Hyaluronan-based delivery of therapeutic oligonucleotides for treatment of human diseases

Introduction: Oligonucleotide therapeutics such as antisense oligonucleotides and siRNA requires chemical modifications and nano-sized carriers to circumvent stability problems in vivo, to reach target tissues, and to overcome tissue and cellular barriers. Hyaluronic acid (HA), already utilized in drug delivery and tissue engineering, possess properties that are useful to solve these problems and achieve full potential of oligonucleotide therapeutics.

Areas covered: Complexes of oligonucleotide therapeutics with HA are discussed in terms of interactions providing the complexes formation and genes targeted by the therapeutics to cure diseases such as cancer, atherosclerosis, liver cirrhosis, and inflammation. The achieved therapeutic effects are rationalized as consequences of biodistribution, cell internalization and endosomal escape provided by HA.

Expert opinion: Design of electrostatic, coordination, and hydrophobic interactions as well as covalent conjugation between oligonucleotide drugs, HA macromolecules and intermediate ligands are crucial for carrier–cargo association and dissociation under different conditions to impart oligonucleotides stability in vivo, their accumulation in diseased organs, cellular uptake, and dissociation in cytoplasm intact. These are the delivery factors that provides eventual complex formation of oligonucleotide therapeutics with their mRNA, microRNA, or protein targets. Elucidation of the impact of structural parameters of oligonucleotide/HA complexes on their therapeutic effect in vivo is important for the future rational design of the delivery agents.     

结核丸联合环丝氨酸治疗耐药性肺结核效果及对患者炎性因子水平的影响

目的 探讨结核丸联合环丝氨酸治疗耐药性肺结核的临床效果以及对患者炎性因子水平的影响。方法 将西安市胸科医院自2015年1月-2017年12月确诊的耐药性肺结核患者106例作为研究对象，按随机法分为观察组和对照组各53例，观察组使用结核丸联合环丝氨酸进行治疗，对照组仅使用环丝氨酸进行治疗，对比观察两组患者的临床疗效和体内炎性因子水平的变化情况。结果 治疗后两组患者痰细菌学转阴率分别为66.04%和62.26%，组间比较差异无统计学意义。治疗后观察组患者病灶吸收有效率为86.79%，明显高于对照组的73.58%，差异有统计学意义（P<0.05）。治疗后两组患者干扰素-γ（INF-γ）水平明显升高，白介素-4（IL-4）、C反应蛋白（CRP）和肿瘤坏死因子-α（TNF-α）水平均明显降低，同组治疗前后比较差异有统计学意义（P<0.05）；其中观察组患者改善程度明显优于对照组，差异有统计学意义（P<0.05）。结论 使用结核丸联合环丝氨酸治疗耐药性肺结核患者可有效提高患者治疗效果，降低机体内炎性反应，可推广使用。     

Clinical pharmacokinetics and pharmacogenetics of tamoxifen and endoxifen

Introduction: Tamoxifen dominates the anti-estrogenic therapy in the early and metastatic breast cancer setting. Tamoxifen has a complex metabolism, being mainly metabolized by CYP2D6 into its 30–100 times more potent metabolite, endoxifen. Recently, a phase I study in which endoxifen as an orally z-endoxifen hydrochloride has been successfully evaluated.

Areas covered: the principal pharmacogenetic and non-genetic differences in the pharmacology of tamoxifen and endoxifen are evaluated. To this end, references from PubMed, Embase or Web of Science, among others, were reviewed As non-genetic factors, important differences and similarities such age, or adherence to tamoxifen therapy are comprehensively illustrated. Additionally, since CYP2D6 genotypes are considered the main limitation of tamoxifen, many studies have investigated the association between the worsened clinical outcomes in patients with non-functional CYP2D6 genotypes. In this review, an overview of the research on this field is presented. Also, a summary describing the literature about individualizing tamoxifen therapy with endoxifen concentrations and its limitations is listed.

Expert opinion: z-endoxifen hydrochloride is only investigated in the metastatic setting, still more research is required before its place in therapeutics is known. Similarly, monitoring tamoxifen efficacy based on endoxifen concentrations might not be overall recommended due to the limited evidence available.     

An update on polymer-lipid hybrid systems for improving oral drug delivery

Introduction: A promising approach that has recently emerged to overcome the complex biobarriers and interrelated challenges associated with oral drug absorption is to combine the benefits of polymeric and lipid-based nanocarriers within one hybrid system. This multifaceted formulation strategy has given rise to a plethora of polymer-lipid hybrid (PLH) systems with varying nanostructures and biological activities, all of which have demonstrated the ability to improve the biopharmaceutical performance of a wide range of challenging therapeutics.

