目的 探讨血清CK19片段检测方法对恶性肿瘤的诊断价值,并与Cyfra21-1进行比较.方法 应用CK19-2G2和Cyrfa21-1的检测试剂盒,分别检测恶性肿瘤患者200例(包括肺癌患者51例、胃癌患者34例、膀胱癌患者47例、胰腺癌患者37例、乳腺癌患者31例)、良性病变患者110例和健康者113例.结果 恶性肿瘤患者CK19-2G2和Cyfra21-1检测结果均显著高于良性病变患者,差异有统计学意义(P＜0.05);良性病变患者CK19-2G2和Cyfra21-1检测结果均显著高于健康者,差异有统计学意义(P＜0.05).CK19-2G2诊断肺癌、膀胱癌、胰腺癌及全部恶性肿瘤的灵敏度要高于Cyfra21-1,差异具有统计学意义(P＜0.05).结论 通过ROC曲线分析,CK19-2G2对于恶性肿瘤的诊断准确性要优于Cyfra21-1,2种标志物联合检测的诊断准确性要高于单一标志物检测.CK19-2G2可以作为一种广谱性肿瘤标志物对恶性肿瘤进行辅助诊断.

OBJECTIVETo investigate the pharmacokinetics of Ambroxol and Clenbuterol Tablets in Chinese healthy volunteers after a single or multiple dosages oral administration.METHODSA total of 9 healthy adult subjects were given Ambroxol and Clenbuterol Tablets in a single dosage or multiple dosages respectively. LC/MS/MS were used for the determination of Ambroxol and Clenbuterol of in plasma. The important pharmacokinetic parameters were calculated by DAS 2.0 software (compartment model).RESULTSSingle and multiple dosage groups of Ambroxol and Clenbuterol were all fitted two-compartment model. The pharmacokinetics fitted first order kinetics process. No difference in pharmacokinetics of Ambroxol in single and multiple dosage groups volunteers was observed, Which showed no marked changes, suggesting that multiple dosing did not influence the velocity of drug metabolism. Moreover, parameters of Clenbuterol had significant difference between the single and multiple dosage groups (P<0.05), showing there was accumulation in the body. 9 subjects had completed single or multiple dosages oral administration test, with no adverse drug reactions appeared during the test.CONCLUSIONThere was no obvious accumulation of Ambroxol after repeated dosing. But obvious accumulation of Clenbuterol was noted in multiple-dose administration. The established method is sensitive, accurate, reliable and specific, and it can meet the requirement of clinical pharmacokinetic trial.

目的 研究厄多司坦胶囊在健康人体的药代动力学,评价其生物等效性.方法 20名男性志愿者随机分为2组,按照两制剂两周期的随机交叉试验设计,分别单剂量口服厄多司坦试验或参比制剂各1粒(0.3 g),采用LC-MS/MS法测定血浆中厄多司坦及其代谢产物M1的浓度,用DAS2.0药动学软件分别计算厄多司坦及其代谢产物M1药动学参数并进行生物等效性统计分析.结果 试验及参比片的厄多司坦的主要药动学参数Cmax分别为(1570.7±488.3)和(1447.8 ±449.9) ng ·ml-1;Tmax分别为(1.1±0.5)和(1.2±0.5)h;t1/2分别为(1.3±0.3)和(1.3±0.4)h;AUC(0-10h)分别为(3444.7±1242.4)和(3229.9±1225.6)ng·h ·ml-1;AUC(0-∞)分别为(3485.0±1233.7)和(3279.6±1233.7) ng·h·ml-1;双单侧t检验结果表明,厄多司坦受试制剂Cmax的90％置信区间落在参比制剂的94.1％～124.4％范围内,AUC(0-10h)的90％置信区间落在参比制剂的90.7％ ～ 123.9％范围内;受试制剂对参比制剂厄多司坦的相对生物利用度F为(116.6±36.6)％.试验及参比片的M1的主要药动学参数Cmax分别为(396.5±177.6)和(385.0±192.7) ng·ml-1;Tmax分别为(1.7±0.8)和(1.9±0.7)h;t 1/2分别为(2.6±0.9)和(2.6±1.1)h;AUC(0-10h)分别为(1259.2±609.8)和(1331.3±694.0)ng·h·ml-1;AUC(0-∞)分别为(1372.4 ±607.3)和(1451.7 ±719.0) ng·h·ml-1;双单侧t检验结果表明,M1受试制剂Cmax的90％置信区间落在参比制剂的89.2％ ～ 121.1％范围内,AUC(0-10h)的90％置信区间落在参比制剂的80.9％ ～111.6％范围内;受试制剂对参比制剂M1的相对生物利用度F为(103.2±39.6)％.结论 对厄多司坦及其代谢产物M1的主要药动学参数进行评价,按照生物等效性判定标准,认为2种制剂生物等效.

