HPLC法测定人血浆中胺碘酮浓度的临床研究

目的建立测定人体内胺碘酮血药浓度的方法。方法以地西泮为内标,用乙酸乙酯提取500μl血样,以KromasilC18柱(5mm×250mm,4.6μm)为固定相,甲醇:水:三乙胺:冰醋酸=80:20:0.1:0.08(体积比)为流动相,流速0.8ml/min,检测波长为240nm,柱温为30℃。结果本方法在0.256～5.12mg/L之间线性良好,回归方程为Y=3.8456X-0.2507,r=0.9951,日内及日间RSD10%,最低检测浓度为0.128mg/L。结论该方法简便、准确,适用于胺碘酮的血药浓度监测和药动学分析。     

改良HPLC法测定人体血浆氯雷他定水平

氯雷他定为新一代抗组织胺药物,在治疗剂量范围内几乎无明显神经系统毒副作用。目前关于氯雷他定水平的测定方法有放射免疫法、化学发光法、气相色谱法、高效液相色谱法（HPLC）等,但均存在不足之处。2010年1月,我们采用改良HPLC法对人体血浆中氯雷他定质量浓度进行测定,效果满意。现报告如下。     

HPLC法测定九味羌活丸中异欧前胡素的含量

近年来,我们应用高效液相色谱法(HPLC)测定了九味羌活丸中的异欧前胡素含量现报告如下.     

肝性低氧血症患者血流动力学及血浆中一氧化氮水平变化研究

目的探讨肝硬变门脉高压患者发生低氧血症的机制.方法采用心脏、腹部彩色超声多普勒测定31例肝硬变门脉高压患者和18例正常对照的血流动力学参数,并同时测定血气分析和肺功能及外周血中一氧化氮浓度.结果肝硬变门脉高压患者中14例发生低氧血症(45.16%),肝硬变组肺动脉收缩压(PASP)、血浆中的一氧化氮(NO)均明显高于正常对照组(P=0.0083,P=0.0327),门静脉血流速度(Vp)明显低于正常对照组(P=0.0416),而肺功能无明显改变.结论肝硬变门脉高压患者的全身高动力循环状态导致肺血管功能性或解剖性分流,造成通气与血流比例失调,是导致低氧血症的主要原因,其中一些血管活性物质如NO等可能参与了低氧血症的发生和发展.     

超高效液相色谱-串联质谱法检测兔血浆中利格列汀及其药代动力学研究

［摘要］　目的　建立一种检测兔血浆中利格列汀浓度的超高效液相色谱-串联质谱（UPLC-MS/MS）的方法。方法　以地西泮为内标,血浆样品用乙腈沉淀后检测。用Acquity UPLC BEH C18柱为分离柱,流动相：乙腈-0.1%甲酸梯度洗脱,总运行时间为3.0 min,利格列汀的洗脱时间为1.09 min;用AcquityXevo TQD三重四级杆质谱仪检测,用多反应监测法测定样品中的药物浓度。考察该方法的专属性、线性关系、精密度、准确度和回收率及稳定性。结果　色谱图显示血浆中的利格列汀保留时间为1.09 min,无内生峰干扰;校准曲线的典型方程：y=0.1646x+0.0303,r=0.9914,线性关系良好;日内、日间精密度及准确度范围均低于15%;药物回收率在76.0%～82.1%范围内;在不同储存条件下浓度的偏差在均值的±15%以内,较稳定。结论　该方法简便、快速,可用于兔血浆利格列汀的检测、药代动力学研究和药物相互作用研究。     

头孢菌素类的临床药物动力学研究及给药方案的制订

为了制订给药方案，作者对第一、二、三代９种头孢菌素在健康志愿者中的药物动力学进行了研究，包括头孢唑啉、头孢拉定、头孢羟氨苄、头孢呋辛、头孢噻肟、头孢唑肟、头孢曲松、头孢他啶和头孢克肟。测定了单剂给药后的血尿浓度，计算了药动学参数，并进行了比较，全部注射给药头孢菌素血药浓度均高，以头孢曲松为最高，口服者头孢克肟最低。消除半减期多为１～２小时，然头孢曲松长达８小时。大部分头孢菌素自肾排泄，给药后２４小时内自尿中排出给药量的８６％￣９６％，而头孢曲松、头孢克肟和头孢噻肟则分别排出３７％、２４％和５１％。根据本研究中获得的药动学资料，提出不同头孢菌素类治疗各种感染的给药方案。     

