分子影像技术在药物研发中的应用

分子影像可在活体状态下对生物和生化过程进行无创研究。该技术包括分子探针和分子成像技术,可通过特异性探针或报告基因成像。运用分子影像技术可筛选侯选化合物,评价药物对肿瘤代谢、增殖、血管发生和凋亡的影响,评价药物对组织缺氧的影响。分子影像技术是药物作用机制研究的重要手段,将大大加快药物研发进程。     

Positron emission tomography molecular imaging for drug development

Human in vivo molecular imaging with positron emission tomography (PET) enables a new kind of 'precision pharmacology', able to address questions central to drug development. Biodistribution studies with drug molecules carrying positron-emitting radioisotopes can test whether a new chemical entity reaches a target tissue compartment (such as the brain) in sufficient amounts to be pharmacologically active. Competition studies, using a radioligand that binds to the target of therapeutic interest with adequate specificity, enable direct assessment of the relationship between drug plasma concentration and target occupancy. Tailored radiotracers can be used to measure relative rates of biological processes, while radioligands specific for tissue markers expected to change with treatment can provide specific pharmacodynamic information. Integrated application of PET and magnetic resonance imaging (MRI) methods allows molecular interactions to be related directly to anatomical or physiological changes in a tissue. Applications of imaging in early drug development can suggest approaches to patient stratification for a personalized medicine able to deliver higher value from a drug after approval. Although imaging experimental medicine adds complexity to early drug development and costs per patient are high, appropriate use can increase returns on R and D investment by improving early decision making to reduce new drug attrition in later stages. We urge that the potential value of a translational molecular imaging strategy be considered routinely and at the earliest stages of new drug development.     

Multimodal molecular imaging in drug discovery and development

In addition to individual imaging techniques, the combination and integration of several imaging techniques, so-called multimodal imaging, can provide large amounts of anatomical, functional, and molecular information accelerating drug discovery and development processes. Imaging technologies aid in understanding the disease mechanism, finding new pharmacological targets, and assessment of new potential drug candidates and treatment response. Here, we describe how different imaging techniques can be used in different phases of drug discovery and development and highlight their strengths, related innovations, and future potential with a focus on the implementation of artificial intelligence (AI) and radiomics for imaging technologies.     

Pharmacological and functional magnetic resonance imaging techniques in CNS drug discovery

Functional magnetic resonance imaging (fMRI) has transformed cognitive neuroscience over the past 10 – 15 years, allowing clinical researchers unprecedented access to the functioning of the human brain under many different conditions including motor, sensory and cognitive stimulation. During the past 5 years, increasing interest has also focused on mapping pharmacologically induced changes in human brain activity produced following exposure to psychoactive agents such as amphetamine and cocaine, and is now frequently termed pharmacological MRI (phMRI). Unfortunately, preclinical fMRI and phMRI studies have not kept pace with human research, largely due to numerous technical hurdles inherent in small laboratory animal imaging, as well as the high cost of necessary equipment. However, this is now set to change with significant investment being made across academic and industry laboratories, as researchers attempt to tap into the huge potential of this noninvasive and powerful translational tool. This review introduces the principles and fundamental assumptions behind the technologies, details some important applications of fMRI and phMRI within a CNS research environment, and examines the potential future impact of the technology.     

Applications for site-directed molecular imaging agents coupled with drug delivery potential

Molecular imaging allows non-invasive characterization and quantification of biological processes at cellular and molecular level. Such technologies make it possible to enhance our understanding of drug activity and pharmokinetic properties, and therefore aid decisions to select candidates that are most likely to benefit from targeted drug therapy. Targeted DDSs are nanometer-sized carrier materials designed for improving the biodistribution of systemically applied (chemo-)therapeutics by strictly localizing its pharmacological activity to the site or organ of action. The parallel development of molecular imaging and targeted drug delivery offers great challenges and opportunities for a single multifunctional platform technology, combining targeted motif, therapeutic agents and imaging agents for imaging guided drug delivery. This review article summarizes the synthesis and characterization of various biomaterials that carry targeting motifs, imaging tags and therapeutic agents as theragnostics.     

