UPLC-MS/MS法快速测定降压类中成药及保健食品中非法添加34种化学药的研究

目的建立一种快速、准确检测降压类中成药及调节血压类保健食品中非法添加34种化学药的方法。方法采用UPLC-MS/MS法,以Waters Acquity BEH-C18柱(100 mm×2.1 mm,1.7μm)为色谱柱,以0.1%甲酸甲醇溶液(A)-0.1%甲酸水溶液(B)为流动相,梯度洗脱(0~5 min,32%A;5~8 min,32%~50%A;8~12 min,50%A;12~14 min,50%~60%A;14~16 min,60%~80%A;16~18 min,80%A;18~19 min,80%~90%A;19~20 min,90%~100%A;20~21min,100%A;21~22 min,100%~32%A);体积流量0.2 m L/min,柱温40℃。选择ESI离子源、正离子扫描、多反应监测(MRM)模式测定34种临床常用的化学降压药,通过比较MRM通道中样品峰与对照品峰的分子离子峰、二级碎片离子峰、色谱保留时间等信息确定添加的化学药物,并根据外标法以质谱峰面积计算添加药物的准确量。结果在上述色谱及质谱条件下,34种化学药物可乐定、卡托普利、利血平、甲基多巴、氢氯噻嗪、呋塞米、吲达帕胺、米诺地尔、肼屈嗪、阿替洛尔、赖诺普利、地巴唑、美托洛尔、比索洛尔、哌唑嗪、特拉唑嗪、普萘洛尔、依那普利、喹那普利、贝那普利、地尔硫卓、多沙唑嗪、尼卡地平、硝苯地平、氨氯地平、尼莫地平、非洛地平、尼群地平、尼索地平、缬沙坦、替米沙坦、坎地沙坦酯、厄贝沙坦、奥美沙坦酯的分离度良好,方法检测限(LOD)均在0.1~0.5 ng/g,定量限(LOQ)均在0.3~1.5 ng/g,标准加样回收率均在81.4%~118.9%。结论本法简便、准确,灵敏度高,可作为降压类中成药及调节血压类保健食品中非法添加化学降压药的定量测定方法。     

EFFECT OF LISNOPRIL,AN ANGIOTENSIN CONVERTING ENZYME (ACE) INHIBITOR ON SPERMATOGENESIS IN RATS

The role of ACE inhibitors (Lisinopril) in reproductive function remains controversial. Some benefits seem to be derivable even in non-hypertensive males with low doses. This study was done using rat model to establish this fact. Male rats were divided into different groups to receive different doses of lisinopril. A control group received no drugs. The mean arterial pressure fell the most with 5 mg of lisinopril. The greatest increase in sperm count and motility was recorded for this same group. This response was dose dependent, falling as the drug dose fell. Lisinopril appeared to, in a dose dependent manner, improve sperm count and motility. In low doses, there is no significant change in arterial pressure. Infertile males with poor quality semen could benefit from a low dose of ACE inhibition. Where they are also hypertensive, ACE inhibition would be an appropriate first line treatment.     

Do severe systemic sequelae of proteinuria modulate the antiproteinuric response to chronic ACE inhibition?

BACKGROUND: ACE inhibition exerts an antiproteinuric and renoprotective effect. However, residual proteinuria is often present. As residual proteinuria is associated with a poor renal outcome, identification of its determinants is important. We found previously that the systemic sequelae of proteinuria enhance renal damage in untreated nephrotic rats. The impact of systemic nephrosis on renal therapy response, however, is unclear. In the present study we therefore investigated whether the severity of systemic nephrosis, estimated from plasma cholesterol, predicts residual proteinuria during ACE inhibition. METHODS: Sixty male Wistar rats with established adriamycin nephrosis were studied. Six weeks after the induction of nephrosis, rats were stratified for proteinuria and treated for 2 weeks with lisinopril (75 mg/l) or vehicle. RESULTS: At the start of treatment, median proteinuria was 744 mg/day (95% confidence interval (CI) 609-860) and plasma cholesterol was 10.4 mmol/l (95% CI 8.0-12.6), reflecting the state of systemic nephrosis. Lisinopril, but not vehicle, reduced blood pressure and proteinuria (-62%; range -70 to -48; P<0.001). Residual proteinuria was 275 mg/day, with a wide range (47-1119 mg/day). Pre-treatment proteinuria and pre-treatment cholesterol correlated positively with residual proteinuria. By multivariate analysis (r(2) of model =0.92), both pre-treatment cholesterol and pre-treatment proteinuria were independent predictors of residual proteinuria. The quantitative impact of this multivariate analysis is illustrated by the difference in residual proteinuria between rats with a cholesterol:proteinuria ratio less than, compared with greater than, the median (residual proteinuria 298 mg/day (CI 129-496) vs 439 mg/day (CI 158-670), respectively). Blood pressure response was not predicted by the tested predictor variables. CONCLUSIONS: In this model of proteinuria-induced renal damage, not only proteinuria as such, but also the concomitant nephrotic alterations predict residual proteinuria. Further studies, applying specific interventions, are needed to determine which components of the systemic derangements could play a causal role in the modulation of therapy response.     