Areas covered: The multitude of polymers that can be combined with lipids to exert a synergistic effect for oral drug delivery have been identified, reviewed and critically evaluated. Specific focus is attributed to preclinical studies performed within the past 5 years that have elucidated the role and mechanism of the polymer phase in altering the oral absorption of encapsulated therapeutics.

Expert opinion: The potential of PLH systems has been clearly identified; however, improved understanding of the structure–activity relationship between PLH systems and oral absorption is fundamental for translating this promising delivery approach into a clinically relevant formulation. Advancing research within this field to identify optimal polymer, lipid combinations and engineering conditions for specific therapeutics are therefore encouraged.     

The role of drug courts in promoting desistance and recovery: a merging of therapy and accountability

Abstract

Criminal behavior and substance abuse are closely connected and many offenders have substance use disorders and related problems. Reducing drug-related crime in this population requires attention to the determinants and processes of both recovery from substance use disorders and desistance from crime, and the provision of individual and social services that can promote and facilitate recovery and desistance. Traditional criminal justice system models do not generally focus on both substance use and criminal behavior, nor do they address the individual and social factors that can affect desistance and recovery. Drug treatment courts represent a therapeutic model of justice that have become popular in many countries over the past two decades. This paper argues that the drug court is an important criminal justice innovation that has the potential to promote both desistance from criminal behavior and recovery from drug use. The drug court model incorporates and implements many of the processes and interventions that are theoretically associated with desistance and recovery. Despite some limitations and the need for additional research, drug courts have the potential to address many of the factors associated with reductions in both drug use and criminal behavior.     

Adverse drug reaction reporting in institutions across six Chinese provinces: a cross-sectional study

Background: Although China’s adverse drug reaction (ADR) reporting and monitoring has developed rapidly, many challenges remain. This study assessed ADR monitoring and reporting in China and identified monitoring problems.

Research design and methods: A cross-sectional survey was conducted of ADR reporting institutions in six Chinese provinces in April–December 2014. Questionnaires assessed ADR systems, basic resources, and pharmacovigilance activity.

Results: Of 720 questionnaires distributed, the response rate was 81.8%. About 93% (n = 371) of pharmaceutical companies and medical institutions had established ADR monitoring departments/units. Few institutions (26%, n = 104) allocated an ADR budget; 7% (n = 30) had received ADR monitoring funding in the last year (2013). Almost all institutions (99%, n = 555) had computers and 47% (n = 263) had a network database. Many institutions conducted public education about drug safety (49%, n = 283), medicine utilization reviews/quality surveys (28%, n = 158), and medicine consultation services (88%, n = 511). Institutions in eastern, central, and western China differed significantly on implementation of existing regulations and pharmacovigilance activities.

Conclusions: The institutions surveyed have established ADR monitoring systems. However, these systems have flaws. Urgent improvements are needed in funding, basic resources, reporting processes, and other pharmacovigilance activities.     

EMA对药用辅料右旋糖酐新的安全性评价

欧洲药品局（EMA）于2018年11月发布了"人用药品辅料右旋糖酐的包装说明书资料"，该文件引用大量文献全面评价了右旋糖酐的安全性，特别指出含有右旋糖酐辅料的注射和吸入制剂的疫苗与药品，应在说明书中描述有关其过敏反应信息的新要求。介绍该文件的主要内容，期望对我国这类药品说明书的撰写和监管有所帮助。     

Functional characterization of 21 CYP3A4 variants on amiodarone metabolism in vitro

1. Cytochrome P450 3A4 (CYP3A4) is an important member of the cytochrome P450 enzyme superfamily, with 33 allelic variants reported previously. Genetic polymorphisms of CYP3A4 can produce a significant effect on the efficacy and safety of some drugs, so the purpose of this study was to clarify the catalytic characteristics of 22 CYP3A4 allelic isoforms, including 6 novel variants in Han Chinese population, on the oxidative metabolism of amiodarone in vitro.

2. Wild-type CYP3A4*1 and other variants expressed by insect cells system were incubated respectively with 10–500?μM substrate for 40?min at 37?°C and terminated at ?80?°C immediately. Then these samples were treated as required and detected with ultra-performance liquid chromatography-tandem mass spectrometry used to analyze its major metabolite desethylamiodarone.