Molecular imaging with copper-64 in the drug discovery and development arena

The contribution of positron emission tomography (PET) to the drug discovery and development (D3) pipeline has been inhibited by the short half-lifes of PET radioisotopes, ¹¹C and ¹⁸F, poor availability and the high cost of infrastructure. Copper-64 (⁶⁴Cu) has a 12.7 h half-life, simple yet flexible radiochemistry and imaging characteristics that make it ideal for a wider application across the D3 arena. Recent scientific breakthroughs in the production of ⁶⁴Cu show that it's, commercial production can be made more widely available. More importantly, for pharmaceutical research and development programmes wishing to incorporate the high sensitivity and spatial resolution of PET, but no desire to implement and maintain expensive radiochemistry infrastructure, ⁶⁴Cu is an exciting option.     

胃舒安颗粒治疗功能性消化不良的有效性和安全性多中心临床评价

目的：评价胃舒安颗粒治疗功能性消化不良的临床疗效和安全性。方法：试验采用分层区组、随机、双盲双模拟、阳性药平行对照、多中心临床研究方法，以西沙必利片作为对照药对比观察。共观察409例（3：1），其中试验组308例，对照组101例．其中脱落4例，剔除5例。结果：中医证候疗效：胃舒安颗粒组愈显率63．03％，总有效率95．70％；西沙必利片组愈显率62．38％，总有效率94．06％。痞满证候疗效：胃舒安颗粒组愈显率62．04％，总有效率92．07％；西沙必利片组愈显率54．45％，总有效率87．12％。胃排空试验胃舒安颗粒组愈显率60．78％，总有效率73．85％；西沙必利片组愈显率59．26％，总有效率70．37％。两组比较无统计学意义（P〉0．05）。结论：胃舒安颗粒治疗功能性消化不良疗效确切，未发现毒副作用。     

Atherosclerosis imaging in drug development

Increasing use of established medical therapies presents a major challenge for the assessment of experimental antiatherosclerotic agents. The requirement to perform clinical trials with increasing numbers of subjects, followed for longer periods of time, creates a scenario that is largely prohibitive for the development of most new agents. Technologic advances in arterial wall imaging provide the opportunity to evaluate the impact of therapies on the natural history of atherosclerosis. The design and implementation of clinical trials that employ serial imaging of the arterial wall has become increasingly used in the development of new therapies to target atherosclerotic cardiovascular disease.     

儿童功能性腹痛药物随机对照试验设计要素的文献研究

目的 系统评估儿童功能性腹痛药物临床试验的设计要素,通过标准化试验设计,为不同试验结果的比较提供一定的可行性。方法 检索PubMed、Cochrane以及EMBASE数据库,纳入儿童功能性腹痛的随机对照临床研究文献,采用罗马诊断标准,干预措施为药物,语种为英文。结果 检索出文献561篇,最终纳入14项研究,均以改善腹痛及其相关症状为主要试验目的,其中改善腹痛12项（85.71%）;均采用随机、安慰剂对照、优效性检验,13项为双盲,1项未提及,8项设计了样本量估算,5项为多中心试验;诊断采用罗马Ⅱ标准4项（28.57%）,罗马Ⅲ标准10项（71.43%）;干预措施依次为益生菌9项（64.29%）、抗抑郁药2项（14.29%）,以及抗过敏药、解痉药、促胃肠动力药各1项（各占7.14%）;6项设计了导入期,时长为1~4周;疗程为2周1项（7.14%）,4周10项（71.43%）,8周2项（14.29%）,12周1项（7.14%）;10项设计了随访,时长为4周~6个月;5项（35.71%）的主要有效性指标为腹痛程度和据此定义的治疗成功或应答,4项（28.57%）为腹痛程度、频率,3项（21.43%）为腹痛程度、频率和持续时间,2项为基于量表的症状改善情况;腹痛评价,采用面部表情量表法（WBS或FPS）9项（64.29%）,视觉模拟评分量表（VAS）或疼痛数字评分法（NRS-11）5项（35.71%）,同时采用VAS和FPS1项（7.14%）。全部研究的主要安全性指标均为不良事件的发生率。结论 纳入研究的文献信息完善、质量较高,结果涵盖了儿童功能性腹痛临床研究设计的基本要素,具有一定的借鉴价值。     

