预混人胰岛素和预混胰岛素类似物的药代动力学特点

预混胰岛素类似物BIAsp30达峰浓度是预混人胰岛素BHI30的1.5倍,达峰时间提前了1 h,持续浓度和作用时间较短,表明BIAsp30比BHI30能更快速、更有效地控制血糖.用AUC6-24h表示,两种预混胰岛素中的中效成分相似,总的生物利用度相似,半衰期也接近,但预混胰岛素类似物的可溶性成分比预混人胰岛素的吸收更快,在餐前即时给药,更好改善餐后血糖.     

临床药理学药代动力学实验课量化分析

做为临床药理学研究内容的给药方案设计、临床TDM等研究都密切依赖于药代动力学理论和实验技能，而目前国内的医学教育模式使国内医学生普遍缺乏药代动力学的理论知识和实验技能培训，这对临床个体化给药目标的实现是十分不利，为此我们在研究生临床药理学课程中，增加了给药方案设计的基础理论和药物动力学实验课教学内容，本文对整个实验     

栀子中藏花素的药理学和药代动力学研究进展

栀子为茜草科植物栀子(Gardenia Jasminoides Ellis)的干燥成熟果实,具有广泛的用途.藏花素是从栀子果实中提取出来的一类天然色素.实验研究发现藏花素具有多种药理学活性,如神经保护作用、抗肿瘤等.本文综述藏花素的药理学及药代动力学方面的研究进展,以期为藏花素的研发和临床应用提供依据.     

基础胰岛素与体重增加的关系

胰岛素所致增重及其引起的心血管事件风险增加,已成为糖尿病患者接受胰岛素治疗的心理障碍之一.目前认为,胰岛素引起的体重增加主要与热量摄入,胰岛素注射量．低血糖发生率．以及生理分泌模式改变等几个方面相关.     

药代动力学—药效学结合模型的应用进展

本主要述评1998－2000年间药代动力学－药效学结合模型在药理学、毒理学、临床治疗以及新药开发等方面最新的应用进展,并展望发展前景。     

基础胰岛素治疗药物地特胰岛素与甘精胰岛素疗效及安全性比较

目的:比较基础胰岛素治疗药物地特胰岛素及甘精胰岛素的疗效及不良反应,为临床合理用药提供参考。方法:通过检索,对已发表的文献进行综述。结果:对于有效降低HbA1c或空腹血糖水平,地特胰岛素与甘精胰岛素作用相似;低血糖及体重增加不良反应的发生风险,地特胰岛素低于甘精胰岛素;药物经济学评估,甘精胰岛素成本低于地特胰岛素。结论:地特胰岛素与甘精胰岛素作为基础胰岛素治疗药物,疗效确切,应根据患者实际需求进行选择。     

Pharmacology and pharmacokinetics of milnacipran

Milnacipran is a dual-action antidepressant drug with equivalent inhibitory action at noradrenaline and serotonin neuronal reuptake systems. This dual action has been demonstrated in vitro and in vivo in experimental animals, and ex vivo in man. Milnacipran has no relevant affinity for any neurotransmitter receptor studied, in particular postsynaptic adrenergic, muscarinic and histamine receptors, and is therefore expected to be devoid of the prominent side-effects of many earlier antidepressants. Studies in human volunteers have not demonstrated any impact of milnacipran on cognitive function, consistent with its lack of anticholinergic properties. These pharmacodynamic properties are well preserved in vivo in humans, because milnacipran is only metabolized to a limited extent, and therefore circulates in the body principally as the unchanged parent drug, which is the only pharmacologically active compound at clinical doses. The pharmacokinetic profile of milnacipran is characterized by rapid absorption, high bioavailability, low protein binding, and rapid elimination, both by hepatic glucuronidation and renal excretion. This gives milnacipran certain pharmacokinetic advantages, such as low inter-individual variation in plasma levels, low potential for drug interactions, and limited impact on hepatic cytochrome P450 systems. These pharmacokinetic properties differentiate milnacipran from most other antidepressant drugs and contribute to the good safety profile of milnacipran and allow it to be used simply and flexibly in clinical practice.     

Pharmacology and pharmacokinetics of amiodarone.

Amiodarone is a unique antiarrhythmic agent originally developed as a vasodilator. Classified electrophysiologically as a Type III antiarrhythmic, it also has both nonspecific antisympathetic and direct, fast channel-membrane effects. Hemodynamic effects of orally administered amiodarone (a negative inotropic agent) are usually negligible, and are usually compensated for by induced vasodilation. Effects on thyroid and hepatic function may help to explain some of the unique pharmacologic as well as toxicologic effects of the drug. Amiodarone is poorly bioavailable (20-80%) and undergoes extensive enterohepatic circulation before entry into a central compartment. The principal metabolite, mono-n-desethyl amiodarone is also an antiarrhythmic. From this central compartment, it undergoes extensive tissue distribution (exceptionally high tissue/plasma partition coefficients). The distribution half-life of amiodarone out of the central compartment to peripheral and deep tissue compartments (t1/2 alpha) may be as short as 4 hours. The terminal half-life (t1/2 beta) is both long and variable (9-77 days) secondary to the slow mobilization of the lipophilic medication out of (primarily) adipocytes. A pharmacokinetically based loading scheme is described, and data suggesting a role for routine amiodarone plasma levels are presented.     

