卡维地洛

<正> 1 概述卡维地洛是一种非选择性β-受体阻滞剂,并具有α-受体阻滞作用,可完全性阻滞β_1、β_2及α_1受体,α_1;β阻滞作用=1:10,无内源性拟交感活性。 2 临床药理学 2.1 结构卡维地洛是立体异构体的外消旋混合物,其非选择性β-受体阻滞效应主要在左旋异构体,而α-受体阻滞作用在两种异构体(左旋、右旋)中都存在。     

Polymer Microneedles for Controlled-Release Drug Delivery

Purpose As an alternative to hypodermic injection or implantation of controlled-release systems, this study designed and evaluated biodegradable polymer microneedles that encapsulate drug for controlled release in skin and are suitable for self-administration by patients. Methods Arrays of microneedles were fabricated out of poly-lactide-co-glycolide using a mold-based technique to encapsulate model drugs—calcein and bovine serum albumin (BSA)—either as a single encapsulation within the needle matrix or as a double encapsulation, by first encapsulating the drug within carboxymethylcellulose or poly-l-lactide microparticles and then encapsulating drug-loaded microparticles within needles. Results By measuring failure force over a range of conditions, poly-lactide-co-glycolide microneedles were shown to exhibit sufficient mechanical strength to insert into human skin. Microneedles were also shown to encapsulate drug at mass fractions up to 10% and to release encapsulated compounds within human cadaver skin. In vitro release of calcein and BSA from three different encapsulation formulations was measured over time and was shown to be controlled by the encapsulation method to achieve release kinetics ranging from hours to months. Release was modeled using the Higuchi equation with good agreement (r² ≥ 0.90). After microneedle fabrication at elevated temperature, up to 90% of encapsulated BSA remained in its native state, as determined by measuring effects on primary, secondary, and tertiary protein structure. Conclusions Biodegradable polymer microneedles can encapsulate drug to provide controlled-release delivery in skin for hours to months.     

卡维地洛固体分散体的初步研制

目的:制备卡维地洛固体分散体并考察其体外溶出度。方法:以聚乙二醇(PEG)、聚乙烯吡咯烷酮(PVP)的混合物(2∶1、1∶2)为载体,采用溶剂熔融法和共沉淀法制备载体与药物不同比例的固体分散体并比较其体外溶出度。结果:药物溶出度随载体比例增加而增加;载体与药物比例越小,固体分散体与药物原料粉之间溶出度差异越显著;PEG∶PVP(1∶2)所制分散体体外溶出行为较优,以3、10、30、60min时溶出百分率进行比较,固体分散体是药物原料粉的3～8倍。结论:所制卡维地洛固体分散体能增加药物体外溶出度。     

Carvedilol overdose with quantitative confirmation

Carvedilol is a non-selective beta-adrenoreceptor antagonist that is also an antagonist at the alpha(1)-adrenoreceptor. This unique pharmacological effect may produce a different toxicodynamic profile compared to other beta-adrenoreceptor antagonists. Only one previous case of carvedilol overdose has been reported. Here, we report massive carvedilol ingestion confirmed by quantitative analysis. The case report deals with an 84-year-old man who chewed a total of 60 (6.25 mg) tablets and rapidly developed symptoms. Vital signs on presentation were systolic blood pressure 70 mmHg; heart rate 45 beats/min.; respirations 18 breaths/min.; temperature 37 degrees . The electrocardiogram showed a junctional rhythm at 49 beats/min. The patient was treated with normal saline boluses, repeated glucagon boluses (2-3 mg each) and a dopamine infusion. At 14 hr after ingestion, he was weaned off vasopressors and was in a normal sinus rhythm. Quantitative confirmation showed a carvedilol serum concentration of 472 ng/ml (steady-state concentration 8.5 ng/ml during 6.25 mg twice daily dosing). Despite its unique pharmacological properties, the clinical manifestations of carvedilol overdose appear similar to other beta-adrenoreceptor antagonists.     