新药开发中的基因导向型个体化发展战略

药物基因组学在新药开发的多个阶段可发挥重要作用。研究者可借助基因组信息更好地发现新药的作用靶点及其作用机制,药物基因组及其相关技术的发展帮助研究者在新药开发的临床前研究阶段淘汰化学性质不良的化合物,还可指导新药开发的临床试验设计以增加药物有效性和安全性,同时降低开发所需的时间和成本。     

Autoradiography: high-resolution molecular imaging in pharmaceutical discovery and development

Autoradiography (ARG) is a powerful, high resolution, quantitative molecular imaging technique used to study the tissue distribution of radiolabeled xenobiotics in biologic models. ARG involves the close apposition of solid specimens containing a radiolabeled substance to a detector layer, such as photographic emulsions, film, phosphor imaging plates and direct nuclear imagers/counters. The two basic types include: macroautoradiography, which is imaging of organs, organ systems and/or whole-body sections (WBA) and microautoradiography (MARG), which provides the localization of radioactivity at the cellular level. ARG has supported drug discovery and development efforts for many years and has provided pivotal decision making information for pharmaceutical research. This paper presents a review of the techniques, study designs and present considerations for use of WBA and MARG to support today’s drug discovery and development efforts. In addition, this review comments on the integration of the ex vivo ARG and in vivo molecular imaging techniques to serve pharmaceutical discovery and development in the future.     

我国药物临床试验的科学发展史与期望

本文通过对药物临床试验的发展历史、现状和在药物创新过程中的不可替代作用的阐述,明确提出了药物临床试验是一门学科的概念。在全面分析我国药物临床试验现状的基础上,提出了推动其快速发展的思考和建议。     

Statistical properties of continuous composite scales and implications for drug development

Little research has been conducted on the statistical properties of composite measures comprising linear combinations of continuous component scales. We assessed the quantitative relationship between the composites and their individual components regarding their abilities to detect treatment effects. In particular, we developed the mathematical derivation of the treatment effect size of a continuous composite in relation to the treatment effect sizes of its components and proved multiple properties of the composite. We demonstrated that the treatment effect size of a composite is greater than the minimum treatment effect size of its components and that above certain thresholds of correlations of components and ratios of component effect sizes, the composite may outperform its components. Examples from Alzheimer’s disease (AD) clinical studies of solanezumab and donepezil using the composite Integrated AD Rating Scale (iADRS) and its components, the AD Assessment Scale-Cognitive subscale (ADAS-Cog) and AD Cooperative Study-Activities of Daily Living inventory, instrumental items (ADCS-iADL) were consistent with the theoretical statistical properties. The understanding of the quantitative relationships between continuous composites and their components will be useful in clinical trial design and the development of new scales and composites across therapeutic areas.     

Liposomes and their applications in molecular imaging

Molecular imaging is a relatively new discipline with a crucial role in diagnosis and treatment tracing of diseases through characterization and quantification of biological processes at cellular and sub-cellular levels of living organisms. These molecular targeted systems can be conjugated with contrast agents or radioligands to obtain specific molecular probes for the purpose of diagnosis of diseases more accurately by different imaging modalities. Nowadays, an interesting new approach to molecular imaging is the use of stealth nanosized drug delivery systems such as liposomes having convenient properties such as biodegradability, biocompatibility and non-toxicity and they can specifically be targeted to desired disease tissues by combining with specific targeting ligands and probes. The targeted liposomes as molecular probes in molecular imaging have been evaluated in this review. Therefore, the essential point is detection of molecular target of the disease which is different from normal conditions such as increase or decrease of a receptor, transporter, hormone, enzyme etc, or formation of a novel target. Transport of the diagnostic probe specifically to targeted cellular, sub-cellular or even to molecular entities can be performed by molecular imaging probes. This may lead to produce personalized medicine for imaging and/or therapy of diseases at earlier stages.     