赖诺普利对急性心肌梗死患者血管内皮功能的影响

目的 :观察急性心肌梗死早期应用血管紧张素转换酶抑制剂赖诺普利治疗对血管内皮依赖性舒张功能和血浆纤溶平衡的影响。方法 :采用高分辨超声技术和发色底物显示法 ,检测 68例急性心肌梗死患者和 3 4例无冠心病患者 (对照组 )肱动脉内皮依赖性舒张功能和血浆组织型纤溶酶原激活物及其抑制物。应用随机编码将 68例急性心肌梗死患者分为赖诺普利组和常规治疗组 ,治疗 8周后复测其肱动脉内皮依赖性舒张功能和血浆组织型纤溶酶原激活物和抑制物活性。结果 :急性心肌梗死患者肱动脉内皮依赖性舒张功能较对照组明显降低 ,血浆组织型纤溶酶原激活物活性显著降低和抑制物活性明显增加 ,有非常显著性差异 (P <0 0 1)。赖诺普利治疗 8周后 ,肱动脉内皮依赖性舒张功能与治疗前基础水平、常规治疗后相比有显著改善 ;血浆纤溶活性也有明显改善 ,均有显著性差异。结论 :急性心肌梗死患者内皮依赖性舒张功能明显减退 ;血浆纤溶活性降低。急性心肌梗死时尽早应用赖诺普利治疗能改善受损的血管内皮功能     

Randomised,Double-Blind Crossover Comparison of Once-Daily Captopril and Lisinopril in Patients with Mild to Moderate Hypertension - a Community-Based Study: By Hunter Hypertension Research Group,Discipline of Clinical Pharmacology,Newcastle Mater Misericordiae Hospital,Waratah 2298 NSW Australia

Of twenty-five patients with mild to moderate hypertension, recruited and managed in the community, seventeen responded fully to, and completed a randomised cross-over study of, captopril (ceiling dose 100 mg) compared with lisinopril (ceiling dose 40 mg) both given as a single daily dose. Mean supine and standing blood pressures measured at the end of the dose interval were significantly reduced compared to placebo by both compounds at three and six weeks. However, a consistent, significant increase in blood pressure occurred between three and six weeks in both arms of the study despite good and unchanged compliance with a fixed dose of each medication. Both captopril and lisinopril were well tolerated. Drug-related cough was the principal adverse effect.     

Lisinopril pharmacokinetics and erythropoietin requirement in haemodialysis patients

Eur J Clin Invest 2012; 42 (10): 1087-1093 ABSTRACT: Background There is ongoing controversy whether angiotensin-converting enzyme inhibitors (ACE-I) contribute to anaemia by causing hyporesponsiveness to erythropoiesis-stimulating agents (ESA). However, it is unknown whether or not plasma levels or area under the curve (AUC) of ACE-I are associated with responsiveness to ESA therapy. Materials and methods We examined the association between lisinopril AUC, lisinopril plasma levels and ESA requirements that was assessed using an ESA index [(ESA IU/week/body weight kg)/(haemoglobin g/dL)]. After screening 184 haemodialysis patients, 14 fulfilled the inclusion criteria, mainly long-term use of oral lisinopril in the upper end of dosage range for this population with stable haemoglobin levels and intravenous ESA therapy. Lisinopril plasma levels were measured at eight different time points (predialysis, immediate post-dialysis and hourly for 6?h thereafter; AUC(1) ), and the seven post-dialysis lisinopril plasma levels were used for calculation of AUC(2) . Results The mean ESA index of all patients was 27·90?±?25·84 (IU/week/kg)/(g/dL). Average lisinopril AUC(1) was 1212·48?±?1209·75 [mg*h/L], whereas AUC(2) averaged 947·67?±?977·07 [mg*h/L]. Two patients (14%) had no detectable lisinopril plasma levels, indicating their noncompliance. There was no association between ESA index and AUC or plasma levels of lisinopril at any time point for all 14 or for the 12 compliant patients. Conclusions Our study shows that long-term, high-dose lisinopril therapy has no effect on ESA responsiveness. Thus, avoidance or a dose reduction of ACE-I in dialysis patients will not necessarily lead to reduced ESA requirements and costs.     

