An Investigation of Oral Exposure Variability and Formulation Strategy: A Case Study of PI3Kδ Inhibitor and Physiologically Based Pharmacokinetic Modeling in Beagle Dogs

It is well acknowledged that drugs with poor aqueous solubility are often associated with poor oral absorption. Fortunately, drugs with a basic pKa can take advantage of solubilization in the stomach under the acidic environment to improve exposure. Consequently, high in vivo variability is often observed when stomach pH is altered. When issue encountered, enabling formulations are often used to solve the problem. However, each enabling formulation has its limitations and the situation can be further complicated by other absorption distribution metabolism elimination parameters. Therefore, formulation strategies need to consider various scenarios in order to be effective. Compound 1 is a potent phosphoinositide 3-kinase delta inhibitor with poor intrinsic solubility and 2 basic pKas. It was dosed as a suspension in dogs and found to have mediocre oral bioavailability with high variability. It was hypothesized that this variability was caused by their stomach pH variability. Pharmacokinetic modeling suggested that the issue could be improved with particle size reduction. Meanwhile, it was found that although the Madin-Darby canine kidney permeability was reasonable, Madin-Darby canine kidney transfected with human MDR1 gene (MDCK-MDR1) suggested that Compound 1 is an efflux transporter substrate. Findings were integrated into the design for in vivo studies in dogs. Data obtained from those studies allowed us to quickly narrow down the formulation approaches.     

Bile Acid as an Effective Absorption Enhancer for Oral Delivery of Epidermal Growth Factor Receptor–Targeted Hybrid Peptide

The aim of this study was to improve the oral absorption of epidermal growth factor receptor–targeted hybrid peptide using bile acid as an absorption enhancer. The oral formulation of this peptide was formed through electrostatic interactions between the cationic peptide and anionic bile acid. Comparative studies of in vitro cell permeability and in vivo antitumor effects of peptide and peptide/bile acid complex were performed in Caco-2 cells and in a xenograft mouse model of human gastric cancer. The in vitro permeability of peptide/bile acid complex across Caco-2 cell monolayers was significantly enhanced to about 5.0-fold over those of peptide alone. Furthermore, in vivo mouse xenograft model treated with peptide/bile acid complex showed a 1.6-fold reduction in the mean tumor volume as compared with the peptide alone. A preliminary safety evaluation of blood cells counts, liver enzyme levels, and histopathology of gastrointestinal tissues and main organs showed that the peptide/bile acid complex did not induce any acute toxicity. These results suggest that bile acid is an effective absorption enhancer for improving the oral bioavailability and bioactivity of epidermal growth factor receptor–targeted hybrid peptide.     

Labrasol® and Salts of Medium-Chain Fatty Acids Can Be Combined in Low Concentrations to Increase the Permeability of a Macromolecule Marker Across Isolated Rat Intestinal Mucosae

In addition to their solubilizing properties, excipients used in lipid-based formulations can improve intestinal permeability of macromolecules. We determined whether admixing of medium-chain fatty acid (MCFA) permeation enhancers with a lipoidal excipient (Labrasol^®) could potentiate transepithelial flux of a poorly permeable macromolecule (fluorescein isothiocyanate dextran 4 kDa [FD4]) across rat intestinal mucosae mounted in Ussing chambers. Low concentrations of sodium caprate (C₁₀), sodium undecylenate (C_11:1), or sodium laurate (C₁₂) combined with Labrasol^® increased the apparent permeability coefficient (P_app) of FD4 to values typically seen with higher concentrations of MCFAs or Labrasol^® alone. For example, combination of C_11:1 (0.5 mg/mL) with Labrasol^® (1 mg/mL) increased the P_app of FD4 by 10- and 11-fold over the respective individual agents at the same concentrations where no enhancement was evident. The increased enhancement ratios seen with the combinations were associated with some perturbation in intestinal histology and with attenuation of an epithelial functional measure, carbachol-stimulated inward short-circuit current. In conclusion, combining three MCFAs separately with Labrasol^® increased the P_app of FD4 to values greater than those seen for MCFAs or Labrasol^® alone. Ultimately, this may permit lower concentrations of MCFA to be used in combination with other excipients in oral formulations of poorly permeable molecules.     

The Influence of In Vivo Metabolic Modifications on ADMET Properties of Green Tea Catechins–In Silico Analysis

The health effects of green tea are associated with catechins: (?)-epigallocatechin-3-O-gallate (EGCG), (?)-epigallocatechin, (?)-epicatechin-3-O-gallate, and (?)-epicatechin. An understanding of compound absorption, distribution, metabolism, excretion, and toxicity characteristics is essential for explaining its biological activities. Herein, absorption, distribution, metabolism, excretion, and toxicity properties of in vivo detected metabolites of green tea catechins (GTCs) have been analyzed in silico. The influence of metabolic transformations on absorption, distribution, metabolism, and excretion profiles of GTCs corresponds to the effects of size, charge, and lipophilicity, as already observed for other small molecules. Mutagenic, carcinogenic, or liver toxic effects were predicted only for a few metabolites. Similar to galloylated GTCs EGCG and (--)-epicatechin-3-O-gallate, the sulfo-conjugates were predicted to bind at the warfarin binding site. The low free plasma concentration of these derivatives may be consequential to their serum albumin binding. The activity cliff detected for methylated conjugates of EGCG indicates that GTCs' pro-oxidative activity in bound state comes primarily from free hydroxyl groups of the pyrogallol ring B.     