Pharmacology, pharmacokinetics and pharmacogenomics of paclitaxel

Paclitaxel is widely used in many cancers including ovarian, breast, lung, head and neck and primary unknown. Paclitaxel is extensively metabolized by cytochrome P450s and excreted in bile. The cytochromes involved include 2C8 and 3A4. This is a review of the pharmacokinetics, pharmacodynamics, drug interactions, metabolism and pharmacogenomics of paclitaxel.     

Pharmacology and pharmacokinetics of imatinib in pediatric patients

Introduction: The tyrosine kinase inhibitor (TKI) imatinib was rationally designed to target BCR-ABL1 which is constitutively activated in chronic myeloid leukemia (CML). Following the tremendous success in adults, imatinib also became licensed for treatment of CML in minors. The rarity of pediatric CML hampers the conduction of formal trials. Thus, imatinib is still the single TKI approved for CML treatment in childhood.

Areas covered: This review attempts to provide an overview of the literature on pharmacology, pharmacokinetic, and pharmacogenetic of imatinib concerning pediatric CML treatment. Articles were identified through a PubMed search and by reviewing abstracts from relevant hematology congresses. Additional information was provided from the authors’ libraries and expertise and from our own measurements of imatinib trough plasma levels in children. Pharmacokinetic variables (e.g. alpha 1-acid glycoprotein binding, drug–drug/food–drug interactions via cytochrome P450 3A4/5, cellular uptake mediated via OCT-1-influx variations and P-glycoprotein-mediated drug efflux) still await to be addressed in pediatric patients systematically.

Expert commentary: TKI response rates vary among different individuals and pharmacokinetic variables all can influence CML treatment success. Adherence to imatinib intake may be the most prominent factor influencing treatment outcome in teenagers thus pointing towards the potential benefits of regular drug monitoring.     

Pharmacology of mitoxantrone: mode of action and pharmacokinetics

Summary Although a number of investigators have established that mitoxantrone (Novantrone^®; dihydroxyanthracenedione) inhibits RNA and DNA synthesis and intercalates with DNA in vitro, its exact mechanism of action is unclear. Mitoxantrone is structurally related to a series of substituted anthraquinones and has features known to be essential for DNA intercalation; however, we have determined recently that mitoxantrone binds DNA in intact L1210 leukemia cells by a non-intercalative, electrostatic interaction and induces both protein associated and non-protein associated DNA strand scissions. The difference between mitoxantrone and doxorubicin with respect to their interactions with DNA could account for their relative lack of cross-resistance in the treatment of lymphoma and acute leukemia.Distribution and half-life data provide a pharmacological rationale for the use of mitoxantrone on an intermittent dosing schedule. Considerable evidence exists to suggest that mitoxantrone undergoes extensive metabolism, probably in the liver. Preliminary data show that abnormal liver function leads to decreased rates of total body mitoxantrone clearance, suggesting a possible need for dose reduction in patients with severe liver dysfunction. The most important route of mitoxantrone elimination appears to be fecal. Because of the relatively low urinary excretion it is unlikely that the standard drug dose must be reduced in the presence of compromised renal function.     

全面认识基础胰岛素

糖尿病高血糖主要由空腹和餐时两部分构成.随着病程延长,空腹血糖对整体血糖控制和糖化血红蛋白(HbA1c)的贡献越来越大.因此,实现空腹血糖的良好控制在糖尿病治疗中占有重要地位.在糖尿病的治疗中,胰岛素无疑是最有效的药物之一.     

Clinical pharmacokinetics and pharmacodynamics of inhaled insulin

The benefits of intensive insulin therapy in the prevention of complications in patients with diabetes mellitus are now well established. However, the current methods of insulin administration fall well short of the ideal. Consequently, alternative routes of insulin administration have been investigated. The pulmonary route has received the most attention, helped by advances in inhaler devices and insulin formulation technology. As a result, several insulin inhalation systems are at varying stages of development, with one already filed for marketing approval in Europe. Knowledge of the pharmacokinetic and pharmacodynamic characteristics of the various inhaled insulin formulations will help to determine their positioning in current and evolving diabetes treatment strategies. For instance, a rapid onset and short duration of action would be desirable for use in postprandial glucose control. Pharmacokinetic studies with inhaled insulin reveal that serum insulin concentrations peak earlier and decay more rapidly following inhalation compared with subcutaneously administered regular insulin, and pharmacodynamic studies measuring glucose infusion rate under euglycaemic glucose clamp show corresponding rapid changes in glucose control. Furthermore, intrapatient variability in the pharmacokinetics and pharmacodynamics of inhaled insulin is low; variability is similar to (or perhaps less than) that seen when insulin is administered subcutaneously. Estimates of the bioavailability and bioefficacy achievable with the current inhalation systems are typically in the region of 10% of that experienced with subcutaneously administered insulin. Most of the losses are in the device, mouth and throat, with approximately 30-50% of the insulin deposited in the lungs being absorbed. Clinical experience to date indicates that inhaled insulin has the potential to be an effective treatment in patients with diabetes, and that it may have particular utility in the treatment of postprandial hyperglycaemia.     