盐酸维拉帕米脉冲控释微丸的研制

采用流化床包衣法制备盐鞍维拉帕米脉冲控释微丸，并考察了羧甲淀粉钠、经丙甲纤维素和乙基纤维素—聚乙烯砒咯烷酮(4：1，ω／ω)的用量对微丸体外释药的影响。结果表明，该包衣微丸可脉冲释药，其中经丙甲纤维素和乙基纤维素—聚乙烯砒咯烷酮(4：1，ω／ω)用量增加，可延长时滞；羧甲淀粉钠用量增加，释药加快；乙基纤维素—聚乙烯毗咯烷酮(4：1，ω／ω)用量增加，释药减慢。     

沙丁胺醇渗透泵控释片的相对生物利用度研究

18名男性健康志愿者,随机交叉口服两种沙丁胺醇控释片,采用反相HPLC-荧光检测法测定沙丁胺醇血浆药物浓度.两种控释片单剂量口服的C     

Carvedilol protects against doxorubicin-induced mitochondrial cardiomyopathy

Several cytopathic mechanisms have been suggested to mediate the dose-limiting cumulative and irreversible cardiomyopathy caused by doxorubicin. Recent evidence indicates that oxidative stress and mitochondrial dysfunction are key factors in the pathogenic process. The objective of this investigation was to test the hypothesis that carvedilol, a nonselective beta-adrenergic receptor antagonist with potent antioxidant properties, protects against the cardiac and hepatic mitochondrial bioenergetic dysfunction associated with subchronic doxorubicin toxicity. Heart and liver mitochondria were isolated from rats treated for 7 weeks with doxorubicin (2 mg/kg sc/week), carvedilol (1 mg/kg ip/week), or the combination of the two drugs. Heart mitochondria isolated from doxorubicin-treated rats exhibited depressed rates for state 3 respiration (336 +/- 26 versus 425 +/- 53 natom O/min/mg protein) and a lower respiratory control ratio (RCR) (4.3 +/- 0.6 versus 5.8 +/- 0.4) compared with cardiac mitochondria isolated from saline-treated rats. Mitochondrial calcium-loading capacity and the activity of NADH-dehydrogenase were also suppressed in cardiac mitochondria from doxorubicin-treated rats. Doxorubicin treatment also caused a decrease in RCR for liver mitochondria (3.9 +/- 0.9 versus 5.6 +/- 0.7 for control rats) and inhibition of hepatic cytochrome oxidase activity. Coadministration of carvedilol decreased the extent of cellular vacuolization in cardiac myocytes and prevented the inhibitory effect of doxorubicin on mitochondrial respiration in both heart and liver. Carvedilol also prevented the decrease in mitochondrial Ca(2+) loading capacity and the inhibition of the respiratory complexes of heart mitochondria caused by doxorubicin. Carvedilol by itself did not affect any of the parameters measured for heart or liver mitochondria. It is concluded that this protection by carvedilol against both the structural and functional cardiac tissue damage may afford significant clinical advantage in minimizing the dose-limiting mitochondrial dysfunction and cardiomyopathy that accompanies long-term doxorubicin therapy in cancer patients.     

部分药物控释技术研究概述

从药物控制释放体系的制备工艺方面对部分药物控释制剂的研究进展进行综述,展望其在新药研制、老药新用途开发方面的广阔前景。     

Preparation and Characterization of Metoprolol Controlled-Release Solid Dispersions

