多沙唑嗪对高血压患者动态血管平滑肌细胞NO产生的影响

采用高血压患者的肠系膜动脉进行分离培养,检测细胞培养液中的NO含量.结果多沙唑嗪治疗组的NO含量高于对照组(74.56±4.56μmol/L,42.77±6.76μmol/L,P<0.05).认为多沙唑嗪增加了高血压患者动脉血管平滑肌细胞NO的产生.     

前列舒丸联合多沙唑嗪治疗前列腺增生症的临床研究

目的研究前列舒丸联合甲磺酸多沙唑嗪片治疗前列腺增生的临床疗效。方法选取2018年7月-2019年7月来郑州大学第一附属医院治疗的100例前列腺增生症患者,将所有患者随机分为对照组和治疗组,每组各50例。对照组患者口服甲磺酸多沙唑嗪片,1mg/次,1次/d;治疗组在对照组治疗的基础上口服前列舒丸,1粒/次,3次/d。两组患者持续治疗3个月。观察两组患者临床疗效,同时比较治疗前后两组患者国际前列腺症状评分(IPSS)、生活质量(QOL)评分、前列腺体积(PV)、膀胱残余尿量(RV)、最大尿流率(Qmax)和血清炎性因子水平。结果治疗后,对照组、治疗组的总有效率分别为86.00%、98.00%,两组总有效率比较差异有统计学意义(P<0.05)。治疗后,两组IPSS评分、QOL评分均显著降低(P<0.05);且治疗组IPSS评分、QOL评分降低较多(P<0.05)。治疗后,两组RV、PV水平均显著降低,Qmax水平显著升高(P<0.05);且治疗组RV、PV水平显著低于对照组,Qmax水平显著高于对照组(P<0.05)。治疗后,两组患者IL-6、TNF-α水平均明显降低(P<0.05);且治疗组IL-6、TNF-α水平降低较多(P<0.05)。结论前列舒丸联合甲磺酸多沙唑嗪片治疗前列腺增生症具有较好的临床疗效,可改善临床症状,降低血清炎性因子水平,值得在临床上推广应用。     

In vitro vs. canine data for assessing early exposure of doxazosin base and its mesylate salt

In this study, we evaluated the usefulness of biorelevant in vitro data and of canine data in forecasting early exposure after the administration of two phases of a BCS Class II compound, i.e., doxazosin base (DB) and its mesylate salt (DM). DB, DM, and doxazosin hydrochloride (DH) were prepared and characterized. In vitro data were collected in various media, including human aspirates. Solubilities of DB and DM in human gastric fluid were forecasted by data in fasted state simulating gastric fluid containing physiological components (FaSSGF-V2) but not by data in HCl_{pH 1.8}. Unlike data in FaSSGF-V2, dissolution of DB and DM tablets in HCl_{pH 1.6} is rapid. Dissolution of DB tablet in FaSSGF-V2 is incomplete and conversion to DH seems to occur. Differences between DB and DM in dissolution in the small intestine are overestimated in the absence of physiological solubilizers. Using the in vitro data and previously described modeling procedures, the cumulative doxazosin profile in plasma was simulated and the 0-2 h profile was used for evaluating early exposure. Individual cumulative doxazosin profiles in plasma, after single DM tablet administrations to 24 adults, were constructed from corresponding actual plasma profiles. Compared with in vitro DM data in pure aqueous buffers, DM data in biorelevant media led to better prediction of early exposure. Based on intersubject variability in early exposure after DM administration and simulated profiles, the administered phase, DB or DM, does not have a significant impact on early exposure. Partial AUCs were used for evaluating early exposure after DB and DM administration in 4 dogs. Early exposure was significantly higher after administration of DM to dogs. Dogs are not appropriate for evaluating differences in early exposure after DB and DM administrations.     

