5-单硝酸异山梨酯脉冲控释片的家犬体内药动学

目的：考察5-单硝酸异山梨酯（IS-5-MN）脉冲控释片在家犬体内药动学特征及相对生物利用度。方法：采用随机化方法将家犬6条分成两组，以市售单硝酸异山梨酯片为对照制荆，交叉灌服自制IS-5-MN脉冲控释片和市售单硝酸异山梨酯片，采用气相色谱电子捕获法测定血药浓度，考察自制IS-5-MN脉冲控释片在体内的脉冲控释效果。结果：Ⅲ型（体外时滞为3h的脉冲片）IS-5-MN脉冲控释片在家犬体内的时滞为2．6h，市售IS-5-MN片的时滞为0．25h，而Cmax、AUC等两者无明显差异。结论：本研究制备的脉冲释放制剂为防治心血管疾病凌晨发作提供了一个良好的剂型选择，达到了设计要求。     

复方盐酸伪麻黄碱缓释片的研究

应用反相ＨＰＬＣ法测定血药浓度，对复方盐酸伪麻黄碱缓释片的体外溶出及兔灌服一次的药物动力学进行了研究，并与自制普通片进行对照。结果表明缓释片维持体内有效血药浓度的时间较长，其相对生长利用度为１２２．４８％。体内外显著相关。理论值与实测值基本相符。     

水杨酸普鲁兰糖涂膜剂体内外透皮释放初步评价

目的:对自制水杨酸普鲁兰糖涂膜剂进行体内外透皮释放行为考察。方法:自制3批涂膜剂,采用HPLC法测定涂膜剂中水杨酸含量。选取昆明种小鼠鼠皮,用立式扩散池评价涂膜剂中水杨酸体外释放行为;选用新西兰兔背敷涂膜剂,测定兔体内水杨酸的药-时曲线,并考察超声促透效果。结果:自制水杨酸普鲁兰糖涂膜剂体外释放缓慢,释放过程可用Higuchi方程模拟。兔体内药-时曲线显示,水杨酸血药浓度1h达峰,峰值35μg·mL-1;而超声处理兔表皮后涂敷涂膜剂,血药浓度0.5h达峰,峰值39μg·mL-1,药-时曲线下面积(AUC)大于未经超声处理组。结论:自制涂膜剂缓慢释放水杨酸,可用于局部治疗。超声处理兔表皮后涂敷涂膜剂,水杨酸药物达峰时间提前,相比未超声其AUC增大,故超声处理兔表皮促进了水杨酸的透皮吸收。水杨酸普鲁兰糖涂膜剂体内外释放具有相关性,体外释放度可预测体内药物吸收情况。     

酮康唑及其生物黏附性阴道片在大鼠体内的药动学

目的：考察酮康唑溶液给大鼠静脉注射后的药动学行为，研究酮康唑生物黏附性阴道片在大鼠体内的绝对生物利用度。方法：采用HPLC法测定大鼠静脉及阴道给予酮康唑后的血药浓度，用矩量法计算药动学参数，隔室模型由3P97软件拟合。     

反卷积分法研究长春西汀推拉式渗透泵控释片体内外相关性

目的：采用反卷积分法评价长春西汀渗透泵控释片的体外释放与Beagle犬体内吸收相关性。方法：以0．5％SDS水溶液为溶出介质，测定长春西汀的体外释放度；高效液相色谱测定犬体内血药浓度，选择长春西汀普通片为参比制剂，应用反卷积分法评价长春西汀推拉式渗透泵体内体外相关性。结果：体外累计释放度（Y）与输入函数（R）回归方程为iY=237．99R-13．544（r=0．9763），表明长春西汀推拉式渗透泵体内体外相关性良好。结论：反卷积分法适合自制长春西汀推拉式渗透泵控释片体内外相关性研究。     

盐酸青藤碱渗透泵控释片的体内外相关性研究

制备了盐酸青藤碱渗透泵控释片.以正清风痛宁缓释片为参比制剂,考察其体外释放度和Beagle犬体内吸收情况.自制控释片与参比制剂的主要药动学系数:AUCo-1(11.01±3.2)和(13.06±3.5)μg·ml-1·h,t1/2(27.8±2.6)和(8.6±1.9)h,cmax(790.8±126.3)和(1334.5±150.5)ng/ml.结果表明,自制控释片的体外释放符合零级动力学方程.采用HPLC法测定血药浓度,照Wagner-Nelson法计算药物的体内吸收分数,对响应时间的体外累积释放率线性回归,所得方程的相关系数为0.98.     

