比较氨氯地平和阿托伐他汀复方片与单剂在健康人体的生物等效性

目的 评价氨氯地平/阿托伐他汀复方片剂与同剂量单剂的生物等效性.方法 66位健康男性志愿者随机交叉单次口服1片氨氯地平(5 mg)/阿托伐他汀(40 mg)复方片剂(受试制剂)和同时服用氨氯地平(5 mg)和阿托伐他汀(40mg)各1片(参比制剂);用GC-ECD法和LC-MS/MS法,分别测定药物血浆浓度,WinNonlin非房室模型计算药代动力学参数,SAS程序评价生物等效性.结果 受试制剂(复方)和参比制剂(单剂)的主要药代动力学参数,氨氯地平:tmax分别为6.0和6.0 h;t1/2分别为(39.2±7.6)和(39.7±9.9)h;Cmax分别为(3.0±0.9)和(3.0±0.5)ng·mL-1;AUC0-∞分别为(145.3±42.1)和(149.8±43.6)ng·h·mL-1;AUC0-t分别为(129.3±39.5)和(133.4±37.2)ng·h·mL-1.阿托伐他汀:tmax分别为1.0和0.5 h;t1/2分别为(6.7±1.8)和(6.9±1.8)h;Cmax分别为(18.8±9.8)和(20.2±11.7)ng·mL-1;AUC0-∞分别为(101.7±35.2)和(97.8±39.2)ng·h·mL-1;AuC0-t分别为(96.7±35.0)和(93.1±39.1)ng·h·mL-1.受试制剂和参比制剂AUC0-t、AUC0-∞和Cmax比值的90%置信区间:氨氯地平:93.3%～100.1%,93.8%～100.6%和95.8%～103.4%;阿托伐他汀:99.2%～111.0%,99.6%～110.6%和81.8%～107.2%.结论 2种制剂为生物等效制剂.     

国产与进口瑞舒伐他汀钙片在健康人体的药代动力学及生物等效性

目的 评价进口与国产瑞舒伐他汀钙片(降血脂药)在健康人体的生物等效性.方法 20例健康成年男性受试者随机分组,按自身对照单次口服瑞舒伐他汀钙片20 mg后,用UPLC-MS-MS法测定瑞舒伐他汀的血浆浓度,非房室模型法计算各主要药代动力学参数,并进行方差分析和生物等效性评价.结果 瑞舒伐他汀片和胶囊的达峰时间tmax分别为(3.35±0.99)和(3.00±1.17)h;达峰浓度Cmax分别为(21.59±15.44)和(16.86±11.03)ng·mL-1;t1/2分别为(11.90±4.34)和(11.27±3.87)h;AUC0-96分别为(173.30±118.18)和(150.58±95.35)ng·h·mL-1;AUC0-∞分别为(175.05±119.02)和(151.88±95.78)ng·h·mL-1.经统计分析,2组间无显著性差异(P＞0.05).结论 国产瑞舒伐他汀钙片(浙江京新药业股份有限公司)与进口瑞舒伐他汀钙片(阿斯利康公司)2种制剂生物等效.     