Objective To establish a pyrosequencing method for detection of AGTR1 A1166 C gene polymorphism,and verify the accuracy of this method study correlation between AGTR1 A1166 C and primary hypertension. Methods The accuracy of the pyrosequencing 192 volunteers are detected by 3 730 type machine provided by ABI company. The genotypes of 100 patients with essential hypertension and 100 healthy persons are detected by pyrosequencing. Results The results of pyrosequencing are consistent with ABI-3730 xl. 1166 C allele frequency(7. 5. %) of EH patients is higher than healthy persons'(6. 0%) without statistical significance(P 0. 05). Conclusion Pyrosequencing is a reliability and convenient method. There is no correlation between AGTR1 A1166 C gene polymorphism and EH.

The aim of the present study was to investigate the pharmacokinetic and pharmacodynamic characteristics of febuxostat following the administration of single and multiple oral doses under fasting conditions to healthy individuals. Thirty-six healthy subjects were randomly divided into three groups, each containing 12 subjects (six male and six female) as follows: Group A, treated with a single oral dose of febuxostat (40 mg); group B, treated with a single oral dose of febuxostat (80 mg) followed by multiple oral doses of febuxostat for 7 days; and group C, treated with a single oral dose of febuxostat (120 mg). Blood samples were collected, and the plasma drug levels and serum uric acid (UA) concentrations were determined by clinical laboratory testing. Febuxostat displayed a linear pharmacokinetic profile for oral doses of 40 to 120 mg. Drug accumulation was not detected following multiple oral doses. When febuxostat was administered as single doses of 40, 80 and 120 mg, the 24-h UA concentration (UA24) values displayed a linear correlation with the dosage. The relationship between UA24 and the three single dose levels (40, 80 and 120 mg) was analyzed. The difference in UA24 between every single dose was significant (P<0.05). After 3 and 7 days of dosing, reductions of 46.67 and 52.69%, respectively, were observed in UA24. On day 7 of dosing, the mean reduction in the UA concentration was 51.83±7.00%. This study demonstrates that febuxostat reduces serum UA concentrations in a dose-linear manner.

Objective To study the allelic frequency of UGT1A1 and UGT2B7 genes,and the relationship be-tween the mutations of UGT1A1 and UGT2B7 genes and colorectal cancer. Methods The DNA of blood sampls from 335 healthy subjects and 348 cases of colorectal cancer was extracted to determine the allelic frequency of the UGT1A1 and UGT2B7 mutant. Results The mutative frequency of UGT1A1*6 was 8. 07% in healthy subjects and 16. 52% in patients with colorectal cancer respectively,being significantly different( P ﹤0. 001,OR= 3. 34,95%CI:2. 12-6. 72). The muta-tive frequency of UGT1A1*28 was 7. 32% in healthy subjects and 11. 50% in patients with colorectal cancer respective-ly,also with significant difference( P =0. 011,OR=1. 73,95%CI:1. 21-1. 84). The mutative frequency of UGT2B7-1 and UGT2B7-2 was not significanthy different between healthy subjects and patients with colorectal cancer. Conclusion The gene mutation of UGT1A1*6 and UGT1A1*28 was related to colorectal cancer. The gene mutation of the UGT1A1*6may increase the risk of colorectal cancer,and UGT1A1*6 gene might be the high-risk predisposing gene of colorectal cancer.

