超声酶水解提取/高效液相色谱-原子荧光光谱联用法测定动物源性中药中的砷形态

目的 采用液相色谱-原子荧光光谱（HPLC-AFS）联用技术对动物源性中药中一甲基砷酸（monomethylarsine,MMA）、二甲基砷酸（dimethyarsine,DMA）、三价砷[As（Ⅲ）]、五价砷[As（V）]的形态进行研究。方法 样品中加入pH 2.5的胃蛋白酶液,于55℃超声20 min,6 000 r·min^-1离心3 min,取其上清液,过滤进样。采用Hamilton PPRP-X100阴离子交换色谱柱（150 mm×4.6mm,5 μm）分离,1 mmol·L^-1磷酸二氢铵溶液（pH 8.5）,20 mmol·L^-1磷酸二氢铵溶液（pH 7.0）体系组成的流动相按一定比例进行梯度洗脱,流速为1.0 mL·min^-1,进样量为100 μL。结果 4种砷形态在13 min内完成分离。MMA、DMA、As（Ⅲ）、As（V）的检出限分别为0.01,0.01,0.01和0.02 mg·kg^-1,样品中加标量为0.03~0.1 mg·kg^-1时,4种砷化合物的回收率为93.4%~105.4%,精密度RSD为0.8%~4.4%。结论 本研究建立的超声酶水解提取/HPLC-AFS测定动物源性中药中砷形态的分析方法样品提取简便,提取率高,测定方法精密度好,准确度高。     

五灵脂中重金属及砷形态、价态的研究和安全性评价

目的 研究五灵脂中重金属及有害元素和砷形态、价态，并对其安全性进行评价。方法 采用微波消解法结合电感耦合等离子体质谱（ICP-MS）法对五灵脂中铅（Pb）、镉（Cd）、砷（As）、汞（Hg）、铜（Cu）5种重金属及有害元素进行测定，参照现行《中国药典》2020年版植物药重金属及有害元素的限量标准、采用单项污染指数法对有害元素潜在的安全性风险进行评价；另外采用高效液相联用电感耦合等离子体质谱（HPLC-ICP-MS）法对一甲基砷（MMA）、二甲基砷（DMA）、亚砷酸（AsⅢ）、砷酸（AsⅤ）、砷甜菜碱（AsB）、砷胆碱（AsC）6种砷形态、价态进行研究。结果 2种方法的线性关系、精密度、重复性、回收率均良好。五灵脂中5种重金属及有害元素的安全性较高。HPLC-ICP-MS结果表明，部分药材中检出微量的无机砷（AsⅢ和AsⅤ），结果相对安全可控。结论 为五灵脂重金属及有害元素限量标准制定提供了数据支持，同时有助于未来准确评价有害元素带来的安全性风险。     

亚砷酸治疗急性早幼粒细胞白血病患者血中总砷及砷形态测定

摘 要 目的：建立氢化物发生 原子荧光光谱法(HG-AFS）和高效液相色谱 氢化物发生 原子荧光光谱法(HPLC HG AFS）分别测定急性早幼粒细胞白血病患者红细胞和血浆中总砷及血浆中无机砷[As(Ⅲ)和As(V)]和甲基化代谢产物(MMA 和 DMA)的浓度。方法: 将患者红细胞和血浆经HNO3H2O2 的混合物消化处理后,利用HG AFS法检测血浆和红细胞中总砷的浓度。将患者血浆经高氯酸沉淀蛋白,取上清液进行 HPLC HG AFS分析,色谱柱为Hamilton PRP X100阴离子交换色谱柱（250 mm×4.1 mm, 10 μm）;以13 mmol·L^-1醋酸钠 3 mmol·L^-1磷酸二氢钠 4 mmol·L^-1硝酸钾 0.2 mmol·L^-1乙二胺四乙酸二钠的混合溶液为流动相。结果:总砷的线性范围为0.2~20 ng·mL^-1（r=0.999 7）,4种砷形态的线性范围为2.0~50 ng·mL^-1（r>0.9950）。红细胞中总砷加样回收率为89.4%~106.3%;血浆中加样回收率为87.6%~100.2%;砷形态加样回收率为81.2%~108.6%。精密度良好。该方法成功应用于5例急性早幼粒细胞白血病患者体内总砷以及砷形态的分析。结论:所建立的方法简便、快速、准确。可应用于急性早幼粒细胞白血病患者血中总砷及砷形态的检测。     