Clinical pharmacokinetics and pharmacodynamics of insulin aspart

Insulin aspart is a novel rapid-acting insulin analogue with improved subcutaneous absorption properties when compared with soluble human insulin. Pharmacokinetic studies show an absorption profile with a time to reach peak concentration (t(max)) about half that of human insulin, a peak plasma drug concentration (Cmax) approximately twice as high and shorter residence time. The potency and bioavailability of insulin aspart are similar to those of human insulin. The pharmacokinetics of insulin aspart have been studied in healthy Caucasian and Asian-Japanese volunteers, in patients with type 1 and 2 diabetes mellitus, and in children with diabetes, with both pre- and postprandial administration and during continuous subcutaneous insulin infusion (CSII). The pharmacokinetic profile was similar to that of another rapid-acting insulin analogue, insulin lispro, on the basis of published information for that agent. Pharmacodynamic studies show a smaller excursion of postprandial glucose with insulin aspart injected subcutaneously just before the meal compared with soluble human insulin injected 30 minutes before the meal in patients with type 1 diabetes mellitus, and an equivalent control in patients with type 2 diabetes displaying residual insulin production. In a treatment study, glucose excursions evaluated from 24-hour glucose profiles showed less variability with insulin aspart compared with human insulin. Adverse events, including hypoglycaemia-induced ventricular repolarisation and hypoglycaemic threshold and awareness, did not differ between insulin aspart and human insulin. The available data suggest that subcutaneous injections of insulin aspart just before meals better mimic the endogenous insulin profile in blood compared with human insulin, resulting in improved glucose control in a meal-related insulin regimen. This review summarises the clinical pharmacokinetics and pharmacodynamics of insulin aspart in relation to human insulin and insulin lispro.     

Clinical pharmacokinetics and pharmacodynamics of insulin glulisine

Insulin glulisine injection [3(B)-Lys, 29(B)-Glu-human insulin] is the newest human insulin analogue product for the control of mealtime blood sugar. As with insulin aspart and insulin lispro products, the insulin glulisine product displays faster absorption and onset of action, with a shorter duration of action than that of regular human insulin.The modifications of the amino acid sequence at positions 3 and 29 in the B chain of human insulin simultaneously provide stability to the molecular structure and render the insulin glulisine molecule less likely to self-associate, compared with human insulin, while still allowing the formation of dimers at pharmaceutical concentrations. Unlike other insulin analogue products, this allows for a viable drug product in the absence of hexamer-promoting zinc and, thus, provides immediate availability of insulin glulisine molecules at the injection site for absorption.Pharmacokinetic studies with insulin glulisine have shown an absorption profile with a peak insulin concentration approximately twice that of regular human insulin, which is reached in approximately half the time. Dose proportionality in early, maximum and total exposure is observed for insulin glulisine over the therapeutic relevant dose range up to 0.4 U/kg.The pharmacodynamic profile of insulin glulisine reflects the absorption kinetics by demonstrating a greater rate of glucose utilization, which is completed earlier and at equipotency on a molar base compared with regular human insulin. Dose-proportionality in glucose utilization has been established for insulin glulisine in patients with type 1 diabetes mellitus in the dose range of 0.075-0.15 U/kg, and a less than dose-proportional increase above 0.15 U/kg, indicating saturation of insulin action in general.The rapid absorption and action of insulin glulisine show similar low intrasubject variability compared with insulin lispro and regular human insulin when given repeatedly, and have been confirmed in healthy subjects of different body mass indices (BMIs) and ethnic groups, as well as adults and children with type 1 and type 2 diabetes. Furthermore, the early insulin exposure and action of insulin glulisine were slightly -- but consistently -- greater than those of insulin lispro in healthy volunteers across a wide range of BMIs.Meal studies in patients with type 1 diabetes show that insulin glulisine provides better postprandial blood glucose control than regular human insulin when administered immediately pre-meal, and equivalent control when given after the meal. In a study in patients with type 2 diabetes, the overall postprandial blood glucose excursions were lower with insulin glulisine than with insulin lispro. Therefore, by virtue of its primary structure, insulin glulisine demonstrates both low self-association in solution and stability for a viable insulin product in the absence of zinc, thereby maintaining immediate availability for absorption after subcutaneous injection. This confers the most rapid onset of glucose-lowering activity and adds to the flexibility in postprandial blood glucose control.     

基础胰岛素的药物经济学研究概述

国际糖尿病联盟(IDF)的数据显示,2010年中国糖尿病患病率已达4.5%.仅次于印度[1].中华医学会糖尿病学分会在中国14个省市进行的糖尿病和代谢综合征患病率调查结果显示,在20岁以上的人口中,糖尿病的年龄标化患病率为9.7%,而糖尿病前期的年龄标化患病率更达到15.5%[2].