酮康唑控释片的研制及体外溶出度考察

研制了酮康唑控释片，同时对它的体外溶出度进行了测定，并与市售普通片进行比较，结果表明：酮康唑控释片ｔ０．８＝４００．５０ｍｉｎ，而普通片ｔ０．８＝９９．４９ｍｉｎ，控释片释药平稳而持久。     

脱卷积法进行自制尼群地平缓释制剂体内外相关性研究

目的用脱卷积法进行自制尼群地平缓释制剂体内外相关性的研究。方法以自制尼群地平口服溶液剂的犬体内血药浓度数据为权函数，根据3种自制尼群地平缓释制剂试验犬体内血药浓度数据，采用脱卷积法计算体内释药特性，与相应的体外释药特性进行比较，考察体内外相关性。结果用脱卷积法计算3种尼群地平缓释制剂的体内外释药相关性良好。结论脱卷积法适用于自制尼群地平缓释制剂的体内外相关性研究。     

非洛地平对茶碱控释片在慢性阻塞性肺疾病患者体内药动学的影响

目的观察非洛地平对茶碱控释片在慢性阻塞性肺疾病患者体内血药浓度与药动学的影响。方法采用高效液相色谱法测定合用非洛地平前后不同时间茶碱的血药浓度，采用3P87程序判别模型并计算参数。结果联用非洛地平后茶碱血药浓度比单用茶碱时消除明显减慢，但只有在给药后8.0 h合并用药比单用茶碱时茶碱血药浓度高，且差异有显著性（P＜0.05）。联用非洛地平对茶碱的消除半衰期(t1/2β)、消除速率常数(Ke)、表观分布容积（Vd）均有显著影响（均P＜0.05），AUC、Cmax、tmax、ka、t1/2α等无明显变化。结论联合使用非洛地平和茶碱时，非洛地平能延缓茶碱在慢性阻塞性肺疾病患者体内的消除，但茶碱的血药浓度能保持在正常治疗浓度范围。长期联用非洛地平和茶碱控释片需要密切监测茶碱的血药浓度。     

卡托普利渗透泵型控释片的药代动力学

目的研究卡托普利渗透泵型控释片在家犬体内的药代动力学。方法以卡托普利普通片为对照 ,应用HPLC法测定血药浓度。结果卡托普利渗透泵型控释片和普通片的tmax分别为 5 5h和 1 5h ,t1/ 2 分别为 6 73h和 3 5 2h ,ρmax分别为 85 5 1和 172 5 3μg·L-1。相对生物利用度为(119 2 0± 2 3 2 0 ) %。结论渗透泵控释片血药浓度平稳 ,可较长时间保持有效血药浓度     

缓释与控释硝苯地平对高血压患者的降压作用比较

目的:比较缓释与控释硝苯地平对高血压患者的降压作用。方法:选取我院2010年1-6月收治的确诊为高血压的患者260例,随机均分为硝苯地平缓释片组与硝苯地平控释片组,观察2组患者的治疗效果以及不良反应。结果:2组患者治疗6周后,临床症状均有明显的下降趋势,硝苯地平缓释片组患者的总有效率为90.0%,硝苯地平控释片组患者的总有效率为93.1%,2组比较差异有统计学意义(P<0.05)。2组患者的临床不良反应均属于轻微症状,且差异无统计学意义(P>0.05),不影响治疗效果。结论:2种剂型的硝苯地平均对患者有良好的降压效果,但控释剂型的疗效高于缓释剂型,且在人体内的药物浓度较稳定。     

家兔体内酮康唑肝毒性和毒代动力学

AIM: To study the relationship between hepatotoxicity and toxicokinetics of ketoconazole in rabbits. METHODS:Normal rabbits were given intragastric gavage ketoconazole 40, 80, and 160 mg/kg. Ketoconazole plasma concentrations were measured by high performance liquid chromatography. Toxicokinetic parameters were determinedfrom the plasma concentration-time data with the 3P97 software package. Activities of serum glutamate-pyruvatetransaminase and glutamate-oxalate-transaminase and hepatic histopathological changes were observed at 36 h afteradministration. The relationship between hepatotoxicity and toxicokinetic parameters of ketoconazole was analyzedby linear correlation. RESULTS: The concentration-time curves of three doses of ketoconazole fitted well into atwo-compartment model. The proportional increase in the area under the plasma concentration-time curve (AUC)was more than that in the dose after the dose reached 80 mg/kg. Ketoconazole resulted in a marked elevation in theenzyme activities and significant damage of hepatocytes. Hepatotoxicity induced by ketoconazole was correlated tothe dose, clearance (CL), maximum plasma concentration (Cmax), and most closely correlated to AUC when it wasassessed by elevation transaminases in serum. CONCLUSION: The severity of ketoconazole-induced hepatotoxicity was closely related to the exposure level (AUC) of the drug.     