抗结核药物药代动力学/药效学的研究及进展

结核病治疗需要联合使用多种药物且治疗时间较长,迫切需要研发抗结核新药。抗结核新药的研发成果十分有限,对现有药物体内外的药代动力学/药效学(pharmacokinetic/pharmacodynamic,PK/PD)进行研究,优化抗结核药物的使用,对提高疗效,减少耐药结核病的发生至关重要。作者主要对PK/PD研究方法及抗结核药物PK/PD特点进行综述,为临床优化抗结核药物治疗方案提供参考。     

妥布霉素经呼吸机进入中老年患者体内后的药物代谢动力学及肺内分布

医院感染性肺炎在重症监护病房（ICU）靠呼吸机辅助呼吸的患者中发生率为9％-60％，死亡率为35％。这些感染60％是由革兰阴性杆菌引起的。妥布霉素为氨基甙类抗生素，常用于革兰阴性杆菌引起的严重感染。但静脉应用妥布霉素渗入到肺薄壁组织的含量低，进入支气管分泌物的更少，极大地影响了疗效。本研究应用高效液相色谱技术研究了妥布霉素在靠呼吸机辅助呼吸的患者吸入后的体内药物代谢动力学及其吸入后的肺内分布。     

Influence of hydrolysis on plasma homocysteine determination in healthy subjects and patients with myocardial infarction

After acid hydrolysis, mean plasma homocysteine concentrations, measured as homocysteine disulphides, of about 1000 and 40 mumol/l have recently been reported in 26 survivors of myocardial infarction and 26 matched control subjects, respectively. This finding contrasts sharply with those more than 50 times lower total homocysteine concentrations found by other research groups in non-hydrolysed plasma from survivors of myocardial infarction. Using the same hydrolysis conditions, we could not detect any homocysteine disulphides in plasma hydrolysates from 9 survivors of myocardial infarction and 10 healthy subjects, who had mean total homocysteine concentrations in non-hydrolysed plasma of 16.9 +/- 6.5 and 15.8 +/- 10.3 mumol/l, respectively. The chromatograms contained several peaks, probably representing peptides, which disappeared with more complete hydrolysis and which might have been misinterpreted as homocysteine disulphides in the reported study. Only after reduction of disulphides and by using a sulphydryl-selective extraction procedure were we able to determine mean homocysteine concentrations in hydrolysed plasma to be 26.2 +/- 7.9 mumol/l in the survivors of myocardial infarction and 24.5 +/- 12.2 mumol/l in the healthy reference subjects. Thus, we could not confirm that survivors of myocardial infarction have homocysteine concentrations that are many times higher than found in healthy subjects.     

中国健康受试者多剂口服吉米沙星的药代动力学及药效学研究

目的 研究中国健康受试者对吉米沙星的临床药代动力学(PK)和药效学(PD),为优化临床给药方案提供依据.方法 随机、双盲临床试验中,招募20名健康受试者按1∶1比例分为给药组或对照组,分别予以多剂口服320 mg吉米沙星或安慰剂.高效液相色谱荧光法测定受试者血浆和尿液的药物浓度.采用微量稀释法测定吉米沙星对190株社区获得性肺炎常见临床分离菌株的最低抑菌浓度(MIC).以给药后24 h血浆药物浓度时间曲线下面积(AUC0～24h)与MIC的比值(fAUC0～24 h/MIC)和药物峰浓度(Cmax)与MIC的比值(fCmax/MIC)为指标(靶值为25和5),评价吉米沙星的PK和PD特性,并采用蒙特卡洛模拟评价吉米沙星320 mg 1次/d在稳态血药浓度下对上述细菌的累积反应百分比(CFR)及不同MIC水平下的PD达标概率.采用F检验对各组数据作方差齐性检验,采用t检验分析各组间数据.结果 健康受试者多剂口服吉米沙星320 mg 1次/d连续7d给药后的首剂和末剂Cmax分别为(1.55±0.32)和(1.57±0.31) μg/mL,AUC0～24h分别为(7.91±1.52)和(8.91±1.15)h·μg·mL-1,积蓄因子为1.13±0.05.吉米沙星在受试者体内的PK符合二房室模型,分布相和消除相半衰期分别为(0.64±0.17)和(7.10±2.10)h.首剂和末剂给药后24 h平均累积尿排出率分别达34.83％和38.95％.PD研究显示,吉米沙星对肺炎链球菌和卡他莫拉菌的MIC90分别为0.25和0.125 mg/L,对流感嗜血杆菌的MIC90为2 mg/L,而肺炎克雷伯菌和甲氧西林耐药金黄色葡萄球菌对吉米沙星大部分呈现耐药( MIC90＞32 mg/L).当吉米沙星对细菌的MIC值≤0.06mg/L时,吉米沙星320mg 1次/d连续7d给药方案达到fAUC0～24h/MIC和fCmax/MIC的药效学达标概率值均接近100％.结论 中国健康受试者单剂口服吉米沙星320 mg后吸收迅速,多剂给药后第3天达到稳态血药浓度,连续7d给药后有轻度蓄积.PK/PD分析显示,对该药敏感的社区获得性肺炎和慢性阻塞性肺病急性加重者预期可获得良好的临床和细菌学疗效.     

