高效液相色谱串联质谱法测人血浆中氯雷他定浓度及其药代动力学研究

目的建立灵敏的氯雷他定血浓度测定方法,评价氯雷他定的药代动力学特点.方法固定相ORBAX Eclipse XDB-C8(5μm,150 mm×4.6 mm),HP1100LC-MSD质谱检测器;流动相乙腈 -0.1%醋酸和0.2%醋酸铵水溶液,流速 1.0 ml·min-1.离子源AP-ESI,正离子模式,雾化电压30 psi,保护气10 L·min-1N2,毛细管电压4000 V,碎片电压为170V.SIM离子采集方式,采集离子(m/z)氯雷他定383.2(M+H),内标罗哌卡因275.1(M+H).结果氯雷他定线性范围0.5～50 ng·ml-1,最低定量限为0.5 ng·ml-1.氯雷他定片(T1)、胶囊(T2)、开瑞坦(R)主要药代动力学参数t1/2为13.52±1.35,13.14±0.98,14.00±1.25 h;Tmax为1.24±0.06,1.18±0.12,1.18±0.12h;Cmax为21.72±7.70,21.49±8.34,20.50±8.65 ng·ml-1;AUC0-48为137.24±47.87,139.65±45.69,134.19±49.03ng·h·ml-1,AUC0-∞为146.61±51.03,148.04±48.10,143.70±52.08 ng·h·ml-1.试验制剂氯雷他定片/胶囊相对生物利用度分别为(105.49±8.08)%和(102.90±10.02)%.结论HPLC-MS法测定氯雷他定血浓度实用、可行,适用于常规治疗药物监测和氯雷他定药代动力学研究.试验制剂和参比制剂为生物等效制剂.     

2种左甲状腺素钠片的人体生物等效性研究

目的:研究2种左甲状腺素钠片的人体生物等效性。方法:按照两制剂两周期随机交叉设计,26名男女健康受试者分别单剂量口服受试制剂(Berlthyrox)或参比制剂(雷替斯)6片(每片含左甲状腺素钠100μg)。采用放射免疫法测定血清中T4、T3浓度,并计算药动学参数,评价2种制剂的生物等效性。结果:受试制剂与参比制剂的T4主要药动学参数分别为:cmax(138.54±16.22)、(147.45±16.92)ng·mL-1,tmax(2.4±1.0)、(2.3±2.2)h,t1/2(253.58±155.94)、(467.97±638.97)h,AUC0～48h(5550.27±679.50)、(5817.83±649.35)ng·h·mL-1,AUC0～∞(48065.79±28322.17)、(85248.31±113292.36)ng·h·mL-1;T3的主要药动学分别为:cmax(1.56±0.23)、(1.55±0.18)ng·mL-1,tmax(39.7±16.5)、(35.4±18.8)h,t1/2(117.55±107.94)、(105.29±65.78)h,AUC0～48h(64.09±7.52)、(65.06±7.60)ng·h·mL-1,AUC0～∞(330.15±250.21)、(307.33±126.61)ng·h·mL-1。受试制剂与参比制剂T4、T3的相对生物利用度分别为(95.9±11.6)%、(99.2±12.6)%。结论:2种左甲状腺素钠片生物等效。     

高效液相色谱法测定人血浆中卡托普利和人体药动学的研究

目的　建立简便的测定人血浆中卡托普利血药浓度的高效液相色谱法 ,研究卡托普利在健康人体中的药动学参数。方法　以对溴苯乙酰基溴为紫外衍生化试剂 ,采用高效液相色谱紫外检测法测定 18名健康志愿受试者口服单剂量卡托普利受试制剂和参比制剂 ( 5 0mg)后血药浓度。结果　卡托普利的血药浓度标准曲线的线性范围为 2 5～ 12 0 0ng·mL- 1 ,其最低定量限为 2 5ng·mL- 1 ,日内及日间RSD均小于 8%。应用所建立的血药浓度检测方法测定 18名健康志愿受试者口服单剂量卡托普利受试制剂和参比制剂 ( 5 0mg)后血药浓度 ,并计算药动学参数。结果表明口服受试制剂或参比制剂后的tmax分别为( 0 6 4± 0 18)h和 ( 0 82± 0 4 1)h ;Cmax分别为 ( 6 0 0 2± 194 3)ng·mL- 1 和 ( 5 82 7± 175 3)ng·mL- 1 ;AUC0→ 8h分别为 ( 14 4 8 5± 4 83 7)ng·h·mL- 1 和 ( 1389 9± 392 5 )ng·h·mL- 1 ;AUC0→∞ 分别为 ( 186 9 4± 70 1 6 )ng·h·mL- 1 和 ( 1781 8± 6 15 5 )ng·h·mL- 1 。结论　本方法操作便捷 ,灵敏度高 ,为血药浓度监测及药代动力学研究提供了方法学基础     