高效液相色谱-电感耦合等离子体质谱法测定大七厘制剂中6种砷形态含量

目的 测定大七厘制剂中砷甜菜碱(AsB)、砷胆碱(AsC)、一甲基砷(MMA)、二甲基砷(DMA)、亚砷酸根(AsⅢ)、砷酸根(As V)6种砷形态的含量，并进行安全性评价。方法 样品用人工肠液置37℃水浴中超声提取，采用高效液相色谱-电感耦合等离子体质谱法检测，色谱条件：Hamilton PRP-X100阴离子交换柱(250 mm×4.1 mm,10μm)，以100 mmol·L^-1碳酸铵溶液(含2%甲醇)-2%甲醇为流动相进行梯度洗脱，流速：0.8 mL·min^-1。结果 方法检测限范围为2.00～6.00μg·kg^-1，在1～200 ng·mL^-1范围内，r均≥0.999 8，加样回收率范围为96.15%～101.76%,RSD小于2%(n=6)。大七厘制剂中砷元素主要以毒性较大的无机砷形式存在，其中AsⅤ含量最高，其次是AsⅢ，AsB、AsC、MMA和DMA均未检出，其潜在的健康安全风险较大。结论 所建立的方法准确、重复性好，可为评价大七厘制剂的安全性提供参考。建议将无机砷(AsⅢ、AsⅤ)...     

HPLC-ICP/MS联用测定滑石粉中6种砷形态化合物

摘要：目的:建立一种高效液相色谱联用电感耦合等离子体质谱（HPLC-ICP/MS）测定滑石粉中亚砷酸根[As（Ⅲ）]、砷酸根[As（Ⅴ）]、一甲基砷（MMA）、二甲基砷（DMA）、砷甜菜碱（AsB）和砷胆碱（AsC）共6种砷形态化合物的方法。方法:样品采用0.15 mol·L-1硝酸溶液热水浴振荡提取,CNW Sep AX阴离子交换色谱柱（4 mm×250 mm, 10μm）,0.025 mol·L-1磷酸二氢铵-水梯度洗脱,ICP-MS检测分析。结果:6种砷形态化合物在1～100μg·L-1浓度范围内线性关系良好,r均>0.997;加标回收率在97.7%～99.5%之间,RSD为2.3%～4.1%（n=9）。结论:本法灵敏度高,重现性好,适用于滑石粉中6种砷形态化合物的测定,试验表明药用滑石粉中检出毒性较大的As（Ⅲ）和[As（Ⅴ）],应关注其无机砷风险。     

蒙药希日乌日乐中砷元素形态分析

目的:研究蒙药希日乌日乐中砷元素的形态.方法:人工胃液提取希日乌日乐后用0.45nm孔径的滤膜分离出可溶态和悬浮态,通过离子交换树脂动态吸附和溶剂萃取相结合的分离技术对可溶态中砷元素的四种存在形态进行分离:无机三价砷As[(Ш)]、五价砷[As(V)]、一甲基砷(MMA)和二甲基砷(DMA).并利用ICP-AES法测定提取液中砷四种形态化合物的含量.结果:砷元素主要以五价砷[As(V)]、一甲基砷(MMA)和二甲基砷(DMA)三种形态存在,未检测到无机三价砷As[(Ш)]形态.结论:蒙药希日乌日乐中砷元素的毒性很低.     