兰索拉唑及其代谢产物的生物等效性研究

目的:评价兰索拉唑及其代谢产物的生物等效性.方法:用LC-MS/MS测定兰索拉唑及其代谢产物的血药浓度.20名健康男性志愿者随机分组、自身交叉口服单剂量受试制剂和参比制剂进行生物等效性评价.结果:受试制剂兰索拉唑的AUC0→t、Cmax、tmax分别为(3887.74±2 766.08 )ng·h·ml -、(1 009.95±321.73 )ng·ml-1、(2.42±0.89)h;参比制剂兰索拉唑的AUC0→t、Cmax、tmax分别为(3 895.25±2 809.82 )ng·h·ml-1、(1 150.74±480.22) ng·ml-1、(2.29±1.07)h.受试制剂5-羟基兰索拉唑的AUC0+t、Cmax、tmax分别为(278.44±106.60) ng·h·ml-1、(95.65±48.50 )ng · ml -1、(2.29±0.84)h;参比制剂5-羟基兰索拉唑的AUC0+t、Cmax、tmax分别为(291.52±131.81) ng·h·ml -、(113.81±66.36) ng ·ml-1、(2.16±1.11)h.受试制剂相比参比制剂的兰索拉唑、5-羟基兰索拉唑的人体相对生物利用度分别是(106.1％±32.7％)、(102.43％±38.87％).受试制剂相对参比制剂的兰索拉唑、5-羟基兰索拉唑主要药动学参数经交叉试验方差分析差异无统计学意义,两制剂的AUC0+t,Cmax经双单侧t检验示90％置信区间均位于有效置信区间范围内.结论:兰索拉唑的2种制剂以兰索拉唑及5-羟基兰索拉唑血药浓度数据评价,具有生物等效性.     

盐酸美金刚片在中国健康人体的生物等效性

目的:评价国产与进口盐酸美金刚片在中国健康人体的生物等效性。方法:20名健康男性受试者随机交叉单剂量口服受试制剂或参比制剂盐酸美金刚片各10mg。用高效液相色谱-串联质谱法测定血浆中美金刚浓度;用DAS3.0软件计算药动学参数,并对两种药物进行生物等效性评价。结果:受试制剂和参比制剂的主要药动学参数:Cmax分别为(18.1±3.8)和(20.3±4.2)ng·mL-1;tmax分别为(12.7±15.1)和(8.8±3.0)h;t1/2分别为(60.8±15.5)和(61.4±19.2)h;AUC0-t分别为(1 748.6±338.9)和(1 720.2±317.3)ng·h·mL-1。AUC0-t、AUC0-∞、Cmax的90%置信区间分别为89.8%～105.6%、89.7%～106.1%、84.8%～93.9%。受试制剂相对生物利用度F0-t为(95.5±2.9)%。结论:受试制剂与参比制剂具有生物等效性。     

克拉霉素分散片的健康人体生物等效性研究

目的:研究克拉霉素分散片在健康人体的药动学及生物等效性.方法:采用两制剂双周期双交叉前后自身对照试验设计.20名健康志愿者分别口服克拉霉素分散片受试制剂或参比制剂500 mg,采用高效液相色谱-质谱法(LC-MS)测定血浆中克拉霉素的浓度,经DAS 2.1软件处理后得药动学数据,并进行等效性检验.结果:受试制剂的t1/2为(3.72±0.42)h,Cmax为(2 350.7±604.2)ng·mL-1,Tmax为(1.48±0.36)h,AUC0-t为(12 425±1 975)ng·h·mL-1;参比制剂的t1/2为(4.22±1.15)h,Cmax为(2 045.0±379.5)ng·mL-1,Tmax为(1.76±0.52)h,AUC0-t为(11 954±2 152)ng·h·mL-1.以AUC0-t计算,与参比制剂比较,受试制剂平均相对生物利用度为(101.7±7.3)%,AUC0-t,AUC-∞和Cmax均拒绝生物不等效假设.结论:测定结果经方差分析及双单侧t检验,表明两种制剂具有生物等效性.     