A multiple-dose pharmacokinetic comparison of naproxen as a once-daily controlled-release tablet and a twice-daily conventional tablet

The bioequivalence and absorption kinetics of naproxen in a new controlled-release tablet (750 mg or 1,000 mg naproxen) administered once daily were determined relative to an equivalent dose of the conventional naproxen tablet (375 mg or 500 mg naproxen) administered q12h. Naproxen was well absorbed from the controlled-release tablet (about 90%) compared with the conventional tablet. Absorption was dependent on drug release from the tablet matrix. The mean absorption time of naproxen averaged 8.4 hours for the 750-mg controlled-release tablet and 9.2 hours for the 1,000-mg controlled-release tablet. Once-daily administration of the controlled-release tablet resulted in equivalent trough concentrations of naproxen, and steady-state plasma concentrations were maintained within narrower limits than with twice-daily naproxen.     

Multiple-dose pharmacokinetics of naproxen from a controlled-release tablet in healthy volunteers

The pharmacokinetics of a new controlled-release tablet of naproxen (750 mg) given once daily has been studied in healthy volunteers, in comparison with two doses of the conventional naproxen tablets (375 and 500 mg) administered twice daily. Steady-state plasma concentrations of naproxen were achieved after two days of repeated administration of both the controlled-release and the conventional tablets. On day seven, peak concentration, cowest concentration and the steady-state average plasma concentration values of the controlled-release tablet were significantly higher than those of 375 mg conventional tablet and comparable to those of 500 mg conventional tablet. Areas under the plasma concentration-time curve indicated an equal extent of absorption between the new and the conventional formulation. Overall the controlled-release tablet administered once daily mimicked a twice daily regimen so suggesting that the new formulation could be suitable for once daily dosing.     

阿斯匹林肠溶缓释胶囊的人体药代动力学及生物利用度研究

本文报道口服阿斯匹林肠溶缓释胶囊及肠溶片后体内水杨酸盐的高效液相色谱测定法及正常人药代动力学和生物利用度研究的结果。12名健康志愿者，随机分为两组，分别交叉口服阿斯匹林肠溶缓释胶囊和肠溶片各600mg。阿斯匹林在体内迅速转化为活性代谢产物水杨酸，测定口服给药后不同时间血中水杨酸的浓度，使用3P87实用药代动力学程序对药一时曲线进行处理，结果表明，水杨酸在体内的代谢过程符合一室模型。单剂空腹口服阿斯匹林肠溶缓释胶囊和肠溶片后，体内水杨酸的平均峰浓度为35．52±8．28mg／L和30．32±8．96mg／L；平均达峰时间为5．70±1．25h和7．40±2．17h开均药-时曲线下面积为328.4±92．2mg／（Lh）和316．0±70．95mg／（L·h)）;消除半衰期为3．11±1．25h和3．84±1．72h；吸收迟滞时间为2．33±0．65h和3．35±1．16h。肠溶缓释胶囊的达峰时间明显短于肠溶片。缓释胶囊对片剂的相对生物利用度为103．9％。     

Effect of Time Interval between Food and Drug Ingestion on the Absorption of Oxybutynin from a Controlled-Release Tablet

Abstract: The effect of time interval between food and drug ingestion on the bioavailability of oxybutynin was investigated in a randomized, three-phase cross-over study in 31 healthy volunteers. The serum concentrations of oxybutynin and the metabolite, N-desethyloxybutynin were measured up to 48 hr after ingestion of a controlled-release 10 mg oxybutynin tablet either in fasting state, 2 hr after breakfast or 1 hr before. The C_max of both oxybutynin (P<0.0001) and N-desethyloxybutynin (P<0.0001) and the AUC_0-t of N-desethyloxybutynin (P<0.05) were significantly larger when oxybutynin was ingested 2 hr after breakfast, than during the fasting, but the AUC_0-t of oxybutynin remained unchanged. Breakfast ingested 1 hr after oxybutynin did not affect the pharmacokinetic parameters of oxybutynin or N-desethyloxybutynin. The saliva secretion rate decreased slightly more (P<0.05), when oxybutynin was administered 2 hr after breakfast than during fasting. The effect of food ingestion on the serum concentrations of oxybutynin and N-desethyloxybutynin is expected to have minor clinical significance only. However, ingestion of the controlled-release tablet 1 hr before meal increases the likelihood of obtaining constant drug levels with lower peak concentrations during the dosage interval, and thus ingestion of the controlled-release tablet 0.5–1 hr before food may well improve tolerability and compliance in patients who suffer from adverse reactions.     