The role of in vivo molecular imaging with PET and SPECT in the elucidation of psychiatric drug action and new drug development

This paper reviews the contribution of human PET and SPECT neuroreceptor occupancy studies to the understanding of drug action in psychiatric illness, and how they can aid the development of new drugs. All effective antipsychotics show significant D₂ receptor occupancy. However, at least for atypical antipsychotics, there is no clear relationship between occupancy and clinical response. The mechanisms underlying antipsychotic efficacy, and the minimal effective D₂ occupancy, remain to be elucidated, particularly for drugs with modest or transient occupancy. The low liability of some atypical antipsychotics for extrapyramidal side effects does not appear to be explained by their 5-HT_2A antagonism, and the muscarinic receptor occupancy of some drugs may be partly explanatory. Previous reports of apparent ‘limbic selectivity’ of atypical antipsychotics may be in error, and may be due to technical differences in radiotracers. For SSRIs, high occupancies at the serotonin transporter (SERT) are achieved at therapeutic doses, although the minimum SERT occupancy required for therapeutic response remains undefined. Previous attempts to augment the antidepressant effect of SSRIs by pindolol have generally used daily doses which result in inadequate 5-HT_1A receptor occupancy. For benzodiazepines, clinical doses would appear to leave a wide margin of unoccupied receptors. For methylphenidate and cocaine, typical doses occupy more than 50% of dopamine transporters, and their profiles are extremely similar. In therapeutic drug development, these techniques may be used to assess receptor occupancy profiles, likely drug dosages and dosing intervals which cannot be reliably assessed in humans by other methods.     

基因药物在临床上的最新应用与研发

应用现代医学和分子药物学手段，即基因和细胞疗法，临床治疗被传统医疗视为难以攻克的病症又进入一个相对的活跃期。本文概述了近年来临床上肿瘤和神经疾病的基因治疗的实践与进展，对基因药物临床上的安全性和基因产物表达的时效性的探索以及临床基因药物研究在研发全新的抗癌病毒载体，给药途径的优化和与干细胞技术的结合提供新思路。     

广东省药物临床试验的发展现状分析与探讨

药物临床试验是药物上市的必经之路,也是生物医药行业发展的重要推动力。近年来,广东省在药物临床试验行业不断尝试创新与变革,积极推动临床试验的发展,助力省内生物医药领域的改革与创新。本研究调研了广东省近5年药物临床试验发展、政策实施等情况,剖析存在问题并探讨解决之道,以期为国内其他兄弟省市的药物临床试验发展提供借鉴和参考。     

Applications of molecular imaging in drug discovery and development process

The process of drug discovery and development requires enormous resources and time, with increasing cost for new drug development. Molecular imaging techniques have tremendous potential for improving the efficiency of drug screening, assessing the pharmacokinetics of new drugs, and evaluating drug effects. Appropriate application of molecular imaging to drug discovery and development can markedly reduce costs and the time required for new drug development. This review focuses on the contributions of molecular imaging for drug discovery and development, particularly drug screening, pharmacokinetic, preclinical and clinical drug evaluation, and for personalized and lesionalized medicine.     

Whole-animal cellular and molecular imaging to accelerate drug development

In the past decade, new technologies (genomics), chemistries and high-throughput (HT) in vitro assays have played a large role in changing the paradigm of drug discovery and development. These technologies have enabled many more targets and potential lead compounds to be introduced into drug development. However, since 1996, the number of drug approvals per year has been decreasing. This reduced pipeline has now compromised the ability of biopharmaceutical companies to deliver the double-digit growth levels that investors expect. This review explores what is lacking in the drug discovery and development process that has caused such a dearth of new chemical entities (NCEs), and looks at how new in vivo imaging technologies might provide an answer in the form of more predictive animal models.