In recent years, great attention has been paid to using solid dispersions to make sustained-release drugs. The objective of this study is to produce sustained-release systems of metoprolol tartrate using solid dispersion techniques and to evaluate their physicochemical characteristics. The solid dispersions were produced by melting and solvent methods, containing 7%, 15%, or 25% of the drug and different ratios of Eudragit RLPO and RSPO in ratios of 0:10, 3:7, 5:5, 7:3, and 10:0. Drug release profiles were determined by USP XXIII rotating paddle method in phosphate buffer solution (pH 6.8). XRD, DSC, IR, and microscopic observations were performed to evaluate the physical characteristics of solid dispersions. Results showed that the drug release from dispersions was at a slower rate than pure drug and physical mixtures. Moreover, the formulations containing greater ratios of Eudragit RSPO showed slower release rates and smaller DE_8% but larger mean dissolution time than those containing greater ratios of Eudragit RLPO. Dispersions with particle size of less than 100 μm containing 7% of metoprolol and Eudragit RL:RS 5:5 (solvent method) and those with the ratio of 3:7 (melting method) had similar release pattern to Lopressor® sustained-release tablets by zero-order and Higuchi kinetics, respectively.     

聚合物水性分散体在茶碱控释小丸包衣上的应用

将Ｓｕｒｃｌｅａｓｅ、Ｓｕｒｅｔｅｒｉｃ、Ｏｐａｒｌｒｙ等聚合物水性分散体应用于茶碱小丸的包衣,得到释放度符合美国药典要求的控释小丸。     

卡维地洛传递体的制备及其质量评价

目的:制备卡维地洛(CA)传递体,并进行质量评价。方法:采用薄膜分散法联合高压乳匀法制备CA传递体;高效液相色谱法测定其中CA的含量;SephadexG-50凝胶柱层析法测定其中CA的包封率;对CA传递体的外观、形态、粒径及电位进行考察。结果:制备的CA传递体为乳白色、近均一透明的胶体溶液;CA平均含量为27.09μg·mL-1,平均包封率为80.84%,RSD均<2.0%;体系粒径在100nm左右,多分散性系数为0.05左右,电位均>41mV,具有较好的质量和稳定性。结论:CA传递体制备工艺可行、方法简单、质量可控。     

Formulation development of Carvedilol compression coated tablet

Purpose: The aim of present research was to produce carvedilol compression coated tablet to provide biphasic drug release.

Method: A compressed coated tablet made of a sustained release core tablet and an immediate release coat tablet. Both the core and the coat contained carvedilol. The sustained release effect was achieved with polymers (HPMC K₄M and PEO WSR 205) to modulate the release of the drug. The powder blends for core and coat tablets were evaluated for angle of repose, bulk density, compressibility index, and drug content. Compressed coated tablets were evaluated for thickness, diameter, weight variation test, drug content, hardness, friability, disintegration and in vitro release studies.

Result: The powder blends showed satisfactory flow properties, compressibility, drug content and all the tablet formulations showed acceptable pharmaco-technical properties. Carvedilol contained in the fast releasing component was released within 3?min, whereas the drug in the core tablet was released at different times up to 24?h, depending on the composition of the matrix tablet. The mechanism of drug release was fickian diffusion or anomalous behavior.

Discussion: Batch F7, containing 10?mg PEO WSR 205 and 5?mg HPMC K₄M, showed maximum similarity with theoretical profile and zero order drug release kinetic.     

Enantioselective pharmacokinetics of Carvedilol in human volunteers

Carvedilol is administered as a racemic mixture of the R(+)- and S(-)-enantiomers, although they exhibit different pharmacological effects. To investigate the stereoselective pharmacokinetics, the enantiomeric separation of carvedilol in human plasma was undertaken using capillary electrophoresis (CE). Resolution of the enantiomers was achieved using 2-hydoxypropyl-beta-cyclodextrin as the chiral selector. Phosphate buffer (50 mM, pH 4.0) containing 10 mM of 2-hydoxypropropyl-beta-cyclodextrin was used as electrolytic buffer. Achiral separation was carried out with the same electrolytic buffer without chiral selector. Following a single oral administration of 25-mg carvedilol to 11 healthy, male volunteers, stereoselective pharmacokinetic analysis was undertaken. The maximum plasma concentrations (Cmax) were 48.9 and 21.6 ng/mL for (R)-carvedilol and (S)-carvedilol, respectively, determined by the chiral method. The profiles of the plasma concentration of (RS)-carvedilol showed Cmax of 71.5, 72.2, and 73.5 ng/mL, as determined by the CE, HPLC/FD methods and calculations from the data of the chiral method, respectively.     