Objective To study the allelic frequency of UGT1A7 and UGT1A8 genes, and relationship between the mutations of UGT1A7 and UGT1A8 genes with colorectal cancer. Methods To determine the allelic frequency of the UGT1A7 and UGT1A8 mutant in a group of 297 healthy subjects and 301 colorectal cancer. To study the relationship of UGT1A7 and UGT1A8 gene polymorphism with colorectal cancer. Results The allelic frequency of the UGT1A7*2*2 and UGT1A7*3*3 were 14.29%and 15.28%in colorectal cancer respectively, obviously super 3.70%and 3.37%in healthy subjects, to compare the allelic frequency of two groups, P=0.013, OR=4.31(95%CI:1.12-6.33) and P=0.002, OR=6.32 (95%CI:2.10-9.61) respectively. they were significant difference. The allelic frequency of the UGT1A8*1*3 were 16.94%and 3.03%in colorectal cancer and healthy subjects respectively, and had also significant difference, P<0.000, OR=8.46(95%CI:2.18-11.54). Conclusions The gene mutation of the UGT1A7*2*2, UGT1A7*3*3, UGT1A8*1*3 and UGT1A8*2*3 were correlation with colorectal cancer. The gene mutation of the UGT1A7*2*2, UGT1A7*3*3, UGT1A8*1*3 and UGT1A8*2*3 may increase risk of the colorectal cancer, and UGT1A7*3*3, UGT1A8*2*3 gene mutation were high risk predisposing gene of the colorectal cancer.

目的 评价人ALDH2基因多态性检测试剂盒(荧光PCR法)用于人ALDH2基因c.1510位点(G/A)核苷酸多态性检测的准确性和有效性.方法 将入选人基因组DNA标本371例采用金标准和临床待考评试剂盒进行同步盲法检测,试验结束后揭盲,将试验试剂检测结果与金标准检测结果进行统计比较分析.结果 人ALDH2基因多态性检测试剂盒(荧光PCR法)与DNA直接测序法(Sanger测序法)金标准检测结果相比,两者基因型总符合率为99.19％,临床诊断评价总符合率99.46％,有较高的一致性.结论 人ALDH2基因多态性检测试剂盒(荧光PCR法),无放射性危害,具有高灵敏性、高特异性、试剂周期长等特点,可以在临床检验中推广使用.

目的 系统评价五酯胶囊(片)对他克莫司(FK506)血药浓度及药动学参数的影响.方法 检索PubMed、中国生物医学文献数据库、中国知网、万方数据,五酯胶囊(片)与FK506合用治疗肝肾移植患者的随机对照试验,检索时限2004年1月 2014年1月.由2位评价员根据纳入与排除标准独立进行文献筛选、资料提取并质量评价后,采用RevMan 5.2软件进行Meta分析.结果 纳入10个临床随机对照试验,共491例患者.根据干预时间的长短进行亚组分析,Meta分析结果显示:(1)干预1个月后:与FK506组相比,合用组血药浓度显著增加[SMD =0.75,95％ CI(0.54,0.97),P＜0.001],FK506剂量减少[SMD=-1.52,95％CI(-1.78,-1.26),P＜0.001];(2)干预3个月后:合用组血药浓度显著增加[SMD=0.44,95％ CI(0.25,0.64),P＜0.001],FK506剂量减少[SMD=-1.71,95％CI(-1.95,-1.47),P＜0.001];(3)药代动力学主要参数:峰浓度Cmax[SMD=1.57,95％CI(0.26,2.09),P=0.002],药时曲线下面积(AUC0h)[SMD=1.66,95％CI(1.10,2.23),P＜0.001]和达峰时间(tmax)[SMD=1.03,95％CI(0.52,1.55),P＜0.001]有显著差异.结论 五酯胶囊(片)对FK506组的血药浓度有显著影响,可提高其血药浓度,降低其用量,提高生物利用度.受限于纳入研究数量,上述结论尚需今后开展更多大样本、高质量的临床试验加以验证.

Objective To explore the correlation between polymorphism of UDP-glucuronosyltransferase 1A ( UGT1A1) and UGT1A3 genes with hyperbilirubinemia in neonates. Methods The DNA of blood samples were extrac-ted from 347 healthy neonates in three hospitals in Beijing ( healthy neonatal group) and 97 neonates with severe neonatal hyperbilirubinemia ( severe hyperbilirubinemia group ) and 139 neonates with hyperbilirubinemia ( hyperbilirubinemia group) to determine the UGT1A1 and UGT1A3 genotypes, and the correlation between the polymorphism of UGT1A1 and UGT1A3 genes and hyperbilirubinemia was also researched. Results The frequency of UGT1A1 gene mutations was compared between healthy neonatal group and severe hyperbilirubinemia and hyperbilirubinemia groups respectively, and the differences in frequencies (M%) of UGT1A1*6, UGT1A1*28 and UGT1A3*2 genes were statistically signif-icant (P<0. 01, P<0. 05);while the differences in the above frequencies between the severe hyperbilirubinemia group and hyperbilirubinemia group were not statistically significant ( P >0. 05 ) . The differences in frequencies of other UGT1A3 genes among the three groups were not statistically significant (P >0. 05). Conclusion Gene mutation of UGT1A1 *6, UGT1A1*28 and UGT1A3*2 is associated with neonatal hyperbilirubinemia, and it is a predisposing gene of hyperbilirubinemia disease, but it is not associated with the severity degree of hyperbilirubinemia.

