Exenatide: pharmacokinetics,clinical use,and future directions

Introduction: The first-in-class glucagon-like peptide-1 receptor agonist (GLP-1RA) exenatide, which was initially approved in 2005, is available in twice-daily (BID) and once-weekly (QW) formulations. Clinical trial data suggest both formulations are effective and safe for patients with type 2 diabetes (T2D), both as monotherapy and as part of combination therapy. Since exenatide was approved, several other GLP-1RAs have become available for clinical use.

Areas covered: Many ongoing clinical trials involving exenatide BID and exenatide QW are investigating new indications (exenatide BID) and new end points and combination therapies (exenatide QW). This review provides an overview of the delivery and pharmacokinetics of both formulations of exenatide, reviews existing data in T2D, and summarizes ongoing investigations.

Expert opinion: Exenatide BID and QW have substantial clinical benefits. Comparisons with other GLP-1RAs demonstrate some differences in efficacy and safety profiles that make assessment of benefit:risk ratios complex. Head-to-head comparisons of QW GLP-1RA formulations may assist in the ranking of GLP-1RAs according to efficacy and safety. Results on the impact of exenatide QW on cardiovascular outcomes are eagerly awaited. The potential clinical utility of exenatide BID in other indications will clarify whether exenatide holds clinical promise in diagnoses other than T2D.     

以他汀类药物为基础的降脂药物联合应用研究进展

降脂治疗是预防动脉粥样硬化性心血管疾病的基石,其主要目标是降低低密度脂蛋白胆固醇和非高密度脂蛋白胆固醇。目前他汀类药物仍是降脂治疗的首选。然而,在临床实践中,许多患者单用他汀类药物治疗其血脂水平仍不能达标。而降脂药物联合应用不仅增加疗效,且可能减少不良反应。本文对以他汀类药物为基础的降脂药物联合应用的临床研究进展进行了综述。     

Preparation and pharmacokinetics of docetaxel based on nanostructured lipid carriers

Objectives This study describes the preparation and pharmacokinetics of docetaxel based on freeze‐dried nanostructured lipid carriers (NLCs). Methods The docetaxel‐incorporated NLCs were developed using hot high‐pressure homogenisation, and lyophilised to obtain freeze‐dried docetaxel NLCs. The influences of different concentrations of lipid matrices, ratio of drug to lipid, and different cryoprotectants on the characteristics of the NLCs were investigated. Key findings Freeze‐dried docetaxel NLCs were spherical, with 5% (w/w) docetaxel loading efficiency and were stable for at least 6 months at 25°C. X‐ray powder diffraction and differential scanning calorimetry analysis suggested that docetaxel was distributed in a molecular or amorphous status. In‐vitro release studies showed sustained drug release, with the cumulated release rate of 13% within 24 h without burst release. The freeze‐dried docetaxel NLCs also showed sustained‐release properties after intravenous injection into rats. The area under the plasma–concentration time curve and mean residence time were increased 4.90 and 2.82 times compared with docetaxel solution. The concentration of docetaxel in the lungs was significantly higher in rats treated with the NLCs than in those given docetaxel solution. Conclusions Docetaxel NLCs have an organ‐targeting effect and prolonged mean retention time and have potential for the treatment of lung cancer.     

Fluphenazine pharmacokinetics and therapeutic response

We conducted a double-blind study of therapeutic outcome versus mean steady-state levels in 29 newly admitted schizophrenic and schizoaffective patients who were treated with a constant dose of fluphenazine HCl over a 2-week period. Both an upper and lower end of the therapeutic window were suggested by three nonresponders whose plasma levels were above 2.8 ng per ml and by two nonresponders and one partial responder whose plasma levels were below 0.2 ng per ml. The mean terminal half-life of fluphenazine (±SD) was 16.4±13.3 h. We found that concomitant use of benztropin mesylate during the initial 4 weeks of fluphenazine treatment did not significantly alter fluphenazine plasma levels.     

Statin response and pharmacokinetics variants

Despite statin therapy being effective in the primary and secondary prevention of coronary heart disease, the benefit of treatment varies between individuals. Interindividual variations in pharmacokinetics play a central role in the cause of variability of drug disposition, and, in turn, the drug's clinical efficacy. Exploring genetic variations that influence pharmacokinetics may lead clinicians to apply the most efficient and safe drug therapy. So far, variants in eight candidate genes related to pharmacokinetics of statins have been investigated as the potential determinant of drug responsiveness or adverse event risk. All reported data remains inconclusive, but it has been suggested that combined analysis of more than two different polymorphisms, or a combination of genetic association and studies using in vitro recombinant expression techniques, may be more informative in predicting the specific phenotype of a genetic variant. Future studies using these approaches could provide more striking evidence, which may be sufficient to justify genetic analysis regarding pharmacokinetic variants in the clinical practice of statin therapy.     