多沙唑嗪的致突变作用研究

应用ＣＨＬ细胞染色体畸变试验、Ａｍｅｓ试验 和小鼠骨髓哮多染色细胞微核试验对多沙唑嗪进行了致突变作用研究。结果显示：３１２．５μｇ／皿－５０００μｇ／皿合剂量组ＴＡ９７、ＴＡ９８、ＴＡ１００、ＴＡ１０２等菌株回复突变率未见明显增加；５１３ｍｇ／ｋｇ、１０２５ｍｇ／ｋｇ、２０５０ｍｇ／ｋｇ各剂量组ＰＣＥ微核率分别为１．７‰、２．５‰、２．６‰，与对照组（２．０）‰比较无明显差异（Ｐ〉０．０５）；１０     

多沙唑嗪治疗输尿管下段小结石的临床研究

目的研究多沙唑嗪对输尿管下段小结石的辅助排石作用。方法100例输尿管下段小结石(结石横径5～10mm)患者,采用随机数字表法分为两组。对照组给予口服金钱草颗粒剂,3次/d,每次3g;治疗组在对照组基础上加用多沙唑嗪控释片,1次/d,每次4mg。其余治疗相同。所有患者治疗时间不超过2周。每周复查B超和KUB了解结石排出情况。记录排石时间、使用止痛药物情况等。结果治疗组中有2例患者因药物反应退出本组实验。对照组患者中有22例排出结石,排石率44%(22/50);治疗组39例患者排出结石,排石率81.3%(39/48),两组比较差异有统计学意义,P<0.05。对照组患者使用止痛药物83次,平均1.7次(83/50);治疗组患者使用止痛药物52次,平均1.1次(52/48),两组比较差异有统计学意义,P<0.05。结论多沙唑嗪与中药排石药物联合使用可以有效提高输尿管下段小结石的排出率,减少因肾绞痛使用止痛药物的频率。     

多沙唑嗪抑制人血管平滑肌细胞增殖的实验研究

目的探讨多沙唑嗪对人血管平滑肌细胞(VSMCS)增殖的抑制作用。方法将0.1、1、10、25μmol/L的多沙唑嗪(Doxazosin,Dox)作用于体外培养的VSMCS,采用氚-胸腺嘧啶核苷(3H-TdR)掺入的方法检测细胞的增殖。结果在1、10、25μmol/L的Dox作用下,VSMCS的3H-TdR的掺入量分别为(983±58.7)cpm、(730±54.9)cpm、(500±64.1)cpm,显著低于对照组的(1270±96.5)cpm(P<0.01),并表现为剂量依赖性(P<0.01)。结论多沙唑嗪能够抑制人VSMCS的增殖,对经皮腔内冠状动脉成形术(PTCA)后再狭窄可能有防治作用。     

Effect of doxazosin in mild to moderate hypertensive patients with insulin-dependent diabetes mellitus

Diabetic patients often develop hypertension, and the presence of both hypertension and diabetes doubles the risk of death from coronary heart disease (CHD). Moreover, the presence and importance of abnormalities such as high low-density lipoprotein (LDL) cholesterol and triglycerides levels as CHD risk factors in insulin-dependent diabetes mellitus type 1 have been downplayed, while increasing evidence suggests that the management of type 1 patients should include control of dyslipidemia and hyperglycemia and an effective antihypertensive treatment able also to reduce risk factors for coronary artery events. In this study we assessed the antihypertensive and metabolic effects of doxazosin in hypertensive patients with type 1 diabetes. We show that the drug normalizes blood pressure, and while no improvement in glucose control was observed, it reduced total cholesterol and increased HDL cholesterol as well as the HDL to total cholesterol ratio. The changes of the various parameters studied, including the calculated CHD risk score based on the Framingham equation, suggest that doxazosine can reduce the CHD risk for hypertensive type 1 patients. Received: 24 September 1997 / Accepted in revised form: 19 December 1997     