匹伐他汀钙片单、多剂量人体药动学评价

目的:建立LC-MS/MS法测定人血浆中匹伐他汀的浓度,研究其在中国健康受试者体内的单、多剂量药动学过程.方法:20名健康志愿者随机分为2组,每组10人(男女各半),分别口服低、中、高3个剂量(1,2,4 mg)进行单剂量药动学研究,2mg剂量组继续给药(每日1次,连续7 d),进行多剂量药动学研究.采用LC-MS/MS法测定血浆中匹伐他汀的浓度,并采用WinNonLin6.2计算药动学参数.结果:健康受试者单剂量口服1、2、4mg匹伐他汀钙片后的药动学参数:t1/2分别为(11.29±4.28)h、(13.52±5.65)h和(11.87±2.87)h;tmax分别为(0.78±0.32)h、(0.75±0.17)h和(0.93±0.31)h;Cmax分别为(15.80±7.34)ng·ml-1、(36.54±6.29)ng·ml-1和(61.32±15.09)ng·ml-1;AUC(0-48)分别为(36.46±21.86)ng·h·ml-1、(107.90±28.55)ng·h·ml-1和(187.76±62.62)ng·h·ml-1;AUC(0-∞)分别为(40.91±23.20)ng·h·ml-1、(112.97±29.08)ng·h·ml-1和(197.55±68.51)ng·h·ml-1.多剂量组口服2mg匹伐他汀后的药动学参数:t1/2为(13.07±2.16)h,tmax为(0.68±0.12)h,Cmax为(33.88±6.91)ng·ml-1,AUCss为(68.21±20.82)ng·h·ml-1,AUC(0-48)为(77.78±26.50)ng·h·ml-1,AUC(0-∞)为(82.59±26.58)ng·h·ml-1.匹伐他汀钙多次给药达稳态后,药动学参数tmax、t1/2与单次给药一致.结论:在1~4mg剂量范围内匹伐他汀的AUC(0-48)、AUC(0-∞)、Cmax均与剂量呈线性关系;匹伐他汀在连续多次给药后,无体内蓄积现象;匹伐他汀的体内过程在男女性别间无显著差异.     

两种西地那非片在健康人体内的生物等效性

目的研究两种西地那非片在中国健康人体内的生物等效性。方法空腹试验48例、餐后试验40例健康男性志愿者随机交叉单剂量口服西地那非片受试制剂与参比制剂100 mg,采用液相色谱-质谱(LC-MS/MS)法测定血浆中西地那非和N-去甲基西地那非的血药浓度,应用SAS 9.4统计软件进行统计分析,计算药动学参数及相对生物利用度,判定两制剂是否等效。结果空腹试验中受试制剂与参比制剂西地那非的主要药动学参数cmax分别为(566±244)和(550±256)ng·mL^-1,AUC0-t分别为(1388±520)和(1407±545)ng·h·mL^-1,AUC0-∞分别为(1403±520)和(1422±544)ng·h·mL^-1;N-去甲基西地那非的主要药动学参数cmax分别为(291±110)和(280±101)ng·mL^-1,AUC0-t分别为(936±381)和(956±429)ng·h·mL^-1,AUC0-∞分别为(953±387)和(974±435)ng·h·mL^-1。餐后试验中受试制剂与参比制剂西地那非的主要药动学参数cmax分别为(424±137)和(422±145)ng·mL^-1,AUC0-t分别为(1660±505)和(1654±536)ng·h·mL^-1,AUC0-∞分别为(1675±506)和(1667±540)ng·h·mL^-1;N-去甲基西地那非的主要药动学参数cmax分别为(206±66)和(206±74)ng·mL^-1,AUC0-t分别为(930±280)和(954±351)ng·h·mL^-1,AUC0-∞分别为(945±283)和(970±356)ng·h·mL^-1。受试制剂与参比制剂cmax、AUC0-t和AUC0-∞几何均数比值的90%置信区间均完全落在80.00%~125.00%之间。结论本研究建立的LC-MS/MS法准确快速,灵敏度高,专属性强,适用于西地那非及N-去甲基西地那非血药浓度测定。两种西地那非片具有生物等效性。     