胆宁片对实验性脂肪肝的保护作用

目的：观察胆宁片对实验性脂肪肝的保护作用。方法：采用高脂饮食分别诱导大鼠和家兔脂肪肝模型，将60只大鼠按体重随机分为空白组，模型组，阳性对照熊去氧胆酸（150mg／kg）组，低（0．5g／kg）、中（1．5g／kg）、高（3．0g／kg）剂量胆宁片组，每组10只。30只家兔按体重随机分为空白组，模型组，阳性对照熊去氧胆酸组（75mg／kg），低（0．25g／kg）、中（0．75g／kg）、高（1．5g／kg）剂量胆宁片组，每组5只。观察低、中、高剂量胆宁片对大鼠和家兔血清中总胆固醇、三酰甘油、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇、天冬氨酸氨基转移酶（AST）、丙氨酸氨基转移酶（ALT）浓度的影响，以及肝组织形态学的变化。结果：与空白对照组比较，胆宁片低、中、高3组剂量能显著降低大鼠血清中总胆固醇、低密度脂蛋白胆固醇水平（P〈0．05或P〈0．01）；胆宁片中、高剂量组能显著降低大鼠血清中ALT水平（P〈0．05或P〈0．01），同时高剂量组能显著降低大鼠血清中AST水平（P〈0．05）。胆宁片中、高剂量能显著降低家兔血清中总胆固醇、三酰甘油、低密度脂蛋白胆固醇水平（P〈0．05或P〈0．01）；胆宁片低剂量组能显著降低家兔血清中三酰甘油水平（P〈0．05）；胆宁片高剂量组能显著降低家兔血清中ALT水平（P〈0．05）；胆宁片中、高剂量组能显著降低家兔血清中AST水平（P〈0．05或P〈0．01）。肝脏病理组织学检查显示，胆宁片可减轻肝脏脂肪变性和点灶状坏死。结论：胆宁片对实验性大鼠和家兔脂肪肝均有一定的治疗作用。     

Matrix properties of a new plant gum in controlled drug delivery

A new plant gum, Okra (extracted from the pods of Hibiscus esculentus), has been evaluated as a controlled-release agent in modified release matrices, in comparison with sodium carboxymethyl cellulose (NaCMC) and hydroxypropylmethyl cellulose (HPMC), using Paracetamol as a model drug. Tablets were produced by direct compression and the in-vitro drug release was assessed in conditions mimicking the gastro intestinal system, for 6 h. Okra gum matrices provided a controlled-release of Paracetamol for more than 6 h and the release rates followed time-independent kinetics. The release rates were dependent on the concentration of the drug present in the matrix. The addition of tablet excipients, lactose and Avicel, altered the dissolution profile and the release kinetics. Okra gum compared favourably with NaCMC, and a combination of Okra gum and NaCMC, or on further addition of HPMC resulted in near zeroorder release of paracetamol from the matrix tablet. The results indicate that Okra gum matrices could be useful in the formulation of sustained-release tablets for up to 6 h.     

Serum binding of ketoconazole in health and disease

The plasma protein binding of ketoconazole, an oral antifungal agent of a weak basic nature, was measured after the addition of the drug (10 micrograms.ml-1) to serum from 35 healthy individuals, ten patients with chronic renal disease and seven patients with hepatic cirrhosis. The percentage of free ketoconazole was markedly increased in patients with chronic renal disease and in patients with hepatic cirrhosis, when it was compared with the group of healthy volunteers (7.33 +/- 0.11 in renal patients; 6.12 +/- 1.43 in hepatic patients compared with 2.93 +/- 0.12 in healthy individuals). The binding ratio of ketoconazole in health and disease was significantly related to plasma albumin concentration, but not to plasma alpha 1-acid glycoprotein (AAG) concentration. Moreover, ketoconazole binds to isolated human serum albumin in a greater proportion but does not bind to isolated AAG indicating that human serum albumin is the major binding protein for this drug in plasma.