甲磺酸多沙唑嗪对大鼠降压作用的研究

自发性高血压大鼠（ＳＨＲ）分为５组作实验。对照组ｌｍｇ／ｋｇ、哌唑嗪组０．３ｍｇ／ｋｇ、ｌｍｇ／ｋｇ、５ｍｇ／ｋｇ多沙唑嗪组。灌胃给药后３个剂量多沙唑嗪对ＳＨＲ２４ｈ的血压观察显示该药降压作用迅速且持久，血压于４ｈ达最低，于８ｈ仍显著降低，与呢唑嗪降血压作用类似。连续３周降血压治疗实验，多沙唑嗪同样有明显的降血压作用，也与哌唑嗪一致。ｌｍｇ／ｋｇ多次唑嗪静脉注射使麻醉ＳＨＲ血压迅速而持久下降，对心电图、心率和呼吸率无明显影响。     

LC-MS determination and relative bioavailability of doxazosin mesylate tablets in healthy Chinese male volunteers

This study aims to develop a standard protocol for the relative bioavailability testing of doxazosin mesylate tablets. For this purpose, a simple rapid and selective LC-MS method using a single quadrupole mass spectrometer was developed and validated to determine the concentration of doxazosin mesylate in human plasma. Using this method, we carried out a study of relative bioavailability. N-Hexylane-tertiary butyl methyl ether (1:1, v/v) was used to extract doxazosin mesylate and terazosin (internal standard, I.S.) from an alkaline plasma sample. LC separation was performed on a Thermo Hypersil-Hypurity C18 (5 microm, 150 mm x 2.1mm) using aqueous solution (20 mmol/l ammonium acetate, pH 4.28), methanol and acetonitrile (55:10:35, v/v/v) as the mobile phase. The retention time of doxazosin and the internal standard was 2.7 and 1.8 min, respectively. Quadrupole MS detection was done by monitoring at m/z 388 (M+1) corresponding to doxazosin mesylate and at m/z 452 (M+1) for I.S. The assay method described above showed acceptable precision, accuracy, linearity, stability, and specificity. The bioavailability of doxazosin mesylate was evaluated in 12 healthy Chinese male volunteers. The following pharmacokinetic parameters were elucidated after administering a single dose of 4 mg doxazosin. The area under the plasma concentration versus time curve from time 0 to 72 h (AUC(0-72 h)) 743.4+/-149.5 ngh/ml; peak plasma concentration (C(max)) 47.66 ng/ml; time to C(max) (T(max)) 3.0+/-1.0 h; and elimination half-life (t(1/2)) 18-20 h. The method was successfully used to determine the relative bioavailability of doxazosin mesylate.     

M受体阻滞剂与α受体阻滞剂联合治疗良性前列腺增生的有效性及安全性研究

目的 评价M受体阻滞剂托特罗定与α受体阻滞剂多沙唑嗪联合治疗良性前列腺增生(BPH)患者的有效性及安全性.方法 2009年5月至2010年4月,选择刺激症状明显的BPH患者76例,主要的排除标准为最大尿流率(Qmax)＜10 ml/s、残余尿＞100 ml、前列腺体积＞50 ml.将患者随机分成2组:多沙唑嗪组(给予多沙唑嗪治疗,36例),联合用药组(给予托特罗定与多沙唑嗪联合治疗,40例).用药时间8周,评估内容包括国际前列腺症状评分(IPSS)、尿流率和残余尿量等,并登记不良事件.结果 两组间基线资料比较差异无统计学意义.用药8周后联合用药组IPSS评分由18.7±2.2降低到12.7±3.9(P=0.000),刺激症状评分由14.2±2.3降至9.1±3.1(P=0.000).多沙唑嗪组IPSS评分由18.6±3.0降低到15.2±3.8(P=0.033),刺激症状评分由12.7±3.0降至11.8±2.7(P=0.001).治疗后两组间比较显示:联合用药组IPSS评分的改善优于多沙唑嗪组(P＜0.01),联合用药组刺激评分的改善优于多沙唑嗪组(P＜0.01),而梗阻症状评分的改善两组间差异无统计学意义(P=0.168).治疗8周后两组间Qmax、残余尿差异无统计学意义(P＞0.05).联合用药组无急性尿潴留和其他严重并发症发生.结论 托特罗定与多沙唑嗪联合应用降低BPH患者IPSS评分,使其刺激症状获得明显的改善;未见严重不良反应和急性尿潴留出现.