OBJECTIVE:To investigate the related influential factors of clopidogrel resistance in northern Han Chinese with coronary heart disease. METHODS:425 northern Han Chinese patients uncerwent first percutaneous coronary intervention were chosen and divided into clopidogrel resistance group(CRG)and clopidogrel sensitivity group(CSG)according to platelet aggregation rate. Genotypes of them were detected,and the carry of CYP2C19*2 allele was analyzed;the relevance of biochemical index as platelet aggregation rate and susceptibility index of coronary heart disease with clopidogrel resistance were compared. RESULTS: The frequency of CYP2C19 gene G861A mutation carriers(GA,AA)in CRG and CSG were 64.4% and 33.1%,respectively; there was statistical significance(P0.000 1). The nongenetic factors showed no statistical difference between 2 groups(P0.05). CONCLUSIONS:The carry of CYP2C19*2 allele is significant relevant with the occurrence of clopidogrel resistance,and G681A mutation is a predictor for clopidogrel resistance. Other nongenetic factors show no significant effect on clopidogrel resistance.

抗菌药物使用的合理与否对减少耐药菌株的产生和预防手术部位感染有重要意义［1］。为进一步加强医疗机构抗菌药物临床应用管理，促进抗菌药物合理使用，有效控制细菌耐药，保证医疗质量和医疗安全，2011年、2012年卫生部在全国范围内开展抗菌药物临床应用专项整治活动，将Ⅰ类切口手术预防用药作为抗菌药物专项整顿的重点内容之一。为落实规定，本院采取一系列措施对抗菌药物的使用进行管理，其中针对Ⅰ类切口围手术期预防用药进行调查分析，并针对性的进行干预。现对调查分析及干预效果报告如下。

Objective :To study the efficacy of Shutong Capsules on promoting large intestine enterokinesia and gastrointestinal hormones of the slow transit constipation in rats.Methods :Sixty Wistar rats were randomly divided into normal control group(10 rats)and model group(STC,50 rats).Fifty STC rats were divided into 5 groups :STC model group,Shutong Capsules low dosage,middle dosage and high dosage(0.54,1.08,2.16 g·kg-1·d-1)groups,and Maren pills group.After 2-week treatment,the discharge time of the first black feces,the black feces' s total number at 5 hours and 12 hours were observed.Levels of plasma substance P(SP),nitric oxide(NO)and motilin(MTL)were determined.Results :Shutong Capsules middle and high dose groups' rats shortened discharge time of the first black feces and increased black discharge points(P<0.05,P<0.01).Shutong Capsules middle dosage and high dosage groups' plasma substance P(SP),nitric oxide(NO)and motilin(MTL)contents difference were statistically significant(P<0.05).Conclusion :Shutong Capsules can obviously promote facilitation function to the STC rats colon,raise SP and MTL levels,and reduce NO level of STC,which is probably due to its regulation of the gastro intestinal hormones levels.

Objective To investigate the effect of Tongxuan Lifei pill on CYP2D6and to provide foundation for clinical drug using.Methods Thirty volunteers were divided into two groups according to CYP2D6gene type with dextromethorphan used as probe drug of CYP2D6.The effect of Tongxuan Lifei pill on the activity of CYP2D6was investigated.Genetic classification was fulfilled by pyrosequencing method,and the blood concentration of probe drug and its metabolic product was determined by HPLC-MS/MS.The volunteers took Tongxuan Lifei pill for two weeks and AUC0~12 was used as the standard of the activity of CYP2D6.Results The activity value was 6.1±1.5before administration of drug and 6.5±1.7after drug using.The activity of CYP2D6was decreased after drug using,t-test was used for comparison,there existed no remarkable difference between the data.Conclusion Tongxuan Lifei pill has no obvious affection on the activity of CYP2D6.