Single-dose pharmacokinetics of dicloxacillin in healthy subjects of young and old age

Dicloxacillin was administered as 2 g single intravenous doses to healthy young and old subjects of both sexes aged 19-32 years and 65-76 years, respectively, and the pharmacokinetics were studied. Peak serum concentrations were higher in young than in elderly subjects and in each age group in females than in males. The elimination rate was similar in all groups and the only striking pharmacokinetic differences observed were that the urinary recovery of active dicloxacillin was higher in young subjects and that the non-renal clearance was higher in elderly volunteers. The findings were interpreted to be due to a systemic metabolism of dicloxacillin, compensating for a reduced renal elimination in the elderly subjects. In all subjects dicloxacillin was well tolerated. No increases of serum creatinine were observed.     

The pharmacokinetics of free insulin-like growth factor-I in healthy subjects.

In a randomized cross-over study in five healthy males we compared 75-min constant i.v. infusion of saline, low-dose recombinant human (rh) insulin-like growth factor-I (rhIGF-I; 1.5 microg/kg/h) and high-dose rhIGF-I (9.0 microg/kg/h). Serum samples were analysed for ultrafiltered free IGF-I (fIGF-I), total IGF-I (tIGF-I), tIGF-II and IGF-binding protein-1 (IGFBP-1) and -3.Free and total IGF-I were unchanged during saline infusion. Low-dose rhIGF-I caused a small increment in fIGF-I [+41%, from 0.64 +/- 0.19 (mean +/- SEM) to 0.90 +/- 0.25 microg/l;P< 0.05] and tIGF-I (+9%, from 220 +/- 31 to 239 +/- 33 microg/l;P< 0.05). High-dose rhIGF-I increased tIGF-I by 40% (from 227 +/- 36 to 329 +/- 31 microg/l;P< 0.05), and fIGF-I by 11.5 times (from 0.56 +/- 0.20 to 6.46 +/- 1.39 microg/l;P< 0.05). The pharmacokinetic profile of fIGF-I was calculated after high-dose IGF-I only. The disappearance of fIGF-I followed first order kinetics with an apparent half-life of 14.4 +/- 1.0 [11.2-17.1 (range)] min. The clearance was estimated to 52 +/- 20 (16-128) ml/min/kg and the volume of distribution to 1102 +/- 464 (388-2899) ml/kg. In the three experiments, there were no differences in IGFBP-1, and tIGF-II and IGFBP-3 remained unchanged.In conclusion, fIGF-I remained within the physiological range after low-dose rhIGF-I, whereas high-dose rhIGF-I resulted in supraphysiological concentrations. Since the half-life estimates for each subject were remarkably similar, this parameter most likely does not explain the observed variation in clearance and volume of distribution of fIGF-I. Instead, differences in the circulating and cellular IGF-I binding capacity may be of importance.     

The influence of food on the pharmacokinetics of piperaquine in healthy Vietnamese volunteers

The combination piperaquine and dihydroartemisinin is emerging as first line treatment of uncomplicated falciparum malaria in Southeast Asia. The aim of this study was to determine the influence of a standard Vietnamese meal on the single-dose pharmacokinetics of piperaquine when administered in combination with dihydroartemisinin, and to gain extended data on the terminal half-life of piperaquine in healthy Vietnamese volunteers. Subjects were randomly assigned to take a single oral dose of piperaquine phosphate (640 mg)+dihydroartemisinin (80 mg) together with a standardized Vietnamese meal (n=16) or to remain fasting for 4h following drug intake (n=16). Frequent blood sampling was conducted during 36 h, followed by weekly samples for 7 weeks. The pharmacokinetic parameters of piperaquine were determined by noncompartmental analysis. The median (80% central range) AUC(0-last) was 11.5 (6.9-17.3)h mg/L in fed and 13.9 (2.8-19.3)h mg/L in fasting subjects, indicating a considerable variability in exposure in both groups. The estimated overall oral clearance was 0.27 (0.12-1.49)L/(h kg), the volume of distribution during the terminal elimination phase was 230 (102-419)L/kg and estimated terminal half-life was 18 (5-93) days. This study did not demonstrate a significant impact of a standardized Vietnamese meal on the oral absorption of piperaquine.     

Plasma uric acid and plasma albumin in healthy subjects.

