高效液相色谱法分离测定大鼠肝微粒体中普萘洛尔葡醛酸化代谢产物

目的　建立分离测定外消旋普萘洛尔两种对映体的葡醛酸化代谢产物的反相高效液相色谱法。方法用生物合成法合成R-(+)-普萘洛尔葡醛酸苷,并经C₁₈固液萃取柱纯化、浓集,得到标准液储备液,以此标准液进行普萘洛尔葡醛酸化代谢物的分析测定。结果　R-(+)-普萘洛尔葡醛酸苷在0.24-73.17μmol·L^-1 浓度范围内线性良好,方法专属性高,平均回收率为99.4%±1.0% ,日内精密度RSD小于3.3% ,日间精密度小于4.5%。结论　此法可用于外消旋普萘洛尔两种对映体体外葡醛酸化代谢研究     

高效液相色谱法测定盐酸普萘洛尔片含量

目的:采用高效液相色谱法测定盐酸普萘洛尔片的含量.方法:Diamonsil C18柱(4.6 mm×150 mm,5μm)为分析柱,流动相为甲醇-0.02 mol·L-1磷酸二氢钾溶液(50:50),流速0.9 ml·min-1,检测波长290nm.结果:盐酸普萘洛尔在50.7～405.9μg·ml-1范围内呈良好的线性关系,r=0.999 9,平均回收率为99.2%,RSD=0.92%(n=9).结论:本方法简单、快速、结果可靠.     

采用微生物转化J法合成5-羟基普萘洛尔

采用短刺小克银汉霉菌(Cunninghamella blakes1eana AS 3.153)对普萘洛尔进行了代谢转化研究.液相色谱-多级质谱和核磁分析结果证明,转化液中主要含有5-羟基普萘洛尔转化产物;考察了单羟化物形成的影响因素,发现在pH 6.5、底物浓度0.25%和转化反应持续48 h等条件下,5-羟基普萘洛尔的产率可达76%,为活性药物代谢产物的合成开辟了一条新途径.     

盐酸普萘洛尔透皮吸收的研究

采用离体小白鼠皮肤为透皮屏障,用简单小室法,以生理盐水为接受液,研究了盐酸普萘洛尔在氮酮,薄荷油促进剂的作用下的透皮吸收效果,在1%盐酸普萘洛尔溶液中加入2%促吸剂,促进效果依次为氮酮、薄荷油。     

儿童用临时调配盐酸普萘洛尔口服混悬液的制备

目的：制备可用于分剂量给药的儿童临时调配盐酸普萘洛尔口服混悬液,并进行初步稳定性实验。方法：通过处方筛选和优化制备空白混悬液,并加入研细的市售盐酸普萘洛尔片制备临时调配的盐酸普萘洛尔口服混悬液。采用紫外分光光度法于289 nm波长处测定混悬液中盐酸普萘洛尔的含量。以离心实验和留样观察进行初步稳定性考察。结果：制备的混悬液均匀细腻,稳定性、分散性良好,各项检查符合相关规定。三次实验的平均回收率分别为96.24%、100.68%、95.10%（RSD分别为4.04%、0.82%、0.86%,n=3）。离心实验中样品外观未见分层,留样观察10 d成品性质稳定。结论：该制备工艺简单方便,药物分散简单快速;含量测定方法准确、可靠;成品性质稳定。     

HPLC测定注射用葡醛酸钠的含量及有关物质

目的　建立测定注射用葡醛酸钠中葡醛酸钠含量及其有关物质的检查方法。方法　采用HPLC法HypersilC1 8色谱柱,1 0mmol·L-1 磷酸盐缓冲液(6mmol·L-1 NaH2 PO4 4mmol·L-1 Na2 HPO4) -甲醇(98∶2 ,磷酸调pH 6 )为流动相,检测波长2 2 5nm ,流速0 .8ml·min-1 。结果　葡醛酸钠在0 .1～2mg·ml-1 范围内,峰面积与浓度线性关系良好(r=0 .9999) ,高、中、低3种浓度的平均加样回收率为1 0 0 .0 %～1 0 0 .3%,RSD为0 .4 4 %～0 .82 %,有关物质检查的限量为1 .0 %。结论　所用方法准确、简便、快速,适用于注射用葡醛酸钠的质量控制。     