Baicalin-loaded PEGylated lipid nanoparticles: characterization,pharmacokinetics, and protective effects on acute myocardial ischemia in rats

Context: Baicalin has many pharmacological activities, including protective function against myocardial ischemia by antioxidant effects and free radical scavenging activity. However, its rapid elimination half-life in plasma and poor water solubility limits its clinical efficacy.

Objective: Novel baicalin-loaded PEGylated nanostructured lipid carriers (BN-PEG-NLC) were developed to improve bioavailability of BN, to prolong retention time in vivo and to enhance its protective effect.

Methods: In this study, BN-PEG-NLC were prepared by the emulsion-evaporation and low temperature-solidification method using a mixture of glycerol monostearate and polyethylene glycol monostearate as solid lipids, and oleic acid as the liquid lipid. The physicochemical properties of NLC were characterized. The pharmacokinetic and pharmacodynamic behaviors of BN-PEG-NLC or BN-NLC were evaluated in acute MI rats.

Results and discussion: The particle size, zeta potential, and entrapment efficiency for BN-PEG-NLC were observed as 83.9?nm, ?32.1?mV, and 83.5%, respectively. The release profiles of BN from both BN-PEG-NLC and BN-NLC were fitted to the Ritger–Peppas modal, which presented burst release initially and prolonged release afterwards. Pharmacokinetics results indicated that BN-PEG-NLC exhibited a 7.2-fold increase in AUC in comparison to BN solution, while a 3-fold increase in comparison to BN-NLC. Biodistribution results revealed that BN-PEG-NLC exhibited higher heart drug concentration compared with BN-NLC as well as BN solution. In the present study, BN-PEG-NLC significantly ameliorated infarct size.

Conclusion: The results of the present study imply that PEG-NLC could be the biocompatible carriers for heart-targeted drug delivery to improve myocardial ischemia.     

Non lipid, dose-dependent effects of pravastatin treatment on hemostatic system and inflammatory response

Objectives: The aim of the present study was to evaluate the effects of pravastatin treatment on lipid, inflammation, and coagulation parameters in patients suffering from myocardial infarction with or without carotid atherosclerotic lesions (groups 1 and 2, respectively). Methods: In the first phase of the study, a cross-sectional comparison of lipid, inflammation, and coagulation parameters was performed between the patients and the control group (group 3). Highly significant differences in these parameters were observed, especially in group 1. In the second phase of the study, we assessed the effects of a persistent reduction in cholesterol synthesis induced by increasing doses of pravastatin (20 mg daily for 8 weeks and 40 mg daily for a further 8 weeks). In addition to the well-established lipid-lowering effect, significant changes in inflammation and coagulation parameters were observed. In particular, pravastatin at a dosage of 20 mg/day significantly reduced only fibrinogen levels, while at a dosage of 40 mg/day significantly reduced factor VII, fibrinogen, prothrombin fragments 1 and 2, thrombin–antithrombin complexes, tissue plasminogen activator antigen (tPA:Ag) before venous occlusion (b.o.), inhibitor of plasminogen activator activity (PAI) b.o., PAI activity after occlusion (a.o.), the human autoantibodies against oxidized low-density lipoprotein (LDL), and the c fraction of the third component system levels, and significantly increased tPA:Ag a.o. levels. Results: Our results show that in patients suffering from myocardial infarction the risk of thrombotic complications can be decreased with pravastatin, especially by larger doses. However, the relationship must be further investigated because the observed reductions in the hemostatic system and inflammatory response seemed to be dose dependent, while the effects of pravastatin treatment were not significantly correlated with total and LDL cholesterol changes. Received: 14 June 1999 / Accepted in revised form: 9 March 2000     

水飞蓟宾脂质微球的制备及在大鼠体内的药物动力学考察

目的制备水飞蓟宾脂质微球并对其理化性质及大鼠体内药物动力学特征进行考察,为水飞蓟宾的临床应用提供理论依据。方法采用高压均质法制备水飞蓟宾脂质微球;分别采用动态光散射法、超速离心法考察制剂的粒径、zeta电位及药物的相分布;以自制水飞蓟宾溶液剂作为参比制剂,采用HPLC法考察大鼠体内药物动力学。结果制剂平均粒径约为192.4 nm,zeta电位为-24.56 mV,约77.5%的药物分布在油水界面膜上;40℃加速实验10 d,药物的相分布无变化;4℃留样观察6个月内稳定;水飞蓟宾脂质微球和溶液剂的药时过程均符合双隔室模型;非隔室模型分析结果表明,脂质微球和溶液剂的AUC0-t分别为(1.90±0.29)、(2.07±0.44)mg.h.L-1,两制剂药-时曲线相似。结论所制备的水飞蓟宾脂质微球性质稳定,大部分药物分布在油水界面膜上;脂质微球未改变药物在大鼠体内的药物动力学特征。     