目的探讨可舒胶囊对酒精所致大鼠急性肝损伤的保护作用及机制。方法采用酒精灌胃辅以高脂饲料法复制急性酒精性肝损伤小鼠模型,以血清谷酰转肽酶（GGT）、血清丙氨酸转氨酶（ALT）和天门冬氨酸转氨酶（AST）水平为模型参考指标。50只雄性昆明小鼠随机分为5组:正常对照组、肝损伤模型组、可舒胶囊低、中、高剂量（0.78、1.56、3.12 g/kg）干预组,每组10只。检测小鼠肝组织天冬氨酸特异酶切的半胱氨酸蛋白酶（Caspase）-3,-8活性。结果模型组小鼠血清GGT[（4.52±0.26）U/L]、ALT[（173.09±8.79）U/L]、AST[（141.90±7.82）U/L]水平较正常对照组显著升高（P＜0.01）;可舒胶囊高、中、低剂量干预组小鼠血清GGT水平分别为（1.42±0.10）、（2.65±0.41）、（3.25±0.56）U/L;ALT分别为（72.19±8.19）、（78.52±9.72）、（98.95±10.70）U/L;AST水平分别为（70.27±8.19）、（77.46±5.94）、（94.57±5.26）U/L;较模型对照组显著降低（P＜0.01）。模型组小鼠肝组织Caspase-3活性为（6.54±0.43）U/mgpro,Caspase-8活性为（2.71±0.23）U/mgpro,较正常对照组显著升高（P＜0.01）;可舒胶囊高、中、低剂量组小鼠肝组织Caspase-3活性分别为（2.57±0.33）、（3.20±0.30）、（4.32±0.35）U/mgpro;Caspase-8活性分别为（1.13±0.25）、（1.43±0.29）、（1.98±0.31）U/mgpro,较模型组显著降低（P＜0.01）。结论酒精肝损伤小鼠肝组织Caspase-3与Caspase-8活性显著升高,可舒胶囊对其具有明显抑制作用。

OBJECTIVE To study the pharmacokinetic and pharmacodynamic characteristics of domestic bivalrudin for injection in Chinese health volunteers.METHODS Forty-eight health volunteers were randomized to receive a bivalirudin 0.5,0.75,1.05 mg·kg-1 by single intravenous injection and a bivalirudin 0.75 mg·kg-1 single intravenous injection followed by a 4-hour infusion at 1.75 mg·kg-1·h-1.At a series of time points before or after administration,the blood samples ware collected for plasma drug level,activated clotting time(ACT),prothrombin activity(PA),prothrombin time(PT),activated partial thromboplastin time(APTT),fibrinogen(FIB).Drug level were determinde by LC-MS-MS.ACT,PA,PT,APTT and FIB were detemined by clinical laboratory.RESULTS When the dosage of bivalirubin are 0.5-1.05 mg·kg-1,there is linear pharmacokinetic character.Drug accumulation was not detected after sequential administration.When bivalirubin were administered at a bolus dose of 0.5,0.75,1.05 mg·kg-1,ACTmax are respectively(149.3±26.4)s,(180.7±21.8)s and(197.3±20.7)s,and are linear corrected to dosage(P<0.05).The relation between peak time of effect(ACT-tmax) and peak time of drug level(tmax) was analysised.The difference between ACT-tmax and tmax was not significant(P>0.05) when the dosage were 0.5 mg·kg-1 and 0.75 mg·kg-1,but it was significant(P<0.05) when the dosage were 1.05 mg·kg-1.When the drug was administered by infusion after bolus sequentially,The difference between ACT-5min and ACT-4h was not significant(P>0.05),this indicated that ACT was maintained in stable range when the drug was infused.The levels of PA,PT,APTT and FIB are linear corrected to dosage and plasma drug level and return to normal range soon after drug discontinuance.CONCLUSION Domestic bivalirdin increase the level ACT,APTT and PT,and dicrease the level of PA,the effect of anticoagulation is linear corrected to dosage and plasma drug level.The clinic indexes of blood clotting return to normal range soon after drug discontinuance.