盐酸曲美他嗪片的生物等效性研究

目的:研究盐酸曲美他嗪片的人体生物利用度和生物等效性。方法:22名男性健康受试者,随机双交叉口服剂量为20mg的受试制剂和参比制剂,采用LC-MS法测定血浆中盐酸曲美他嗪的浓度,使用DAS2.1.1软件对各药代动力学参数进行计算,同时对其生物等效性进行统计分析。结果:22名健康受试者服用20mg盐酸曲美他嗪片受试制剂和参比制剂的Cmax分别为(42.64±17.00)ng/ml和(41.32±19.66)ng/ml,Tmax分别为(2.2±1.5)h和(2.7±1.7)h,AUC0-t分别为(418.1±177.4)ng·h/ml和(397.8±147.1)ng·h/ml,AUC0-∞分别为(428.5±181.1)ng·h/ml和(407.9±150.5)ng·h/ml,t1/2分别为(5.9±1.6)h和(5.6±1.3)h。受试制剂中曲美他嗪Cmax的90%置信区间为参比制剂的100.1%～111.1%,AUC0-t的90%置信区间为参比制剂的97.0%～111.9%,AUC0-∞的90%置信区间为参比制剂的96.9%～111.9%。以AUC0-t计算,受试制剂中曲美他嗪的相对生物利用度为(105.9±18.6)%。结论:两制剂具有生物等效性。     

国产替米沙坦分散片与进口替米沙坦片在健康志愿者中的生物等效性研究

目的在24名男性健康受试者中比较国产替米沙坦分散片与原研进口替米沙坦片的生物等效性。方法筛选24名健康男性志愿者,采用随机交叉试验设计,应用高效液相色谱-荧光检测法测定血浆中替米沙坦的浓度,根据测定结果计算主要药动学参数,并以进口替米沙坦片为参比制剂,评估替米沙坦分散片的生物等效性。结果经DAS2.1.1数据统计软件计算药动学参数,受试制剂A的t1/2:(27.94±9.94)h、Cmax:(757.9±238.3)ng/mL、Tmax:(1.18±0.49)h、AUC0-t:(4423±2645)ng/(h·mL)、AUC0-∞:(4804±3146)ng/(h·mL);受试制剂B的t1/2:(25.58±8.56)h、Cmax:(763.4±283.3)ng/mL、Tmax:(1.22±0.52)h、AUC0-t:(4195±1988)ng/(h·mL)、AUC0-∞:(4437±2122)ng/(h·mL);参比制剂的t1/2:(28.98±11.66)h、Cmax:(755.6±268.2)ng/mL、Tmax:(1.15±0.51)h、AUC0-t:(4327±2039)ng/(h·mL)、AUC0-∞:(4622±2201)ng/(h·mL)。以AUC0-t计算,与参比制剂相比受试制剂A、受试制剂B中替米沙坦的相对生物利用度分别为(99.2±26.8)%、(98.3±26.4)%。结论国产替米沙坦分散片与原研进口替米沙坦片具有生物等效性。     

非那雄胺片的药物动力学和人体相对生物利用度

20名健康男性志愿者交叉口服非那雄胺的受试制剂与参比制剂,采用LC-MS法测定血浆中的非那雄胺.单剂量口服受试或参比制剂10 mg后,Cmax分别为(94.15±18.71)和(99.13±20.10)ng/ml;tmax分别为(2.2±0.7)和(2.4±0.9)h;t1/2分别为(43±0.7)和(4.2±1.1)h;AUC0～24h分别为(614.57±129.11)和(627.65±145.40)ng·h·ml-1;AUC0～∞分别为(631.94±136.97)和(646.20±150.63)ng·h·ml-1;受试制剂的相对生物利用度为(100.2±18.4)%.经方差分析和双单侧t检验,两种片剂具有生物等效性.     

Affective and Anxiety Disorders and Alcohol and Drug Dependence:

Depression and anxiety frequently coexist in patients with substance use disorders. This clinically-oriented article examiens the relationship between these conditions and emphasizes data showing that substances of abuse can cause signs and symptoms of both depression and anxiety. These substance-related syndromes appear to have a different course and prognosis than uncomplicated, independent anxiety and major depressive disorders, and clinicians should consider the role of alcohol and other drugs in all patients presenting with these complaints. The authors will also outline an approach for diagnosing and managing patients with the combination of a substance use and depressive or anxiety disorder.     