LC／MS／MS测定大鼠血浆中普萘洛尔及其代谢物4-羟普萘洛尔、N-去异丙基普萘洛尔的浓度

目的:用高效液相色谱-质谱联用方法同时测定大鼠血浆中普萘洛尔及其代谢物4-羟普萘洛尔、N-去异丙基普萘洛尔的浓度。方法:大鼠血浆用乙醚萃取法处理后,采用 LC/MS/MS 方法,测定大鼠血浆中普萘洛尔及其代谢物4-羟普萘洛尔、N-去异丙基普萘洛尔的浓度。HPLC 条件:大连依利特 Hypersil BDS C_(18)柱(2.1 mm×50 mm,3μm),流动相:水(含0.1%甲酸)-乙腈(39:61,v/v),柱温:12℃,流速:200 μL·min~(-1),进样量:10 μL;质谱检测参数为电喷雾电离源(ESI);喷雾电压:3500 V;碰撞压力:0.1333 Pa;源内碰撞诱导电压:普萘洛尔,10 V;4-羟普萘洛尔,15 V;N-去异丙基普萘洛尔,15 V;扫描时间:0.3 s;检测离子:普萘洛尔 m/z 260[M H]~ ;4-羟普萘洛尔 m/z 276[M H]~ ;N-去异丙基普萘洛尔218[M H]~ 。结果:普萘洛尔线性范围2—1000 ng·mL~(-1),最低定量限为2 ng·mL~(-1)。4-羟普萘洛尔和 N-去异丙基普萘洛尔的线性范围1～200 ng·mL~(-1),最低定量限为1 ng·mL~(-1)。普萘洛尔的萃取回收率在90%以上,4-羟普萘洛尔和 N-去异丙基普萘洛尔的萃取回收率均为50%以上,日内、日间 RSD 皆小于15%。结论:适用于测定大鼠血浆中普萘洛尔及其代谢物4-羟普萘洛尔、N-去异丙基普萘洛尔的浓度及药动学的研究。     

采用微生物转化法合成5—羟基普萘洛尔

采用短刺小克银汉霉菌（Cunninghamella blakesleana AS3.153）对普萘洛尔进行了代谢转化研究。液相色谱-多级质谱和核磁分析结果证明，转化液中主要含有5-羟基普萘洛尔转化产物；考察了单羟化物形成的影响因素，发现在pH6.5、底物浓度0.25%和转化反应持续48h等条件下，5-羟基普萘洛尔的产率可达76%，为活性药物代谢产物的合成开辟了一条新途径。     

普萘洛尔对映异构体的血浆样品测定

建立以2,3,4,6-四乙酰基--βD-吡喃葡萄糖基异硫氰酸酯(GITC)为手性衍生化试剂测定血浆中普萘洛尔对映体浓度的反相高效液相色谱方法。血浆样品经甲醇除蛋白。采用C18色谱柱(4.6 mm×250 mm,5μm,Bnentnach),流动相为甲醇-20 mmol/LKH2PO4的水溶液(75∶25);流速1 mL/min;检测波长220 nm。结果:S(-)-普萘洛尔和R(+)-普萘洛尔检测浓度在1.00~277.78μg/mL浓度范围内与色谱峰面积有良好的线性关系。日内、日间精密度均小于5%,回收率分别为98.95%和105.76%,RSD均小于7.13%。结论:本方法灵敏度高,重现性可用于血浆中普萘洛尔对映体的分离测定。     

小剂量普萘洛尔治疗婴儿血管瘤的疗效观察

目的评价小剂量普萘洛尔口服治疗婴儿血管瘤的近期疗效与安全性.方法 20例血管瘤患儿接受并完成普萘洛尔治疗方案.结果疗效明显,优15%、好65%、中15%.患儿瘤体越大,服药后瘤体缩小越明显,近期疗效越好;主要不良反应为心率减慢(100%)、腹泻(10%)和睡眠改变(15%).讨论小剂量口服普萘洛尔治疗婴儿血管瘤近期疗效良好,不良反应轻微,较为疗效观察.     

The use of long-acting propranolol (‘Inderal’ LA) in the management of elderly hypertensive patients

Summary Fifteen elderly patients whose hypertension was controlled by conventional propranolol 80 mg twice a day had their medication changed to one capsule of Inderal LA¹ (160 mg) daily. The blood pressure, heart rate and propranolol concentrations were measured at various time points when the patients were receiving the conventional preparation and these assessments were repeated when the long-acting preparation was administered. Although the heart rate was lower with conventional propranolol than with Inderal LA there was no significant difference in the blood pressure levels. The mean peak blood level of propranolol was, however, significantly lower with Inderal LA compared with conventional propranolol and occurred later. At 12 h the plasma propranolol levels were higher after Inderal LA than following the intake of conventional propranolol (p<0.01); there was no difference in the plasma levels at 24 h. The area under the concentration time curve was significantly higher on conventional propranolol. Compared with published data, the plasma levels were higher than those in younger patients. Inderal LA was well tolerated and side effects were minimal.     