尾加压素Ⅱ诱导乳鼠心肌成纤维细胞增殖及胶原合成的信号转导机制研究

目的 探讨尾加压素Ⅱ(urotensin Ⅱ,UⅡ)对乳鼠心肌成纤维细胞(cardiac myofibroblasts,CFs)增殖及胶原合成的影响。方法 体外培养CFs作为实验模型,不同浓度UⅡ处理细胞后,通过ELISA法检测各组培养细胞上清中TGF-β1的含量变化,分别利用CKK-8细胞增殖法及Western blot分析UⅡ受体拮抗剂(SB-611812)及PKA特异性阻断剂(KT5720)对UⅡ诱导的CFs增殖及胶原蛋白col-Ⅰ、col-Ⅲ表达的影响。结果 UⅡ 10^-10,10^-9,10^-8 mol·L^-1处理细胞后,CFs培养上清中TGF-β1的含量及各组CFs的吸光度值与对照组相比明显增加(P<0.05),而在10^-7 mol·L^-1 UⅡ处理细胞后,上述参数与对照组比较无显著差异。1 mol·L^-1 SB-611812+10^-8 mol·L^-1 UⅡ组和1 mol·L^-1 KT5720+10^-8 mol·L^-1 UⅡ组的TGF-β1的含量及CFs的吸光度值均显著高于对照组(P<0.05),但显著低于10^-8 mol·L^-1 UⅡ组(P<0.05),且两组col-Ⅰ、col-Ⅲ型胶原蛋白表达均低于10^-8 mol·L^-1 UⅡ组。结论 UⅡ上调TGF-β1水平促进了CFs的增殖,诱导细胞表达胶原蛋白col-Ⅰ、col-Ⅲ,这一过程可能涉及cAMP-PKA信号转导通路。     

雄黄及含雄黄复方中砷含量、形态和晶形分析

目的 对雄黄及含雄黄复方制剂中的砷含量、砷形态和雄黄晶形进行分析.方法 采用微波消解-原子荧光法测定雄黄和复方制荆中的总砷含量,人工胃液提取.原子荧光法测定可溶性砷,离子树脂交换分离.原子荧光法测定可溶性三价砷(AⅢ)和五价砷(AsV),X衍射荧光法对雄黄粉末进行物相(晶形)分析,X荧光光谱法进行雄黄粉末的全元素分析.结果 受试雄黄含硫化砷97.3%,主成分是β-雄黄(As4S4)和α-雄黄(AsS)的混合物,同时含有少量二硫化二砷(As2S2)和雌黄(As2S3).As/S(摩尔数之比)为1.00001.还含有少量Al、Si、K、Ca、Ti、Fe、Sb、Ni、Cu、W等杂质.在雄黄及含雄黄复方制剂的人工胃液提取液中均检出了可溶性砷、AsⅢ和AsV;且不同来源的雄黄,可溶性砷以及两种价态的砷的比例也不同.雄黄中可溶性砷百分含量为0.62%,其中AsⅢ和AsV比例为2.30:1.结论 雄黄及含雄黄复方中混杂存在三价和五价无机砷.有必要加强对雄黄药材的质量监控.     

化学—酶法立体控制合成光学纯L-羟基苯丙氦酸的新方法

Optically pure L-3(2-hydroxyphenyl) alanine(L-o-tyrosine ,Ⅲa,),L-3-(3-hydroxyphenyl) alanine(L-m-tyrosine,Ⅲb )and L-3-(4-hydroxyphenyl )alanine(L-p-tyrosine,Ⅲc )were synthesized by the stereocontrolled amination of corresponding hydroxycinnamic acld(Ⅱ)catalyzed by L-phenylalanine ammonia-lyase(PAL,EC4.3.1.5 )contained in Rhodoterula rubramycelium. The amination of compound Ⅱ was completed in aqueous ammonia solution( 6.4mol·L^-1,pH10.5, 30℃) with the conversion of 74.9%(Ⅱa),21.1%(Ⅱb)and 20.6%(Ⅱc)respectively.The absolute configuration of the products Ⅲa～c were confirmed by circular dichroism(CD),and chiral high-performance ligand exchange chromatography(HPLEC)showed that productsⅢ were optically pure L-isomers.     