Objective To investigate the effect of CYP2C9 polymorphism on the pharmacokinetics of meloxicam in Chinese healthy subjects.Methods The CYP2C9 genotypes of twenty-four Chinese healthy male subjects were selected by the pyrosequencing method.The subjects were genotyped with CYP2C9*3 wild-type and mutation.HPLC-MS-MS method was used for the determination of meloxicam in plasma.The important pharmacokinetic parameters were caculated by DAS 2.0 software.The pharmacokinetics of meloxicam based on identification of genotypes(CYP2C9*3 wild-type and mutation) was compared.Results Two kinds of CYP2C9*3 phenotype existed in the subjects.CYP2C9* 3(A/A) was found in twenty-two subjects while CYP2C9*3(A/C) in two subjects.For meloxicam,the A/A of CYP2C9*3 alleles was more active than the A/C.Conclusion CYP2C9 genetic polymorphism has significant influence on the pharmacokinetics of meloxicam.A/A is more active than A/C.Pharmacogenomic studies will help rational and individualized medication.

Objective To screen the proper excipients and the preparation process for Shutong Sugar-free Particles.Methods By analyzing the resistance to moisture and moldability,the types and ratio of the excipients and the different preparation process were screened out.Results The most proper preparation was consisted of 95% of the extract of Shutong,4% of lactose,1% of mannit,and then adding 15% of phycite as flavor.Conclusion The optimized granules are characterized with a high resistance to moisture,solubility and moldability.

Objective To study the relative bioavailability of levofloxacin hydrochloride oral liquid and tablets in healthy volunteers. Methods In a randomized two- way crossover design,a single oral dose of 200mg levofloxacin hydrochloride oral liquid and tablets were given to 24 male healthy volunteers.The plasma levofloxacin concentration within 36 h after administration was determined by HPLC and parameters C_(max),T_(max),T_(1/2),AUC_((0-1)),AUC_((0-∞)) were obtained and analyzed by two- one side test.Results The C_(max) were(2.80±0.59) and(2.64±0.56)μg /ml,respectively;T_(max) were(0.66±0.18 ) and(0.82±0.34) h,respectively;T_(1/2) were (6.60±1.37)and(7.26±1.20) h,respectively;AUC_((0-t)) were(14.97±2.32)μg.h/ml和(15.04±2.32)μg·h/ml,AUC_((0-∞)) were(15.66±2.38 ) and(15.92±2.35 )μg.main pharmacokinetic parameters of levofloxacin hydrochloride oral liquid and tablets were as follows:C_(max) was(2.80±0.59) and(2.64±0.56)μg/ml,respectively;T_(max) was(0.66±0.18) and(0.82±0.34) h,respectively; T_(1/2) was(6.60±1.37) and(7.26±1.20) h,respectively;AUC_((0-t)) was(14.97±2.32)μg·h/ml and(15.04±2.32)μg·h/ml,respectively.AUC_((0-∞)) was(15.66±2.38) and(15.92±2.35)μg·h/ml,respectively.There was no statistically significant difference between these two test groups.The relative bioavailability of the test oral liquid was(100.1±10.6)%.Conclusions The levofloxacin hydrochloride oral liquid and tablets are bioequivalent.

OBJECTIVE To study the pharmacokinetics and pharmacodynamics of amlodipine in healthy subjects and explore the relationship between the blood concentration of amlodipine and the antihypertensive effect. METHODS 24 male volunteers were administered 10 mg amlodipine by single dose.The blood samples of different time points in these subjects were sampled and the drug concentrations of amlodipine were analyzed by LC-MS-MS,and the primary variables measured in this study were systolic and diastolic blood pressure(SBP and SDP) and pulse rate in a sitting position. RESULTS Amlodipine was a two-compartment model with slow elimination(t1/2,36 h) and a large apparent volume of distribution.The Cmax was(6.1±1.5)ng·mL-1.SBP and SDP were depressed after administration,and it was related to the change of drug concentration.The efficacy hysteresis rings were found from the curves of efficacy-concentration. CONCLUSION Amlodipine can depress the SBP and DBP with efficacy hysteresis.The most efficacy Emax(SBP:6.3±3.2 mmHg,DBP:10.1±2.9 mmHg) was appeared after administration 6-10 h.The efficacy hysteresis was better form on the antihypertensive effect in clinical therapy.