Effects of Various Pharmaceutical Excipients on the Intestinal Transport and Absorption of Sulfasalazine,a Typical Substrate of Breast Cancer Resistance Protein Transporter

Breast cancer resistance protein (BCRP) transporter is an efflux transporter that utilizes energy from adenosine triphosphate hydrolysis to push its substrates, regardless of the concentration gradient. Its presence on the apical membrane of the intestinal mucosa is a major obstacle for the intestinal absorption of its substrates. In this study, we examined the effects of various pharmaceutical excipients on the intestinal transport and absorption of sulfasalazine, a BCRP substrate. Four excipients, including 0.05% and 0.075% BL-9EX, 0.01% and 0.05% Brij 97, 0.075% Labrasol, and 0.05% and 0.1% Tween 20 decreased the secretory transport of sulfasalazine in an in vitro diffusion chamber. Further investigation in an in situ closed loop experiment in rats showed that 0.05% and 0.1% BL-9EX and 0.1% Brij 97 effectively enhanced the intestinal absorption of sulfasalazine while maintaining minimal toxicity to the intestinal mucosa. However, 0.1% Brij 97 also increased the intestinal absorption of 5(6)-carboxyfluorescein, a paracellular marker compound. These findings suggest that BL-9EX might effectively inhibit the BCRP-mediated efflux of sulfasalazine in vivo, indicating that BL-9EX could improve the intestinal absorption of sulfasalazine and other BCRP substrates.     

hs-CRP联合D-二聚体对急性心梗PCI术后亚急性支架内 血栓形成的预测价值

摘要：目的 探究超敏C反应蛋白（hs-CRP）和D二聚体（D-dimer）联合预测急性心肌梗死（AMI）患者经皮冠状 动脉介入治疗（PCI）术后发生亚急性支架内血栓形成（SST）的价值。方法 分析自2012年1月—2018年1月收治的 因AMI接受PCI治疗的9 261例患者,其中术后发生SST的72例（0.78%）患者为SST组,根据年龄、性别比例在术后未 发生SST的患者中抽取210例作为对照组。对比2组患者冠心病危险因素（性别、年龄、体质量指数等）、临床资料［收 缩压、舒张压、磷酸肌酸激酶（CK）、肌酸激酶同工酶（CK-MB）等］、冠脉造影结果情况（病变血管、支架贴壁不良等）。 将上述资料统计学分析时P < 0.1的指标纳入多因素Logistic回归分析。将hs-CRP和D-dimer进行ROC曲线分析, 评估两者联合对SST的预测价值。结果 SST组患者术后D-dimer、hs-CRP和Glu水平、支架贴壁不良例数、支架置 入数目均高于对照组,左室射血分数（LVEF）低于对照组,差异有统计学意义（P＜0.05）。多因素Logistic回归分析显 示 D-dimer 升高、hs-CRP 升高、血糖升高、支架贴壁不良是 SST 的独立危险因素,LVEF＞0.50 是 SST 的保护因素。 hs-CRP和D-dimer的联合指标hs-CRP-D-dimer在ROC曲线下面积为0.875,对SST的最佳cutoff值为14.28,其敏感 度为 77.8%,特异度为 80.5%。结论 D-dimer、hs-CRP 和血糖升高、支架贴壁不良是影响 SST 的独立危险因素, LVEF>0.50是SST的保护性因素。hs-CRP和D-dimer联合是预测AMI患者PCI术后发生SST的理想指标,值得临床 推广应用。     

一步扩张法与逐级扩张法建立微通道在经皮肾镜碎石术中的应用比较

目的 比较一步扩张法与逐级扩张法建立微通道在经皮肾镜碎石术中的应用效果.方法 58例肾结石患者,根据入院顺序进行分组,奇数为观察组,偶数为对照组,每组各29例.两组均采用经皮肾镜碎石术治疗,其中观察组在建立微通道时采用的是一步扩张法,对照组采用逐级扩张法,比较两组手术时间、术中出血量、结石清除情况及术后并发症发生情况,同时评价两组入院时及出院时的生活质量.结果 观察组手术时间明显短于对照组(P<0.01),两组术中出血量、结石一期清除率比较差异无统计学意义(P>0.05).观察组并发症发生率为7.94％,显著低于对照组的22.22％(P<0.01).两组出院时生活质量各维度评分均有显著上升(P<0.01),但观察组上升更明显(P<0.05).结论 在经皮肾镜碎石术中采用一步扩张法建立微通道相对于逐级扩张法能有效简化手术操作程序,缩短手术时间,同时减少手术并发症的发生,安全性高.     

