Pharmacology of drugs used to treat osteoarthritis in veterinary practice

As in humans, pain in animals may be associated with a wide range of conditions and circumstances, ranging from acute trauma to joint diseases. Joint diseases are common in companion animal medicine (horse, dog, cat) and at least 80% of cases are classified as osteoarthritis (OA). Several drug classes are available for OA therapy, including corticosteroids, non-steroidal antiinflammatory drugs (NSAIDs), agents with potential disease modifying properties and nutraceuticals. For long-term maintenance OA treatment, particularly in the horse and dog, NSAIDs are routinely and extensively used. This review outlines the pharmacokinetics (PK) and pharmacodynamics (PD) of NSAIDs in companion and farm animal species. NSAID PK and PD have been studied in models of acute inflammation, which enable use of PK-PD modeling to facilitate (a) studies of mechanism of action at the molecular level and (b) prediction of dosages for clinical use. The PK-PD approach is a powerful but underutilized tool which also facilitates inter-species comparisons.     

基于药动学与药效学相关联的养阴通脑颗粒主要有效部位正交配伍研究

目的探讨养阴通脑颗粒主要有效部位(总生物碱、总黄酮、总皂苷、总酚酸)配伍后在脑缺血再灌注模型大鼠体内药物浓度及其药动学与药效学变化。方法采用正交试验法组成上述主要有效部位用量配比不同的9个组方,供脑缺血再灌注模型大鼠ig给药,高效液相色谱-二极管阵列检测器(HPLC-DAD)测定不同时间点血浆中的葛根素、阿魏酸和川芎嗪血浆药物浓度。DAS 3.2.6软件以非房室模型拟合药动学参数,并运用总量统计矩法和综合评分法对整体药动学特征进行评价。同时采用酶联免疫吸附测定(ELISA)法测定大鼠血浆中超氧化物歧化酶(SOD)和过氧化氢酶(CAT)的含量。最后进行药动学-药效学(PK-PD)模型研究,获得各药物浓度与药效之间的定量方程。结果葛根素、阿魏酸和川芎嗪在模型大鼠体内的药动学特征有所差异。总量统计矩和综合评分研究表明不同配伍对总量零阶矩、总量平均滞留时间、综合评分等参数影响不一。主要有效部位正交配伍给药后,一定程度上会抑制脑缺血再灌注大鼠血浆中SOD和CAT的降低。各PK-PD模型均采用Sigmoid-Emax模型,拟合结果与实测数据之间相关性良好,R值均大于0.85。结论养阴通脑颗粒主要有效部位配伍对模型大鼠体内的药动学行为和抗氧化指标具有一定影响;中药复方多成分药物代谢动力学可采用总量统计矩和综合评分法进行研究;PK-PD结合模型可用于中药复方多成分药动学与药效学之间相关性的评价与预测。     

PK-PD模型在中药药动学中的应用

药动学-药效学(PK-PD)结合模型是综合研究药物在体内的动态变化过程与其药效消长之间关系的一种有力工具,其借助数学方法定量表述浓度(或剂量)、时间和效应三者之间的内在关系,对药物的研究开发及合理使用具有普遍的指导意义.针对目前PK-PD结合模型在中药药物动力学研究领域的应用现状进行系统的阐述,并就中药效应基础的确定、效应指标的选择等关键问题进行探讨并提出建议,以期为今后的相关研究提供参考.     

Pharmacokinetics and pharmacodynamics of midazolam administered as a concentrated intranasal spray. A study in healthy volunteers