Propranolol pharmacokinetics and pharmacodynamics after single doses and at steady-state

Summary The duration and extent of cardiac beta-blockade and their relationship to propranolol pharmacokinetics were assessed in nine healthy volunteers. Each subject received 160 mg of regular propranolol (R), 160 mg of sustained-release propranolol (SR) and no drug (control), both as single doses and once daily for 7 days.After single doses and at steady-state, both products caused a decrease in exercise heart rate for at least 24 h, compared to control. The time course of effect was similar to the time course of serum propranolol concentration. The oral clearance of propranolol decreased from single doses to steady-state for both R and SR; however, the difference achieved statistical significance only for R. These changes were reflected in mean accumulation ratios (AUC steady-state 0–24 h/AUC single dose 0-infinity) of 1.49 and 1.68 for R and SR, respectively.The pharmacokinetic data are consistent with a decrease in intrinsic hepatic clearance of propranolol, leading to an increase in bioavailability at steady-state. Despite a two-fold difference in the bioavailability of R and SR, there was no difference in the area under the effect-time curve at steady-state.Presented in part at the IIIWorld Conference on Clinical Pharmacology and Therapeutics, Stockholm, Sweden, July 1986     

Propranolol and blood glucose: Simultaneous measurements over a wide range of doses and the effect of propranolol on the glucose tolerance test

Summary No correlation was found between blood glucose and simultaneous measurements of plasma propranolol concentration in patients with schizophrenia, on a daily dose of 80 mg to 1800 mg of propranolol as an adjunct to phenothiazine medication. The Glucose Tolerance Test (GTT) in ten patients on propranolol and phenothiazines did not differ significantly from those of a matched control group on phenothiazine alone. Two patients with mild diabetes showed no significant change in their GTT after stopping propranolol. These observations accord with the view that relatively high doses of propranolol as an adjunct to phenothiazine medication in schizophrenia are safe from the standpoint of glucose metabolism. This does not apply to the insulin dependent diabetic who is in danger of severe hypoglycaemia when glycogenolysis is blocked by propranolol.     

Comment on efficacy and safety of propranolol in the treatment of parotid hemangioma

A brief comment on efficacy and safety of propranolol in the treatment of parotid hemangioma is presented, with illustration of a typical case.     

普萘洛尔与维拉帕米治疗药物性窦性心动过速的比较

目的：用双盲对照法比较普萘洛尔与维拉帕米治疗抗精神病药所致窦性心动过速（简称窦速）的疗效。方法：因服抗精神病药物后引起窦速１００例，分为甲、乙２组。甲组５０例（男性３１例，女性１９例；年龄３２±ｓ１３ａ）采用普萘洛尔１０ｍｇ，ｐｏ，ｔｉｄ×２ｗｋ．乙组５０例（男性３１例，女性１９例；年龄３３±１２ａ）采用维拉帕米２０ｍｇ，ｐｏ，ｔｉｄ×２ｗｋ。结果：甲组痊愈４３例，有效７例；乙组痊愈１９例，有效２１例，无效１０例，经Ｒｉｄｉｔ分析法统计，Ｐ＜０．Ｏ５；２组均无明显不良反应。结论：治疗抗精神病药物性引起的窦速普萘洛尔优于维拉帕米。     

甲状腺功能状态对普萘洛尔药物动力学的影响

本文通过建立具有亚临床病例特点的实验性甲亢和甲低模型，以及通过参照文献的方法建立应用荧光分光光度计测定血浆中普萘洛尔（ｐｒｏｐｒａｎｏｌｏｌ）的方法，研究了甲状腺功能状态对普萘洛尔药物动力学的影响。结果如下：对照组，甲亢组和甲低组大鼠ｉｐ普萘洛尔４ｍｇ／ｋｇ，求得其主要药物动力学参数：Ｔ１／２β（ｈ）分别为４．５４±０．６５，３．５８±０．３５（Ｐ＜０．０５）和６．４±０．８（Ｐ＜０．０５）；Ｋ１０（ｈ－１）分别为０．９９±０．０２，１．２３±０．０９（Ｐ＜０．０１）和０．６６±０．０８（Ｐ＜０．０１）；ＡＵＣ〔ｎｇ／（ｍｌ·ｈ）〕分别为６５４．２±９０．４，４４８．２±６６．８（Ｐ＜０．０１）和１０３４．６±１３２．３（Ｐ＜０．０１）；ＣＬ〔ｍｇ／（ｋｇ·ｈ）／（ｎｇ·ｍｌ）〕分别为０．００６２２±０．０００９６，０．００９１±０．００１６（Ｐ＜０．０１）和０．００３９２±０．０００５８（Ｐ＜０．０１）；Ｃｍａｘ（ｎｇ／ｍｌ）分别为５０１．４６±４０．１３，４０８．３３±５７．６５（Ｐ＜０．０１）和６０７．８±２７．２（Ｐ＜０．０１）。     