2种氯诺昔康制剂的人体药动学及生物等效性研究

目的:研究2种氯诺昔康制剂在人体内的药动学及生物等效性。方法:20名健康男性志愿者随机交叉单剂量口服氯诺昔康颗粒(受试制剂)与氯诺昔康片(参比制剂)8mg后,采用高效液相色谱-电喷雾串联质谱法测定其血药浓度,并用DAS软件计算药动学参数及评价二者生物等效性。结果:受试制剂与参比制剂药动学参数分别为:Cma(x1331±192.1)、(1366±220.5)ng·mL-1,tma(x2.20±0.30)、(2.28±0.60)h,AUC0～2(46264±1581)、(6460±1535)ng·h·mL-1,AUC0～∞分别为(6379±1671)、(6571±1599)ng·h·mL-1,受试制剂相对于参比制剂的生物利用度为(97.5±11.9)%。结论:2种氯诺昔康制剂具有生物等效性。     

氯雷他定片在健康志愿者的药代动力学与生物等效性研究

目的比较深圳市海滨制药有限公司研制的氯雷他定片(受试制剂)和上海先灵葆雅制药有限公司生产的氯雷他定片(商品名开瑞坦,参比制剂)在健康人体内的药代动力学过程,并评价两制剂的生物等效性.方法20例健康男性受试者随机交叉单次口服氯雷他定片40 mg后,采用固相萃取反向HPLC法测定氯雷他定血浆浓度,进行有关生物利用度研究,并评价二者的生物等效性.结果单次口服参比与受试氯雷他定片40 mg后,主要药代动力学参数Cmax分别为34.9±16.6 μg·L-1与33.5±17.4μg·L-1,tmax分别为0.76±0.24h与0.75±0.26h,f1/2分别为1.63±0.48h与1.73±0.49h,AUC0-m分别为53.7±25.9μg·h·L-1与48.8±21.0μg·h·L-1,AUC0→∞分别为58.5±28.01μg·h·L-1与54.6±23.8μg·h·L-1.受试制剂相对于参比制剂的生物利用度F为94.5%±14.5%.结论统计分析结果显示,受试制剂与参比制剂生物等效.     

2种硫酸氢氯吡格雷片在健康人体内的药动学及生物等效性研究

目的:研究国产与进口硫酸氢氯吡格雷片在健康人体内的药动学特征及生物等效性。方法:采用标准两周期交叉设计自身对照试验方法,20名健康志愿者单剂量口服硫酸氢氯吡格雷片受试制剂(国产)或参比制剂(进口)75mg后,用液-质联用(LC-MS)法测定人血浆中氯吡格雷的浓度,计算其药动学参数并评价2种制剂的生物等效性。结果:受试制剂与参比制剂的各主要药动学参数分别为:tmax(0.64±0.21)、(0.68±0.27)h,cmax(1.724±1.38)、(1.752±1.856)ng·mL-1,t1/2(6.6±4.9)、(6.3±7.0)h,AUC0～36h(1.996±1.223)、(2.112±1.493)ng·h·mL-1,AUC0～∞(2.114±1.209)、(2.117±1.500)ng·h·mL-1。受试制剂相对于参比制剂的生物利用度为(108.9±52.2)%。结论:2种硫酸氢氯吡格雷片具有生物等效性。     