降糖药物与艾塞那肽

目前临床上用到的降糖药物种类众多，作用机制各异。本文依作用机制将降糖药物进行了分类，并对各类药物的作用机制和特点进行了简要介绍。对全球首个上市的胰高血糖素样肽-1（Glucagon-like peptide-1，GLP-1）类似物艾塞那肽进行了重点阐述，包括氨基酸序列、作用机制、药物动力学、上市制剂和在研制剂等。     

Clazepam: pharmacokinetics and effects on performance.

1. The effects of clazepam, a new benzodiazepine (30 mg orally) on performance tests and the cardiovascular system have been compared to those of chlordiazepoxide (30 mg orally) and a placebo in a double-blind trial involving six healthy volunteers. Simultaneously, the pharmacokinetics of clazepam were investigated. 2. While clazepam itself could be detected neither in plasma nor in urine, it gave rise to two plasma metabolites, the former, an alcoholic derivative with a short half-life, and the second, desmethyldiazepam, with a long half-life. These two metabolites and oxazepam were excreted in urine and, within the 24 h period following drug intake, accounted for 73% of the ingested dose. 3. Seven hours after its administration, clazepam slightly improved performance and reduced anxiety. The kinetics of these effects and the metabolic data suggest that clazepam acts mainly through the formation of desmethyldiazepam. However, owing to the low blood levels of this metabolite, the activity of clazepam was very moderate.     

The effects of age on carbamazepine pharmacokinetics and adverse effects.

The pharmacokinetics and effect of single oral doses of carbamazepine (400 mg) were compared in a group of six young volunteers aged between 20 and 25 years, and a second group of five elderly volunteers aged between 66 and 84 years. No age related changes in salivary or plasma pharmacokinetics or in psychomotor function were detected.     

他汀类药物时代烟酸调脂临床应用评价和思考

烟酸属水溶性B族维生素,其在大剂量使用时具有广谱的调脂作用。在他汀类调脂药物上市之前,烟酸及其缓释剂是较常用的调脂药物之一。在他汀类药物上市之后,多项大规模随机对照的临床研究已证实他汀在有效降低胆固醇的同时可显著减少心血管事件的发生率和死亡率,目前他汀已成为动脉粥样硬化相关疾病防治的首选降脂药物。本文综述了他汀时代烟酸调脂治疗的临床研究、荟萃分析和近年血脂异常管理指南对烟酸的应用建议,为今后烟酸的临床应用和研究提供参考。     

托伐普坦纳米结构脂质载体的制备与药动学研究

目的 制备托伐普坦纳米结构脂质载体（Tol-NLCs）,以提高托伐普坦（Tol）的口服生物利用度。方法 根据溶解度对辅料进行筛选,包括固体脂质（双硬脂酸甘油酯、山嵛酸甘油酯、聚乙二醇-8山嵛酸甘油酯、单硬脂酸甘油酯和单亚油酸甘油酯）、液体脂质（油酸聚乙二醇甘油酯、单油酸甘油酯、月桂酸聚乙二醇甘油酯和单辛酸丙二醇酯）和表面活性剂（聚山梨酯80、聚氧乙烯蓖麻油、聚乙二醇-15羟基硬脂酸酯和泊洛沙姆188）,采用乳化超声-低温固化法制备TolNLCs,并使用Box-Behankn效应面法优化处方;分别采用电镜（TEM）观察、粒径分布及Zeta电位测定、差示扫描量热法（DSC）对制备的Tol-NLCs进行表征,同时比较Tol原料药和Tol-NLCs体外药物释放特点、跨膜转运特征;比较Tol混悬液和Tol-NLCs经大鼠ig给药后的体内药动学特征。结果 根据溶解度确定以山嵛酸甘油酯作为固体脂质,单油酸甘油酯作为液体脂质,聚乙二醇-15羟基硬脂酸酯作为表面活性剂,通过优化得到Tol-NLCs的最佳处方：总脂质质量浓度为40.0 mg·mL^-1,表面活性剂质量浓度为25.0 mg·mL^-1,超声时间为6 min。在透射电镜下可观察到制备的Tol-NLCs呈类球状,分布均匀;Tol-NLCs的平均粒径为（106.2±14.7）nm,PDI为（0.196±0.004）,Zeta电位为（-26.6±0.6）mV;药物在Tol-NLCs中以非结晶形式存在。Tol-NLCs在pH 6.8磷酸盐缓冲液中表现为前期药物释放较快,后期药物释放平缓。Caco-2细胞跨膜转运结果显示,Tol-NLCs的P_{app（AP→BL）}值为（11.16±0.58）×10^-6 cm·s^-1,P_{app（BL→AP）}值为（4.51±0.46）×10^-6 cm·s^-1,与Tol溶液相比,P_{app（AP→BL）}表现出明显增加趋势,P_{app（BL→AP）}表现出明显降低趋势,说明Tol包裹在NLCs中促进了药物吸收,抑制了P-糖蛋白（P-gp）的外排作用。与Tol混悬液相比,大鼠ig Tol-NLCs后,Tol生物利用度提高了2.5倍。结论 按优化处方制备的Tol-NLCs,能够显著提高药物的生物利用度。     

