AUC. Bioavailability of tablets relative to suspension and intra- and inter-subject variability were assessed by statistical analysis. Results and Conclusions. The overall variabilities in absorption kinetics of CGP 33101 in healthy subjects were small with CV's of the population mean values for AUC and C_max less than 26% for both tablets and suspension. Contribution of intra-subject variability to the overall variability was also small (~20%). Both the overall and intra-subject variabilities of AUC and C_max after suspension were larger than after the tablets. However, the differences in variability between tablets and suspension were not statistically significant (p > 0.05). The tablet formulation was bioequivalent to suspension in terms of rate and extent of absorption based on 90% conventional confidence intervals (for AUC and C_max) and Wilcoxon rank-sum test (for T_max).     

Bioequivalence, pharmacokinetic and pharmacodynamic response to combined extended release formulations of felodipine and metoprolol in healthy volunteers

Objective: The primary aim of this study was to investigate whether bioequivalence is achieved for a new fixed combination of extended-release (ER) felodipine and controlled-release (CR/ZOK) metoprolol␣compared with the free combination of felodipine ER metoprolol CR/ZOK. The second aim was to study whether there was an interaction in pharmacokinetics and pharmacodynamics between felodipine and metoprolol when administered as ER formulation. Methods: Two four-way cross-over studies were performed in 36 young subjects and 24 elderly subjects with frequent measurement of drug plasma concentrations, blood pressures and heart rate. The pharmacokinetic analysis included enantioselective analysis in six subjects. Results: Bioequivalence between the fixed combination and the free combination was observed for the two drugs (mean difference 27%) except for a minor deviation regarding C_max of metoprolol in the elderly. No significant interaction was shown except for a small increase (6%) of metoprolol AUC in the younger subjects. Mean plasma S-/R-enantiomer ratios were almost identical for the different treatments. Blood pressure and heart rate was significantly reduced for the fixed combination compared with felodipine ER in the younger and the elderly subjects. No significant difference regarding pharmacodynamics was detected between the fixed combination and the corresponding free combination. Conclusion: The fixed combination consistently provides fairly constant and effective felodipine and metoprolol concentrations after once-daily administration of one tablet. It is clinically interchangeable with the free combination of metoprolol CR/ZOK tablets and felodipine ER tablets. Finally, felodipine and metoprolol do not interact on a pharmacokinetic level when administered as the fixed combination. Received: 29 October 1996 / Accepted in revised form: 21 March 1997     

盐酸普萘洛尔缓释片与常释片的生物利用度比较研究

目的：通过双交叉试验证明盐酸普萘洛尔缓释片有缓释作用。方法：用HPLC方法,测定血清中普萘洛尔浓度,进行盐酸普萘洛尔缓释片与常释片的生物利用度比较及峰谷浓度波动研究。结果：12位健康男性受试者一次交叉口服缓释片和常释片(均为40 mg)后的C_max分别为62.4±23.3和95.9±12.6 ng.mL^-1,AUC分别为360.2±80.6和383.5±74.2 ng.h.mL^-1,缓释片相对于常释片的相对生物利用度为95%;12位受试者连续服缓释片和常释片后平均稳态浓度分别为42.2±12.2和32.7±7.1 ng.mL^-1,波动度(DF)分别为0.90±0.35和2.09±0.34。结论：两种制剂具生物等效性,且缓释片比常释片有峰谷浓度差异小、血药浓度波动幅度小的特点。