愈美分散片人体药动学及制剂生物等效性研究

建立了同时测定人血浆中氧去甲右美沙芬及愈创木酚甘油醚浓度的高效液相色谱 紫外检测法 ,并初步研究了以上两种药物在人体内的药动学性质。运用此法对 18名健康男性受试者单剂量交叉口服愈美分散片 (受试制剂 )和速立糖浆 (参比制剂 )后的酶水解血浆进行测定 ,并绘制了血浆药物浓度 时间曲线。口服愈美分散片测得 :氧去甲右美沙芬Tmax为 (1 89± 0 5 3)h ,Cmax为 (892 6±315 0 )ng/mL ,AUC0 -t为 (4 15 3 2± 115 1 9)ng·h·mL-1;愈创木酚甘油醚Tmax为 (0 6 5± 0 2 7)h ,Cmax为 (15 45 1± 493 6 )ng/mL ,AUC0 -t为 (2 6 89 8± 72 8 2 )ng·h·mL-1。口服速立糖浆测得 :氧去甲右美沙芬Tmax为 (1 81± 0 2 5 )h ,Cmax为 (85 5 0± 2 0 7 6 )ng/mL ,AUC0 -t为 (4 0 0 1 8± 75 3 5 )ng·h·mL-1;愈创木酚甘油醚Tmax 为 (0 5 0± 0 2 1)h ,Cmax 为 (1942 4± 437 6 )ng/mL ,AUC0 -t为 (3382 8±85 6 5 )ng·h·mL-1。氧去甲右美沙芬的相对生物利用度平均为 (10 3 6± 19 3) % ,愈创木酚甘油醚的相对生物利用度平均为 (86 9± 13 4) %。统计结果表明 ,两种制剂生物等效     

雷贝拉唑钠肠溶胶囊Beagle犬体内药动学及生物等效性研究

目的：建立HPLC-MS测定方法分析Beagle犬血浆中雷贝拉唑的含量,并作不同厂家两种雷贝拉唑钠肠溶胶囊的药动学及生物等效性研究。方法：6只Beagle犬随机分为两组,采用单剂量双周期交叉试验,分别口服给予60 mg雷贝拉唑钠肠溶胶囊受试制剂或参比制剂,给药后不同时间点采血,测定血药浓度,利用DAS3.0软件计算药动学参数,并比较两个厂家生产的制剂的生物等效性。结果：Beagle犬单次给予雷贝拉唑钠肠溶胶囊受试制剂和参比制剂后的tmax分别为（3.57±0.91）h和（3.43±0.87）h,Cmax分别为（539.03±129.13）ng·mL-1和（554.90±135.75）ng·mL-1,t1/2分别为（2.20±0.90）h和（2.09±0.78）h,药时曲线下面积AUC（0→24 h）分别为（1341.40±442.03）ng·h·mL-1和（1319.41±402.29）ng·h·mL-1。结论：结果表明不同厂家的两种雷贝拉唑钠肠溶胶囊具有生物等效性。     

进口与国产尼扎替丁制剂在中国健康人体的生物等效性

目的　研究进口与国产尼扎替丁在健康人体的药代动力学,并评价2种制剂的生物等效性。方法　用双交叉试验设计, 20名健康志愿者口服国产尼扎替丁片剂和进口胶囊剂,服药后0~8. 5h内间隔取血,用HPLC法测定血药浓度。计算主要药代动力学参数,并以胶囊剂为参比制剂,计算尼扎替丁片剂的相对生物利用度,判断其生物等效性。结果　国产片剂和进口胶囊剂的体内药代动力学参数分别为:tmax为(1. 49±0. 48), (1. 38±0. 58)h;Cmax为(2319±511), (2408±572)ng·mL-1;MRT为(3. 08±0. 44), (2. 97±0. 46)h;t1 /2为(1. 55±0. 33), (1. 51±0. 21)h; AUC0-t为(6625±964), (6725±1078)ng·h·mL-1;AUC0-∞为(6836±973), (6928±1114)ng·h·mL-1。尼扎替丁片剂的相对生物利用度F0-8. 5h为(99. 67±13. 93)%。结论　2种制剂具有生物等效性。     

达那唑胶囊人体生物等效性研究

目的　研究达那唑胶囊的人体生物等效性与药动学。方法　 18名健康女性志愿者单剂量随机交叉口服达那唑胶囊的受试制剂和参比制剂 2 0 0mg ,用HPLC法测定血浆中达那唑浓度。结果　口服达那唑胶囊的受试制剂和参比制剂的药动学参数 :t1/ 2 (消除半衰期 )分别为 (8 73± 3 33)h和 (8 0 4± 4 19)h ;达峰时间分别为 (3 5± 1 3)h和 (3 7± 1 7)h ;达峰浓度分别为 (112 4 0± 6 7 34)ng·ml 1和 (12 4 79± 73 91)ng·ml 1;AUC0 2 4分别为 (976 5 4± 6 33 6 )ng·h·ml 1和 (94 6 6 4± 6 0 5 85 )ng·h·ml 1;AUC0 ∞ 分别为 (1189 2 2± 6 92 75 )ng·h·ml 1和 (1118 5± 6 37 11)ng·h·ml 1;达那唑胶囊的相对生物利用度F为(10 4 4± 17 9) %。对参数经统计学处理 ,两种制剂的药代动学参数相近。结论　两种达那唑胶囊具有生物等效性。     

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.     