Effects of chlorpromazine on the disposition and beta-adrenergic blocking activity of propranolol in the dog

The effects of chlorpromazine (100mg p.o., 2hr before propranolol) on the disposition and beta-adrenergic blocking actions of both intravenous (6 mg) and oral (40 mg) propranolol were studied in the dog. Chlorpromazine pretreatment significantly reduced (69%) the oral clearance of propranolol, resulting in significant increases in propranolol bioavailability (159%), and in the total beta-adrenergic blocking activity (111%) after the oral dose. The increase in the total beta-adrenergic blocking activity of oral propranolol after chlorpromazine pretreatment was mostly due to an increased contribution from the parent compound; the apparent activity from active propranolol metabolites was not affected by chlorpromazine. Chlorpromazine pretreatment had no significant influence on the systemic clearance, elimination half-life, apparent volume of distribution, and plasma binding of propranolol, or on the apparent hepatic blood flow. After intravenous propranolol, chlorpromazine pretreatment had no effect on either the total amount of beta-adrenergic blocking activity or the amount of activity attributable to active metabolites. The decreased oral propranolol clearance by chlorpromazine was seen as a shift to the left in the propranolol dose vs. AUCrelationship, eliminating the apparent nonlinear kinetic behavior of oral propranolol, and reducing the apparent oral threshold dose. Chlorpromazine's major, if not only, effect on propranolol disposition was to reduce the presystemic elimination of propranolol, possibly through inhibition of its metabolism via a pathway other than ring oxidation.This work was supported by a US Public Health Grant No. HL-22718.     

Solubilization of Liposomes by Weak Electrolyte Drugs. I. Propranolol

The solubilization of dimyristoylphosphatidylcholine (DMPC) liposomes by a weak electrolyte drug, propranolol (PPL) hydrochloride, has been studied as a function of pH, [PPL], [DMPC], and temperature. The solubilization of liposomes at 40°C by 0.2 mM PPL occurred at different rates from 2.9 to 14.4 mM DMPC but converged at complete solubilization after 13 hr at pH 12.0. At the same [PPL], solubilization was complete after 18 days at pH 11.0, but incomplete solubilization occurred at pH 10.0 and not at all at lower pH's. In 14.4 mM DMPC liposomes, solubilization was gradual and proportional to the [PPL] from 0.001 to 0.10 mM up to 95 hr, then rapid thereafter. The [PPL] at which the solubilization efficiency began to increase rapidly was determined to be 0.078 mM. The rate of solubilization was also influenced by the fluidity of the bilayers, a sevenfold increase in the time for complete solubilization being observed upon cooling from 40 to 20°C. Surface tension (st) data confirmed a low critical micelle concentration (CMC) and continued decrease in the st above the CMC. It is concluded that the critical ratio of PPL to DMPC for solubilization occurs in localized regions of the bilayers, with total solubilization at different rates depending on the [PPL] and the physical properties of the liposomes. The processes may be used advantageously to prepare small vesicles or to extract lipids or proteins, more efficiently than detergents, from biological membranes.     

增窦复脉颗粒抗缓慢性心律失常的实验研究

目的 观察中药复方制剂增窦复脉颗粒对实验性缓慢性心律失常的疗效.方法 取家兔随机均分成7组,各组分别按剂量灌胃给药,1次/天,连续7 d,末次药后30 min,用20%乌拉坦5 ml·kg-1麻醉,记录不同时间段心电变化及采用生物信号采集处理系统的全程动态监控,观察实验药物对动物的心率、P-R间期、QRS波时间、出现心律失常及心律失常的持续时间和出现传导阻滞等指标的影响.结果 增窦复脉颗粒对普萘洛尔所诱导的缓慢性心律失常模型家兔有明显的加快心率,缩短P-R间期、QRS波时间,减少心律失常和传导阻滞的发生率的作用.结论 增窦复脉颗粒能够有效地治疗普萘洛尔导致的缓慢性心律失常.