Carvedilol: Therapeutic Application and Practice Guidelines

Current knowledge of the mechanisms contributing to progression of heart failure suggests that therapies that limit or interfere with the consequences of neurohormonal activation and improve myocardial energetics appear to be most beneficial. Carvedilol, a nonselective β-adrenergic blocker with peripheral vasodilating properties, reduces mortality, slows progression of disease, and improves quality of life in patients with heart failure when added to standard therapy. When administered according to recommended guidelines, carvedilol is well tolerated. Clinical guidelines on the use of carvedilol in heart failure are provided.     

Carvedilol stability in paediatric oral liquid formulations

ObjectiveTwo carvedilol aqueous solutions and one carvedilol aqueous suspension for paediatric oral use (1 mg/ml) were studied to determine their stability.MethodAll samples were stored at 4, 25 and 40° C. Carvedilol content of each of the three formulations was tested using high performance liquid chromatography (HPLC). Each sample was analysed in triplicate at 0, 3, 7, 14, 28 and 56 days.ResultsCarvedilol stayed stable in the acidic aqueous solution at the three different temperatures during the 56 days of the study. In the alkaline solution, carvedilol was stable during 56 days at 25° C, but only 28 days at 4 and 40° C. In the aqueous suspension, carvedilol was stable during 56 days at 4 and 25° C, but only 28 days at 40° C.ConclusionsAll the formulations that were tested can be stored at 25° C for at least 56 days.     

Carvedilol versus other beta-blockers in heart failure

Carvedilol is a beta-blocker with ancillary properties. Pilot clinical studies with carvedilol, added to the standard therapy of digoxin, diuretics and ACE inhibitors, showed beneficial effects in mild, moderate and severe heart failure. Patients consistently showed improvement in LV ejection fraction and NYHA functional class. Subsequently large clinical trials showed decreased morbidity and mortality with carvedilol in mild and moderate and more recently, severe heart failure. However, there is little or no improvement in exercise tolerance with carvedilol. The beneficial effects of carvedilol in heart failure are associated with cardiac remodelling. Metoprolol and bisoprolol are selective beta(1)-blockers without ancillary properties. Early studies showed benefits with metoprolol and bisoprolol in heart failure. Large clinical trials established that metoprolol and bisoprolol decreased mortality and morbidity in heart failure. In contrast no benefit has been shown with celiprolol, a selective beta(1)-blocker and beta(2)-stimulant in heart failure. There is a debate as to whether the ancillary properties of carvedilol contribute to its beneficial effect in heart failure, making it a better drug to use than metoprolol. Short-term studies suggested that carvedilol and metoprolol were equivalent in heart failure but short-term is probably not an appropriate way to compare the drugs. A recent long-term study and study in poor responders to metoprolol, suggest that carvedilol may be better than metoprolol in heart failure.     

卡维地洛治疗慢性心力衰竭75例临床疗效观察

目的评价卡维地洛治疗慢性心力衰竭的临床疗效。方法 75例慢性心衰患者被随机地分为常规治疗组38例和卡维地洛治疗组37例。常规治疗组用强心、利尿药和扩血管药物治疗,卡维地洛治疗组在常规治疗药物的基础上加用卡维地洛,疗程6月。观察其临床效果并测定治疗前后左心室射血分数（LVFF）、左心室舒张末期内径（LVEDD）、左心室收缩末期内径（LVESD）的变化。结果治疗6月后,卡维地洛治疗组总有效率高于常规治疗组（P〈0.05）,卡维地洛治疗组LVFF、LVEDD、LVESD与常规治疗组比较,差异均有统计学意义（P