AIMS: To investigate the pharmacokinetic and pharmacodynamic profile of midazolam administered as a concentrated intranasal spray, compared with intravenous midazolam, in healthy adult subjects. METHODS: Subjects were administered single doses of 5 mg midazolam intranasally and intravenously in a cross-over design with washout period of 1 week. The total plasma concentrations of midazolam and the metabolite 1-hydroxymidazolam after both intranasal and intravenous administration were described with a single pharmacokinetic model. beta-band EEG activity was recorded and related to midazolam plasma concentrations using an exponential pharmacokinetic/pharmacodynamic model. RESULTS: Administration of the intranasal spray led to some degree of temporary irritation in all six subjects, who nevertheless found intranasal administration acceptable and not painful. The mean (+/-s.d.) peak plasma concentration of midazolam of 71 (+/-25 ng ml-1) was reached after 14 (+/-5 min). Mean bioavailability following intranasal administration was 0.83+/-0.19. After intravenous and intranasal administration, the pharmacokinetic estimates of midazolam were: mean volume of distribution at steady state 1.11+/-0.25 l kg-1, mean systemic clearance 16.1+/-4.1 ml min-1 kg-1 and harmonic mean initial and terminal half lives 8.4+/-2.4 and 79+/-30 min, respectively. Formation of the 1-hydroxymetabolite after intranasal administration did not exceed that after intravenous administration. CONCLUSIONS: In this study in healthy volunteers a concentrated midazolam nasal spray was easily administered and well tolerated. No serious complications of the mode of administration or the drug itself were reported. Rapid uptake and high bioavailability were demonstrated. The potential of midazolam given via a nasal spray in the acute treatment of status epilepticus and other seizure disruptions should be evaluated.     

板蓝根总生物碱中表告依春在发热大鼠体内的药动学-药效学结合模型研究

目的应用药动学与药效学结合模型,研究板蓝根总生物碱中主要成分表告依春在酵母致热大鼠体内的药动学和药效学之间的关系。方法给大鼠ig板蓝根总生物碱,不同时间取血并对体温进行观察,采用高效液相法测定血浆中表告依春的浓度,用一房室模型计算药动学参数,采用3种药动学与药效学拟合模型,分别对药效学参数进行拟合。结果表告依春在正常大鼠和发热大鼠体内的主要药动学参数t1/2、Cmax、AUC分别为:(4.94±0.84)h、(4.01±0.21)μg/mL、(28.37±2.42)μg.h/mL和(5.71±0.91)h、(4.15±0.25)μg/mL、(30.35±2.58)μg.h/mL。药理效应与效应室浓度之间的关系用间接反应中的药效产生抑制模型拟合较好,相应的药效学参数分别为Kin为(0.70±0.10)h-1,Kout为(0.54±0.12)h-1,R0为1.33±0.16,IC50为(0.94±0.66)mg/L。结论板蓝根总生物碱中表告依春在正常大鼠和发热大鼠体内的药动学行为无明显差异,表告依春在发热大鼠体内药动学与药效学间符合间接反应中的药效产生抑制模型。     

Pharmacokinetics and pharmacodynamics of a known active PPI with a novel Dual Delayed Release technology,dexlansoprazole MR: a combined analysis of randomized controlled clinical trials

ABSTRACT

Background: Dexlansoprazole MR is a novel Dual Delayed Release formulation of dexlansoprazole, an enantiomer of lansoprazole, designed to prolong the plasma concentration–time profile of dexlansoprazole and extend duration of acid suppression with once-daily (QD) dosing.

Objectives: To assess the pharmacokinetics and pharmacodynamics of dexlansoprazole at different doses of dexlansoprazole MR and delineate the exposure–response relationship following oral administration of dexlansoprazole MR.

Methods: Dexlansoprazole MR was evaluated in two prospective randomized studies in healthy subjects. In study 1 (n?=?40), subjects received dexlansoprazole MR 60, 90, and 120?mg and lansoprazole 30?mg QD. In study 2 (n?=?45), subjects received dexlansoprazole MR 30 and 60?mg and lansoprazole 15?mg QD. Data from these trials were pooled and analyzed to describe the relationship between intragastric pH and dexlansoprazole systemic exposure.