Synthesis and anti-nociceptive and anti-inflammatory effects of gaultherin and its analogs

The synthesis of gaultherin (1) and its analogs was carried out to provide 11 glycosides under phase-transfer catalytic conditions. The activities of all synthesized compounds were evaluated by nitric oxide production inhibitory assay in vitro. Methyl 2-O-(4-O-β-d-galactopyranosyl)-β-d-glucopyranosylbenzoate (5f) showed significantly anti-nociceptive and anti-inflammatory effects by the evaluation in vivo. Structure–activity relationships within these compounds were discussed.     

Modelling and simulation of variability and uncertainty in toxicokinetics and pharmacokinetics

Two important methodological issues within the framework of the variability and uncertainty analysis of toxicokinetic and pharmacokinetic systems are discussed: (i) modelling and simulation of the existing physiologic variability in a population; and (ii) modelling and simulation of variability and uncertainty when there is insufficient or not well defined (e.g. small sample, semiquantitative, qualitative and vague) information available. Physiologically based pharmacokinetic models are especially suited for separating and characterising the physiologic variability from the overall variability and uncertainty in the system. Monte Carlo sampling should draw from multivariate distributions, which reflect all levels of existing dependencies in the intact organism. The population characteristics should be taken into account. A fuzzy simulation approach is proposed to model variability and uncertainty when there is semiquantitative, qualitative and vague information about the model parameters and their statistical distributions cannot be defined reliably.     

成骨细胞的功能与损伤和骨质疏松的防治

骨质疏松是一种全身性骨骼疾病,导致骨折风险增加。成人的骨量通过破骨细胞的骨吸收和成骨细胞的骨形成作用来维持动态平衡,治疗骨质疏松症的理想策略是抑制破骨细胞的骨吸收和/或增强成骨细胞的骨形成功能。目前针对保护成骨细胞及增强其功能的骨质疏松疗法相对较少。因此,本文针对成骨细胞相关功能蛋白、各种细胞损伤机制（内质网应激、氧化应激、机械过载、微小RNA和长链非编码RNA的影响等）及骨质疏松的治疗与预防作一综述,以期为针对增强成骨细胞功能的骨质疏松治疗策略提供新思路。     

Self-stimulation and amphetamine: Tolerance to d and l isomers and cross tolerance to cocaine and methylphenidate

The effects of the d and l isomers of amphetamine on self-stimulation responding were tested following acute and chronic administration. Tolerance and post-drug depression of responding occurred in tests with both isomers, indicating no role for p-hydroxynorephedrine (PHN) which is one of the metabolites of d-amphetamine. In the second experiment, d-amphetamine, methylphenidate and cocaine all produced quantitatively and qualitatively similar effects on self-stimulation responding following acute administration. Following chronic administration of d-amphetamine, animals showed tolerance to all three drugs, indicating cross-tolerance among them. These data are consistent with an hypothesis that tolerance and post-drug depression following chronic amphetamine treatment are the result of decreases in postsynaptic receptor sensitivity, which would lead to a decreased effectiveness of all three drugs, regardless of their pre-synaptic mechanisms.     

益生菌与肿瘤防治

益生菌广泛存在于自然界中,通过维持宿主体内菌群平衡、影响肠屏障功能和调节免疫应答等作用,提高宿主健康水平,被公认为"肠道健康卫士".一些益生菌可以增强机体的免疫功能,抑制致癌物质,影响肿瘤细胞的基因表达,对肿瘤具有拮抗作用.大量研究表明,益生菌在未来的肿瘤防治中有很好的应用和发展前景.     