冠状动脉旁路移植手术与经皮冠状动脉介入治疗多支血管病变合并糖尿病患者的预后比较

目的比较冠状动脉旁路移植手术(CABG)与经皮冠状动脉介入(PCI)治疗多支血管病变(MVD)合并糖尿病(DM)患者的预后结果。方法连续收集2010年1月至2012年12月于咸阳市中心医院住院接受CABG和PCI的MVD合并DM患者入组。收集并获取患者基线资料,包括性别、年龄、既往病史、左心室射血分数、血生化指标、住院天数、住院费用、出院诊断等信息,并进行术后定期随访。结果本研究共收集MVD合并DM患者625例,其中接受CABG的共205例,接受PCI的共420例。与PCI组相比,CABG患者冠状动脉狭窄程度及左主干狭窄程度更严重(P<0.001),患者遭受的并发症更多(P<0.001);CABG组的主动脉内球囊反搏使用率高,住院总花费也显著偏高(P<0.001);CABG组患者的住院死亡率(1.5%)略高于PCI组患者(0.5%),但差异不显著(P>0.05);CABG组的五年生存率(98.0%)显著高于PCI组(74.5%);CABG组患者的预后显著优于PCI组,五年内发生心梗和心脑血管不良事件的概率也更低(P<0.05)。结论对于MVD合并DM患者,CABG手术的长期预后结局优于PCI手术。     

替格瑞洛治疗急性冠状动脉综合征患者的临床研究

目的观察长期服用替格瑞洛对急性冠状动脉综合征患者的临床疗效及其对肌钙蛋白T(cTnT)、脑钠素(BNP)、C-反应蛋白(CRP)和D-二聚体(D-D)水平的影响。方法将84例急性冠状动脉综合征患者随机分为对照组42例和试验组42例。2组均给予常规治疗及对症治疗,术前服用阿司匹林150mg联合氯吡格雷300 mg,口服,每日1次,持续用药7 d,进行经皮冠状动脉介入(PCI)术。对照组术后服用阿司匹林100 mg,每日1次,连续服用6个月。试验组术后服用阿司匹林100 mg+替格瑞洛90 mg,每日1次,连续服用6个月。比较2组患者的临床疗效和急性心肌梗死发作次数、发作持续时、ST段下移水平、cTnT、BNP、CRP、D-D水平及药物不良反应发生情况。结果治疗后,对照组和试验组临床总有效率分别为78.57%(33例/42例)和95.24%(40例/42例),差异有统计学意义(P<0.05)。对照组和试验组治疗后急性心肌梗死发作次数分别为(4.52±0.55)和(2.02±0.27)次/周,发作持续时间分别为每次(4.14±0.43)和(2.76±0.31)min,ST段下移水平1.25±0.17和0.63±0.07,差异均有统计学意义(均P<0.05)。治疗后,对照组血清cTnT、BNP、CRP、D-D水平分别为(1.54±0.18)ng·mL^-1,(63.52±6.73)ng·mL^-1,(8.94±0.94)mg·mL^-1和(133.53±15.73)ng·mL^-1,试验组分别为(0.25±0.03)ng·mL^-1,(28.43±3.02)ng·mL^-1,(4.57±0.55)mg·mL^-1和(59.54±5.74)ng·mL^-1,差异均有统计学意义(均P<0.05)。对照组出现头痛2例,腹泻2例,恶心呕吐1例,眩晕2例,药物不良反应发生率为16.67%(7例/42例);试验组出现胃肠道出血1例,血肌酸酐轻度上升1例,眩晕1例,药物不良反应发生率为7.14%(3例/42例),2组差异无统计学意义(P>0.05)。结论长期服用替格瑞洛治疗急性冠状动脉综合征患者的临床疗效显著,安全性高。     

Anticoagulant and antiplatelet therapy choices for patients with atrial fibrillation one year after coronary stenting or acute coronary syndrome

Introduction: Guidelines recommend a combined anticoagulant and antiplatelet approach for patients with atrial fibrillation (AF) after coronary stenting (CS) or acute coronary syndrome (ACS). Finding the optimal balance of reducing ischemic risk and minimizing bleeding risk is challenging. Recent trials have evaluated a variety of regimens for up to one year for AF patients after CS/ACS. Little empiric evidence exists about the best antithrombotic strategy beyond one year.

Areas covered: In this review two key areas are covered. First, a summary of the overall risk and benefits of anticoagulant and antiplatelet therapy in patients with AF and CS or ACS is provided. Second, despite limited empiric evidence to guide therapeutic decisions for combined anticoagulant and antiplatelet therapy in patients with AF one year after CS/ACS we provide guidance for shared patient-physician decision making.

Expert opinion: The evidence is limited. For all patients with AF and stable CAD (≥1 year after CS or ACS) the risk for thromboembolism, cardiovascular events and bleeding should be assessed individually. For patients with low bleeding risk and high risk for cardiovascular events, antiplatelet therapy might be added to anticoagulant therapy.