Absorption, disposition and pharmacokinetics of solid lipid nanoparticles

Solid lipid nanoparticles (SLNs) are primarily composed of solid lipids, which thus impart to them some of the fundamental properties of these lipids, including biocompatibility, biodegradability and low-toxicity. SLNs represent a unique class of colloidal drug delivery systems that possess the advantages of both the "soft" drug carriers such as emulsions and liposomes and polymeric nanoparticles. In this review, we will provide an overview on the absorption, disposition and pharmacokinetics of SLNs. The lipidic nature, as well as the relatively small particle size, of SLNs ensures sufficient affinity with the biomembranes, and results in improved absorption by either of the oral, transdermal, pulmonary, nasal, ocular, rectal or buccal route. One special aspect of oral SLNs is the enhanced lymphatic absorption by either the chylomicron-association pathway or the M cell uptaking pathway. Intravenous SLNs are predominantly uptaken by the liver or spleen following opsonization by the complementary system. Modification of SLN surface with PEGs chains will mask the hydrophobic surface and divert SLNs to non-hepatic and non-splenic organs, while ligand-modification will achieve active targeting to specific tissues or organs. Degradation of SLNs is primarily based on the degradation of the lipids themselves by lipase. Pharmacokinetics reflects the effect of the lipidic vehicles of SLNs on in vivo disposition of the loaded drugs.     

Frequency response method in pharmacokinetics

The paper presents the demonstration of applicability of the frequency response method in a bioavailability study. The frequency response method, common in system engineering, is based on an approximation of the frequency response of a linear dynamic system, calculated from input-output measurements, by a frequency model of the system transfer function in the frequency domain. In general, the influence of the system structure on the form of the system frequency response is much more distinct than on the form of the system output. This is of great advantage in modeling the system frequency response instead of the system output, commonly used in pharmacokinetics. After a brief theoretical section, the method is demonstrated on the estimation of the rate and extent of gentamicin bioavailability after intratracheal administration to guinea pigs. The optimal frequency model of the system describing the gentamicin pathway into the systemic circulation and point estimates of its parameters were selected by the approximation of the system frequency response in the frequency domain, using a noniterative algorithm. Two similar estimates of the system weighting function were independently obtained: the weighting function of the selected frequency model and the weighting function estimated by the numerical deconvolution procedure. Neither of the estimates of the weighting function does decrease monotonously after the maximum of about 2.2–2.5 unit of dose·hr⁻¹ recorded approximately 0.1 hr after drug administration. Both estimates show a marked additional peak approximately at 0.3 hr after administration and possible peaks in the further time period. We hypothesized that the loop found in the frequency response calculated and in the selected optimal frequency model, the high-order of this model, and several peaks identified in the estimates of the system weighting function indicated the complexity of the system and the presence of time delays. Three estimates of the extent of gentamicin intratracheal bioavailability obtained by the three different ways: directly from the calculated frequency response, calculated using the selected frequency model, and by the deconvolution method were 0.950, 0.934, and 0.907 respectively. Thus the conclusion can be made that gentamicin injected intratracheally to guinea pigs is almost completely available. This work was supported in part by Grant 283 from the Slovak Grant Agency, 814 38 Bratislava, Slovak Republic.     

他汀类药物降脂外作用的研究进展

10年前,《美国心脏病学杂志》主编Roberts教授曾把20世纪90年代的他汀类药物和40年代的青霉素相媲美,认为他汀类药物对心血管病的治疗就如同青霉素治疗感染性疾病一样神奇。随着他汀类药物的广泛应用,其强大的降脂外功能逐渐被认识,本文综述他汀类药物降脂外作用的研究进展。