Acamprosate and naltrexone treatment effects on ethanol and sucrose seeking and intake in ethanol-dependent and nondependent rats

Rationale  Two pharmacotherapies are approved for treating alcohol craving (acamprosate and naltrexone), but both have shown mixed findings in animals and humans. Objectives  The present experiments utilized a “reinforcer blocking” approach (i.e., rats were able to consume ethanol during treatment) to better understand the efficacy of these treatments for ethanol seeking and drinking using ethanol-dependent and nondependent rats. Materials and methods  In “nondependent” experiments, drugs (acamprosate 50, 100, and 200 mg/kg; naltrexone 0.1, 0.3, and 1.0 mg/kg) were administered over 3-week periods prior to operant sessions with a low response requirement to gain access to reinforcers for 20 min. For “dependent” experiments, rats were made dependent in vapor/inhalation chambers. Results  Acamprosate and naltrexone had similar effects on intake in nondependent and dependent rats; neither drug was selective for ethanol over sucrose drinking. In nondependent animals, naltrexone was more efficacious at more doses than acamprosate, and acamprosate’s effects were limited to a dose that also had adverse effects on body weight. Both pharmacotherapies showed more selectivity when examining reinforcer seeking. In nondependent rats, acamprosate and naltrexone had response-attenuating effects in ethanol, but not sucrose, groups. In dependent animals, acamprosate had selective effects limited to a decrease in sucrose seeking. Naltrexone, however, selectively decreased ethanol-seeking in nondependent rats. Conclusions  The naltrexone-induced decreases in seeking suggested a change in incentive motivation which was selective for ethanol in nondependent rats. The “nondependent” paradigm may model early stages of “problem drinking” in humans, and the findings suggest that naltrexone could be a good intervention for this level of alcohol abuse and relapse prevention.     

Antiinfective and encrustation-inhibiting materials--myth and facts

Catheters, urethral and ureteral stents and other urological implants are frequently affected by encrustration and infection due to their permanent contact with urine. Indwelling urinary catheters provide a haven for microorganisms and thus require extensive monitoring. Several surface modification techniques have been proposed to improve the performance of devices including the immobilization of biomolecules, the incorporation of hydrophilic grafts to reduce protein adsorption, the creation of hydrophobic surfaces, the creation of microdomains to regulate cellular and protein adhesion, new polymers and antimicrobial coatings. Physico-chemical explanation to elucidate the mechanism of such encrustation or infection inhibiting materials is still not available. Our series of experiments showed a marked decrease of silver-activity in biological fluids which corresponds with the controversial clinical results obtained with silver coated urinary catheters. Rifampicin/minocycline coated catheters had very low activity against Gram-negative rods, enterococci and Candida spp., the main causing organisms of urinary catheter infection. Surface engineered materials and antimicrobial drug delivery systems will be the next generation of sophisticated urinary catheters and stents, if both efficacy as well as efficiency has been proved clinically.     

Alprazolam and lorazepam single and multiple-dose effects on psychomotor skills and sleep

Summary The effects of alprazolam 0.5 mg and lorazepam 2 mg on cognitive and psychomotor skills were assessed in twelve normal volunteer subjects in a randomised, double-blind, crossover design. Single and multiple dose effects were monitored using a battery of tests comprising critical flicker fusion threshold (CFFT), choice reaction time (CRT), simulated car tracking, and subjective ratings of perceived sedation (LARS) and of sleep behaviour (LSEQ). Compared with placebo baseline scores, treatment with lorazepam 2 mg (both single and multiple doses) resulted in a widespread impairment of CRT, tracking accuracy, and CFFT. Single doses of alprazolam 0.5 mg reduced CFFT with respect to the placebo baseline. Single and multiple dose treatment with both drugs resulted in subjective reports of sedation, a reduction of sleep onset latency, and improved sleep quality. Only lorazepam 2 mg significantly disrupted the integrity of behaviour on waking from sleep. These results suggest important pharmacodynamic differences between the two drugs in the doses used.