基于转基因血管荧光斑马鱼的芦丁、甘草酸、汉防己甲素、葛根素、柚皮素、鞣花酸、黄芩苷、大黄素、穿心莲内酯、苦参碱促血管新生活性初探

目的 采用转基因血管荧光斑马鱼研究芦丁、甘草酸、汉防己甲素、葛根素、柚皮素、鞣花酸、黄芩苷、大黄素、穿心莲内酯、苦参碱促进血管新生的作用。方法 选取48 hpf转基因血管荧光Fli-1品系斑马鱼3 480尾于六孔板中,每孔均处理30尾(实验组),分别水溶给予芦丁81.90~1 637.95 μmol·L^-1、甘草酸60.76~1 215.17 μmol·L^-1、汉防己甲素5.02~80.29 μmol·L^-1、葛根素120.08~2 161.49 μmol·L^-1、柚皮素3.67~734.59 μmol·L^-1、鞣花酸0.21~3.31 μmol·L^-1、黄芩苷28.00~448.07 μmol·L^-1、大黄素0.19~740.08 μmol·L^-1、穿心莲内酯35.67~570.69 μmol·L^-1、苦参碱50.33~805.28 μmol·L^-1,同时设置对照组(养鱼用水处理斑马鱼),处理24 h后观察记录斑马鱼的毒性表型和死亡情况,确定供试品对斑马鱼的最大耐受浓度(MTC)。用10个化合物的MTC与斑马鱼共培养24 h,检测肠下血管面积和肠下血管出芽数。结果 与对照组比较,芦丁组、甘草酸组、汉防己甲素组、葛根素组、柚皮素组、黄芩苷组、穿心莲内酯组、苦参碱组斑马鱼肠下血管面积像素升高,其中甘草酸组、汉防己甲素组、黄芩苷组、穿心莲内酯组差异显著(P<0.05、0.01、0.001);鞣花酸组、大黄素组斑马鱼肠下血管面积像素降低,差异不显著;芦丁组、汉防己甲素组、葛根素组、柚皮素组、鞣花酸组、苦参碱组斑马鱼肠下血管出芽数比对照组多,芦丁组差异显著(P<0.05);甘草酸组、黄芩苷组、穿心莲内酯组斑马鱼肠下血管出芽数比对照组少,大黄素组斑马鱼肠下血管出芽数与对照组相当。结论 芦丁、甘草酸、汉防己甲素、黄芩苷和穿心莲内酯对斑马鱼具有促进血管新生作用;葛根素、柚皮素、鞣花酸、大黄素和苦参碱对血管新生无明显影响。     

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.     

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.     

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     

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.     

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.     

Benzodiazepines,amnesia and sedation: Theoretical and clinical issues and controversies

The amnestic effect of benzodiazepines, first described in 1965, and the subsequent attempts to identify the precise nature of this effect, are reviewed. The difficulty in deciding to what extent this effect is secondary to the sedative action of these drugs is shown by the lack of agreement between studies. Nevertheless, it is concluded that, given the right experimental design, all benzodiazepines can be shown to cause an anterograde amnesia which is probably primarily a result of reduced attention or rehearsal and secondary to sedation. Its onset, degree and duration are influenced by dose, rate of absorption, route of administration, potency and the receptor occupancy rate of the particular benzodiazepine involved, but plasma elimination t_½ appears to be relatively unimportant. The clinical relevance of this for the long-term use of hypnotics and anxiolytics is not clear. Tolerance appears to be greater than for the anxiolytic but less than the sedative or anticonvulsant effect of benzodiazepines. It seems that transient amnestic effects could occur in chronic users related to post-dose, peak benzodiazepine levels. The great variability in individual response means that transient amnesia is a potential adverse drug reaction in certain individuals taking benzodiazepines.     

Pharmacokinetics and pharmacodynamics of ramipril and piretanide administered alone and in combination

The pharmacokinetics and pharmacodynamics of single oral doses of 5 mg ramipril and 6 mg piretanide administered separately and in combination were determined in a single blind, randomised, 3-period cross-over study in 24 healthy male volunteers.The peak plasma concentrations of ramipril and ramiprilat increased slightly (from 11.9 to 14.8 ng/ml, and from 6.39 to 8.96 ng/ml, respectively) as did the area under the plasma concentration-time curve of ramipril (0–4 h) and ramiprilat (0–24 h) (from 15.8 to 19.8 ng·ml^–1·h, and from 63.4 to 74.6 ng·ml^–1·h, respectively). The urinary excretion of ramiprilat also rose (from 6.82 to 7.73 % of dose) following simultaneous treatment with piretanide. These effects were probably due to reduced first-pass metabolism of ramipril/ramiprilat to inactive metabolites. The blood pressure lowering effect, the time course of inhibition of ACE activity in plasma and the concentration-response relationship for the inhibition of plasma ACE activity were not affected by piretanide.The peak plasma concentration of piretanide was somewhat reduced (from 285 to 244 ng/ml) following simultaneous treatment with ramipril. No other pharmacokinetic parameter was affected. Piretanide increased urine flow, and sodium, chloride and potassium excretion, especially during the first 2 hours following administration. These pharmacodynamic parameters were not affected by ramipril.Thus, simultaneous administration of single oral doses of ramipril and piretanide caused modest changes in the peak and average plasma concentrations of both drugs, which did not lead to detectable alterations in the pharmacodynamic parameters measured in healthy volunteers.