抗菌药物在868例剖宫产患者围手术期的应用

目的建立HPLC-MS/MS测定人血浆中赖诺普利的浓度并研究其药动学特征,为该药的临床应用提供依据。方法20名健康受试者单剂量口服赖诺普利片20 mg后,采用HPLC-MS/MS测定其血药浓度,利用DAS软件对血药浓度-时间数据进行药动学模型拟合和参数计算,应用AIC法判别房室模型。结果血浆中赖诺普利在2.0~200 ng.mL-1内线性关系良好(r=0.997 5),平均回收率为88.8%,日内RSD≤6.62%,日间RSD≤13.0%。最佳房室模型为单室模型(Wi=1/C2,AIC=4.61),主要药动学参数t1/2为(10.91±3.71)h,tmax为(6.65±1.50)h,Cmax为(98.15±23.66)ng.mL-1,Ka为(0.83±1.28)h-1,Vd/F为(220.70±62.82)L,AUC0-72为(1 437.41±399.68)ng.h.mL-1,AUC0-∞为(1 516.54±376.83)ng.h.mL-1。结论该分析方法专属性强、灵敏度高,适合大样本分析,满足临床血药浓度监测的要求并适用于药动学领域的研究。     

赖诺普利对多囊卵巢综合征并伴有高血压患者雄激素水平的有益影响

目的：探讨赖诺普利治疗多囊卵巢综合征并伴有高血压患者过程中对血清雄激素和性激素结合球蛋白水平的影响。方法：30例多囊卵巢综合征并伴有高血压患者以赖诺普利10mg／d治疗8wk作为前瞻性观察研究。每例对象进入本研究时和治疗12wk结束时,均观察主要指标：1）收缩压和舒张压;2）生殖内分泌激素,包括促性腺激素、硫酸脱氢表雄酮、总睾酮、游离睾酮、17α-羟孕酮血清水平、雄烯二酮、雌二醇、性激素结合球蛋白、促甲状腺激素和催乳素含量;3）胰岛素抵抗。结果：多囊卵巢综合征并伴有高血压患者服用赖诺普利治疗后,获下列效果：1）良好降压效果（收缩压平均下降2．39kPa,舒张压平均下降1．73kPa,P皆〈0．05）。2）改善胰岛素抵抗（7．2±2．8vs6．3±2．0,P〈0．05）。3）对性激素有有益影响。血清游离睾酮降低（3．1±1．2VS2．0±0．6,P〈0．05）,但没有影响性激素结合球蛋白水平。结论：赖诺普利除有效降低血压和改善胰岛素抵抗之外．还可使睾酮水平下降。     

ACE Inhibitors for Prophylaxis of Migraine Headaches

Seventeen patients with migraine headaches, occurring at least twice a month, were successfully treated with an ACE inhibitor for prophylaxis. Most were given enalapril, some used lisinopril. Duration of treatment ranged from 3 months to 3 years. Side effects were generally not noted. Cough occurred in four patients. The mechanism of action is unknown. The lack of side effects and the presence of clearly sustained benefit in this small group of migraineurs should prompt further study and use of this class of drugs for prophylaxis.     

RELATIVE INHIBITORY POTENCY AND PLASMA DRUG LEVELS OF ANGIOTENSIN CONVERTING ENZYME INHIBITORS IN THE RAT

1. 125I-351A, a tyrosyl derivative of the angiotensin converting enzyme (ACE) inhibitor lisinopril, was used as a radioligand, and radioinhibitor binding and displacement assays have been established. 2. The in vitro potency of a range of ACE inhibitors against rat ACE was determined using the radioinhibitor binding displacement assay. 3. The concentration of an ACE inhibitor needed to displace 50% of 125I-351A bound to rat ACE (ID50) was closely correlated with the concentration needed to inhibit 50% of ACE enzymatic activity (IC50). 4. Radioinhibitor binding displacement assay was used to measure the plasma concentrations of lisinopril, cilazapril and perindopril in rat plasma. 5. Plasma concentrations of lisinopril measured by radioimmunoassay were identical with that measured by radioinhibitor binding assays.