3. Among the 21 CYP3A4 variants, compared with the wild-type, the intrinsic clearance values (V_max/K_m) of two variants were apparently decreased (11.07 and 2.67% relative clearance) while twelve variants revealed markedly increased values (155.20～435.96%), and the remaining of seven variants exhibited no significant changes in enzyme activity.

4. This is the first time report describing all these infrequent alleles for amiodarone metabolism, which can provide fundamental data for further clinical studies on CYP3A4 alleles.     

CACNA1C基因表达水平对弥漫性大B细胞淋巴瘤利妥昔单抗耐药的预测价值

目的:探讨钙离子通道A1C（calcium voltage-gated channel subunit alpha1 C，CACNA1C）基因表达水平对弥漫性大B细胞淋巴瘤（diffuse large B cell lymphoma，DLBCL）患者利妥昔单抗耐药的预测价值。方法:选取我院在2015年3月至2017年5月收治的DLBCL患者93例，均采用利妥昔单抗+CHOP方案化疗，随访2年，根据淋巴瘤化疗疗效评定标准，分为利妥昔单抗耐药组和敏感组；免疫组化法检测所有患者肿瘤组织的钙调蛋白CACNA1C基因、B淋巴细胞瘤-2（B-cell lymphoma-2，BCL-2）基因、PRDM1基因表达情况；绘制受试者工作曲线（receiver operating characteristic curve，ROC），分析CACNA1C基因、BCL-2基因、PRDM1基因水平在预测DLBCL利妥昔单抗耐药中的效能。结果:93例患者中共出现利妥昔单抗耐药病例26例，耐药率为27.96%；在一般资料方面耐药与敏感病例比较差异无统计学意义（P>0.05）；耐药组患者CACNA1C着色细胞比例（40.12±15.44)% vs (69.62±17.65）%低于敏感组，BCL-2着色细胞比例（66.31±15.92)% vs (47.43±14.66）%高于敏感组，PRDM1着色细胞比例（73.42±21.64)% vs (56.73±18.59）%高于敏感组，差异具有统计学意义（P<0.05）；ROC曲线显示，CACNA1C基因（AUC=0.848，95%CI=0.765~0.932）曲线下面积大于BCL-2基因（AUC=0.777，95%CI=0.673~0.881）和PRDM1基因（AUC=0.615，95%CI=0.486~0.744）；CACNA1C与BCL-2基因表达联合预测的曲线下面积（AUC=0.915，95%CI=0.854~0.976）显著高于三种基因表达水平单独预测，其中CACNA1C基因的最佳截点值为58.61%，BCL-2的最佳截点值为48.33%，此时联合预测在预测利妥昔单抗耐药的敏感性和特异性分别为80.77%和89.55%。结论:CACNA1C基因表达水平在预测DLBCL患者利妥昔单抗耐药方面具有较好的价值，其中CACNA1C与BCL-2联合预测利妥昔单抗耐药价值更高。     

益气化瘀解毒方对MRP、GST-π和Topo Ⅱ基因在Sorafenib获得性耐药人肝癌QGY7702细胞表达的干预研究

目的探讨益气化瘀解毒方干预后对Sorafenib获得性耐药人肝癌QGY7702细胞(QGY7702/Sora)增殖及MRP、GST-π和Topo Ⅱ基因表达的影响。方法培养QGY7702/Sora细胞和QGY7702细胞,利用Cell Counting Kit-8(CCK-8)法检测Sorafenib对细胞的半数抑制率浓度(IC50值),计算耐药指数RI;观察益气化瘀解毒方对耐药细胞的增殖影响;采用荧光定量PCR检测药物干预前后2种细胞中MRP、GST-π和Topo Ⅱ基因表达水平。结果亲本细胞和耐药细胞Sorafenib的IC50值分别为(7.993±0.522)μmol/L和(19.651±1.216)μmol/L,RI约为2.5。益气化瘀解毒方可抑制耐药细胞的增殖活性。2种细胞的MRP、GST-π、Topo Ⅱ表达量无明显差异(P>0.05)。Sorafenib组可促进耐药细胞MRP 、GST-π基因的过表达(P<0.05),益气化瘀解毒方组可抑制GST-π基因的过表达(P<0.01),且联合Sorafenib可显著提高Topo Ⅱ基因的表达量(P<0.01)。结论 QGY7702/Sora细胞MRP、GST-π和Topo Ⅱ的表达水平与亲本细胞无显著差异。耐药细胞对Sorafenib敏感性降低与MRP、GST-π过表达相关,而益气化瘀解毒方拮抗Sorafenib耐药与抑制GST-π过表达相关。