In healthy male subjects there was a positive correlation between plasma uric acid and plasma albumin (r = 0 - 43, P less than 0 - 005, n = 49) when repeated measurements of both variables were used for each subject. Changes in plasma albumin induced by in vivo ultrafiltration were not accompanied by changes in plasma uric acid. The correlation of plasma uric acid with plasma albumin cannot be attributed to protein binding of urate. The two variables are probably related indirectly through a common association with an unknown factor or factors.     

Effect of food and antacids on the pharmacokinetics of pirfenidone in older healthy adults

Pirfenidone is a small, synthetic molecule under investigation for treatment of idiopathic pulmonary fibrosis. In an open-label, single-dose crossover study, the pharmacokinetics (PK) of pirfenidone were investigated with or without food and antacids in healthy adult volunteers. Concentrations of pirfenidone and its metabolites in plasma and urine were determined by liquid chromatography with tandem mass spectrometry, and candidate pharmacokinetic models were fit to plasma data using weighted, non-linear regression. The effect of food and antacids on pirfenidone exposure was evaluated by determining ‘equivalence’ using FDA guidelines. Adverse events were recorded by site personnel and classified by investigators on the basis of severity and relationship to study drug.Sixteen subjects yielded 64 pharmacokinetic profiles. The best fit was achieved using a five-compartment, linear model with an allowance for direct conversion to the primary metabolite (5-carboxy-pirfenidone). Coadministration with food decreased the rate and, to a lesser degree, the extent of pirfenidone absorption of absorption. Analysis of adverse events revealed a correlation between pirfenidone C_max and the risk of gastrointestinal (GI) adverse events, suggesting that food may reduce the risk of certain adverse events associated with pirfenidone. Administration of pirfenidone with food has a modest effect on overall exposure but results in lower peak concentrations, which may improve tolerability.     

The significance of the blood glucose level for plasma insulin response to intravenously administered tolbutamide in healthy subjects

Summary The effect of intravenous tolbutamide on insulin release in normal human subjects was investigated under various experimental conditions. The blood glucose level was either allowed to fall after i.v. tolbutamide or kept within normal limits by a concomitant glucose infusion. In other experiments, tolbutamide was given during different degrees of hypoglycaemia induced by insulin. It was found that tolbutamide provoked a rapid and short-lasting insulin release as well as a post-initial and extended insulin release, provided the blood glucose concentration was kept within normal limits. The hitherto accepted transiency of tolbutamide action in healthy subjects seems to be due to the hypoglycaemia which follows the administration of the drug. During more marked hypoglycaemia induced by exogenous insulin, the insulin releasing capacity of tolbutamide was almost blunted. Tolbutamide markedly enhanced the insulin release following glucose administration. The findings presented might clarify some of the therapeutic effects of the drug in diabetes mellitus.This study was supported by grants to E.C. and R.L. from the Swedish Medical Research Council (B69-19X-34-05A) and the Knut and Alice Wallenberg Foundation.     

MK-0873, a PDE4 inhibitor, does not influence the pharmacokinetics of theophylline in healthy male volunteers

BACKGROUND: MK-0873 is a novel selective phosphodiesterase-4 inhibitor, which has been in development for the treatment of chronic obstructive pulmonary disease (COPD). In this indication, theophylline is still an important treatment, despite its relatively small therapeutic window. In view of this, it is important to investigate whether MK-0873 could affect the pharmacokinetics, safety and tolerability of theophylline, when both drugs are given concomitantly. AIM: The objective of this study was to investigate the effect of multiple doses of oral MK-0873, a selective phosphodiesterase-4 inhibitor, on the pharmacokinetics, safety and tolerability profile of orally administered theophylline in healthy volunteers. METHODS: Eight healthy, non-smoking male subjects participated in this randomized, open-label, 2-period, cross-over study. In one period subjects received an oral dose of 2.5mg MK-0873 for 6 days co-administered with a single oral dose of 250 mg theophylline on day 5. The other period consisted of a single dose of 250 mg theophylline on day 1. In each period, blood samples were collected at predefined time points to evaluate theophylline pharmacokinetics. RESULTS: All subjects completed the study. The study medications were generally well tolerated and no clinically relevant changes were observed in either treatment periods. No significant difference was found in the AUC 0-infinity (77.7 vs. 83.8h ng/ml; p=0.280) and Cmax (6.70 vs. 7.77 ng/ml; p=0.125) of theophylline between the MK-0873+theophylline and theophylline only treatment, and bioequivalence was demonstrated for AUC0-infinity (geometric mean ratio with 90% confidence interval: 0.930 (0.826, 1.047)). CONCLUSION: In this study, in a limited number of subjects, co-administration of oral MK-0873 did not affect the pharmacokinetics, safety, and tolerability of oral theophylline in non-smoking healthy male subjects.