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。     

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.     

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.     

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.     

Interaction of estrone and estradiol with DNA and protein of liver and kidney in rat and hamster in vivo and in vitro

[6,7-³H] Estrone (E) and [6,7-³H]estradiol-17 (E₂) have been synthesized by reduction of 6-dehydroestrone and 6-dehydroestradiol with tritium gas. Tritiated E and E₂ were administered by oral gavage to female rats and to male and female hamsters on a dose level of about 300 g/kg (54 mCi/kg). After 8 h, the liver was excised from the rats; liver and kidneys were taken from the hamsters. DNA was purified either directly from an organ homogenate or via chromatin. The radioactivity in the DNA was expressed in the units of the Covalent Binding Index, CBI = (mol chemical bound per mol DNA-P)/(mmol chemical administered per kg b.w.). Rat liver DNA isolated via chromatin exhibited the very low values of 0.08 and 0.09 for E and E₂, respectively. The respective figures in hamster liver were 0.08 and 0.11 in females and 0.21 and 0.18 in the males. DNA isolated from the kidney revealed a detectable radioactivity only in the female, with values of 0.03 and 0.05 for E and E₂, respectively. The values for male hamster kidney were < 0.01 for both hormones. The minute radioactivity detectable in the DNA samples does not represent covalent binding to DNA, however, as indicated by two sets of control experiments. (A) Analysis by HPLC of the nucleosides prepared by enzyme digest of liver DNA isolated directly or via chromatin did not reveal any consistent peak which could have been attributed to a nucleoside-steroid adduct. (B) All DNA radioactivity could be due to protein contaminations, because the specific activity of chromatin protein was determined to be more than 3,000 times higher than of DNA. The high affinity of the hormone to protein was also demonstrated by in vitro incubations, where it could be shown that the specific activity of DNA and protein was essentially proportional to the concentration of radiolabelled hormone in the organ homogenate, regardless of whether the animal was treated or whether the hormone was added in vitro to the homogenate.Carcinogens acting by covalent DNA binding can be classified according to potency on the basis of the Covalent Binding Index. Values of 10³–10⁴ have been found for potent, 10² for moderate, and 1–10 for weak carcinogens. Since estrone is moderately carcinogenic for the kidney of the male hamster, a CBI of about 100 would be expected. The actually measured limit of detection of 0.01 places covalent DNA binding among the highly unlikely mechanisms of action. Similar considerations can be made for the liver where any true covalent DNA binding must be below a level of 0.01. It is concluded that an observable tumor induction by estrone or estradiol is unlikely to be due to DNA binding.Paper presented at the Satellite Symposium of the European Society of Toxicology, Rome, March 29, 1983     

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.     

Isolation and characterization of glycosylated and non-glycosylated prolactins from alligator and crocodile

Two molecular forms of prolactin (PRL). glycosylated and non-glycosylated, were isolated from pituitary glands of two reptiles, alligator and crocodile. The reptilian PRLs were extracted under alkaline conditions from the precipitate obtained after pituitaries were first extracted with 0.25 m sucrose, 1 mM NH₄HCO₃, pH 6.3. Purification was performed by ion exchange chromatography on DE-52, gel filtration on Sephadex G-75 superfine, and reversed phase high performance liquid chromatography. Two forms of both alligator and crocodile PRL, designated PRLI and PRLII, with molecular weights of 26000 and 24000 were isolated. Alligator and crocodile PRLI and PRLII were stained specifically in immunoblots with anti-sea turtle PRL and anti-ostrich PRL. Sequence analysis revealed that both forms of alligator and crocodile PRLs consisted of 199 amino acid residues with a glycosylation consensus sequence (Asn-Ala-Ser) at position 60 in alligator and crocodile PRLs with a molecular weight of 26000 (PRLI). In contrast, Thr was substituted for Asn at position 60 in the PRLs with a molecular weight of 24000 (PRLII). The sequences of alligator PRLs differed from crocodile PRLs only in position 134: Val for alligator PRLs and He for crocodile PRLs. There is a high degree of structural conservation between the reptilian PRLs isolated in this study and avian PRL; each showed 92% sequence identity with chicken PRL and 89% with turkey PRL.