Results: Data from 83 subjects were analyzed. The dexlansoprazole plasma concentration–time profile following administration of dexlansoprazole MR was characterized by two distinct peaks and a prolonged drug exposure during the 24-h dosing interval. Approximate dose proportionality was observed for mean peak plasma concentration and area under the plasma–concentration time curve after administration of dexlansoprazole MR. In each study, doses of dexlansoprazole MR generally produced greater gastric acid suppression than lansoprazole. Based on the exposure–response analysis using combined data from these two trials, the predicted mean 24-h intragastric pH values were 4.06 and 4.35 for the dexlansoprazole MR 30- and 90-mg doses, respectively. The percent of time pH?>?4 over 24?h values were 59.2% and 66.7% for dexlansoprazole MR 30 and 90?mg, respectively. No appreciable additional gain in the pharmacodynamic response was predicted for dexlansoprazole MR 120?mg. Despite combining data from two studies to evaluate a broader dose range, this analysis provided a reasonable estimate of the pharmacodynamic parameters and a good characterization of the dexlansoprazole MR exposure–response relationship.

Conclusions: Dexlansoprazole MR, a proton pump inhibitor that uses Dual Delayed Release technology, produced a pharmacokinetic profile with a plasma concentration–time curve characterized by two distinct peaks and an extended duration of pharmacologically active dexlansoprazole concentration in plasma. Exposure–response analysis indicated a progressive increase in the pharmacodynamic response as dexlansoprazole MR doses increased from 30 to 90?mg.     

冠心病患者氯吡格雷群体药动学-药效学模型研究

目的 建立冠心病患者氯吡格雷群体药动学-药效学模型,为尽早诊断和干预氯吡格雷抵抗提供临床依据.方法 前瞻性收集使用双联抗血小板治疗冠心病的患者101例,分别以患者体内氯吡格雷活性代谢产物(clopidogrel active metabolite,Clop-AM)浓度和血小板最大聚集率(maximum platelet...     

Pharmacokinetics,pharmacokinetic–pharmacodynamic relationship,and withdrawal period of amoxicillin sodium in olive flounder (Paralichthys olivaceus)

1.?The pharmacokinetics (PK) and withdrawal period of amoxicillin sodium in olive flounder and its activity against pathogenic bacteria of olive flounder were investigated.

2.?Intramuscular administration (12.5 or 125?mg/kg, n?=?160) and HPLC analysis of sera were used.

3.?Rapid absorption (T_max 2.6 and 2.2?h), prolonged action (terminal half-life, 15.52 and 10.42?h; MRT, 18.79 and 14.44?h), and dose-proportional exposure (AUC_0–∞, 273.69 and 2755.37?h. μg/ml) were observed after 12.5 and 125?mg/kg doses.

4.?The withdrawal period of amoxicillin sodium from muscle plus skin of olive flounder (n?=40, water temperature, 23?°C) was 12 d (276 degree days).

5.?Amoxicillin sodium had small MICs against Streptococcus iniae (0.008–0.06?μg/ml) and Streptococcus parauberis (0.03–1.0?μg/ml), whereas higher concentrations were required to inhibit Edwardsiella tarda isolates (0.06–16?μg/ml).

6.?While large AUC_0–24?h/MIC₉₀ and C_max/MIC₉₀ ratios were obtained for S. iniae and S. parauberis, with drug concentrations in serum greater than MICs for the entire dosing interval (T?>?MIC₉₀ of 100%), the lower dose (12.5?mg/kg) could not achieve target values of the PK–pharmacodynamic (PD) indices for E. tarda isolates, suggesting the need for higher doses to combat pathogenic bacteria with large MICs.     

中药复方双参通冠方的PK/PD数据分析研究

中药复方指征药代动力学是以复方在体内发挥作用的机制为黑箱系统,将各成分的药代动力学数据为该系统的输入,多指标的药效动力学产生相应变化的数据为输出,通过定量描述成分和药效并结合适当的数学方法来分析和研究其间的关系和规律.在此思路指导下,本研究进行了13个时间点15个成分的PK数据和24个药效指标的PD数据测定,并在此基础上通过稳健变换、基线漂移处理、有效性判断和差值分析等方法对数据进行分析处理,最终从复方中得到了12个指征成分.