美国患者报告结局测量工具在药物研发与注册中的应用

对患者报告结局测量工具在美国药物研发与注册中的应用进行研究,通过阐述患者报告结局测量工具定义、分类、资格认定、法规及指南要求,分析美国FDA根据患者报告结局工具为临床终点批准药物,为我国提供参考和借鉴.     

患者报告结局在药品不良反应报告中的应用和思考

目的探索患者报告结局在药品不良反应报告中的应用。方法通过文献回顾的方法,对国外药品安全性研究中纳入患者报告结局的背景、驱动因素、当前监管情况进行了全面综述。结果目前数据收集的局限性、患者和医务人员间的不一致、通过患者能获取更丰富的信息等多个因素的驱动,且美国、英国等国家对此制定了监管措施,有效推动了患者报告结局在药品安全性研究中的应用。结论患者报告结局以患者为中心,为药品使用的效益、风险和结局的全面分析提供了丰富而宝贵的信息,可用作目前药物警戒和上市后研究的补充内容,为我国将患者报告结局的方法纳入药品安全性研究提供重要参考。     

Pharmacogenetics: data, concepts and tools to improve drug discovery and drug treatment

Variation in the human genome is a most important cause of variable response to drugs and other xenobiotics. Susceptibility to almost all diseases is determined to some extent by genetic variation. Driven by the advances in molecular biology, pharmacogenetics has evolved within the past 40 years from a niche discipline to a major driving force of clinical pharmacology, and it is currently one of the most actively pursued disciplines in applied biomedical research in general. Nowadays we can assess more than 1,000,000 polymorphisms or the expression of more than 25,000 genes in each participant of a clinical study -- at affordable costs. This has not yet significantly changed common therapeutic practices, but a number of physicians are starting to consider polymorphisms, such as those in CYP2C9, CYP2C19, CYP2D6, TPMT and VKORC1, in daily medical practice. More obviously, pharmacogenetics has changed the practices and requirements in preclinical and clinical drug research; large clinical trials without a pharmacogenomic add-on appear to have become the minority. This review is about how the discipline of pharmacogenetics has evolved from the analysis of single proteins to current approaches involving the broad analyses of the entire genome and of all mRNA species or all metabolites and other approaches aimed at trying to understand the entire biological system. Pharmacogenetics and genomics are becoming substantially integrated fields of the profession of clinical pharmacology, and education in the relevant methods, knowledge and concepts form an indispensable part of the clinical pharmacology curriculum and the professional life of pharmacologists from early drug discovery to pharmacovigilance.     

Metabolic modeling: a tool of drug discovery in the post-genomic era

The Human Genome Project, DNA microarrays, proteome chips and metabolic profiles, among others, are generating unprecedented amounts of valuable information about the genetic and metabolic responses of organisms to stimuli. This wealth of information poses a great scientific challenge, namely the development of novel, effective methods for functional analysis and interpretation. It is proposed here that biomathematical systems models must accompany data generation and management. A particularly effective framework for this purpose is canonical modeling based on Biochemical Systems Theory. The key concept of this theory is the formulation of biological phenomena as systems of differential equations, in which all processes are represented as products of power-law functions.     

Improvement of cardiac efficacy and safety models in drug discovery by the use of stem cell-derived cardiomyocytes

Background: The pharmaceutical industry suffers from high attrition rates during late phases of drug development. Improved models for early evaluation of drug efficacy and safety are needed to address this problem. Recent developments have illustrated that human stem cell-derived cardiomyocytes are attractive for using as a model system for different cardiac diseases and as a model for screening, safety pharmacology and toxicology. Objective: In this review, we discuss contemporary drug discovery models and their characteristics for cardiac efficacy testing and safety assessment. Additionally, we evaluate various sources of stem cells and how these cells could potentially improve early screening and safety models. Conclusion: We conclude that human stem cells offer a source of physiologically relevant cells that show great potential as a future tool in cardiac drug discovery. However, some technical challenges related to cell differentiation and production and also to validation of improved platforms remain and must be overcome before successful application can become a reality.     

Studying the impact of a medication use evaluation by the community pharmacist (Simenon): Patient-reported outcome measures

BackgroundIn the SIMENON study, medication use reviews were conducted for older polymedicated home-dwelling patients across 56 Belgian community pharmacies.ObjectiveTo evaluate the impact of the service on patient-reported outcome measures and patient-reported experience measures, and to evaluate the suitability of the chosen instruments.MethodsA before-after design was used to measure the impact of the medication use review in a subset of patients, participating in the SIMENON study. Patients completed self-report questionnaires before and 3 and 12 weeks after the intervention by letter, phone or e-mail. Six outcomes were evaluated: medication-related quality of life, adherence, self-management, patient satisfaction, fall incidents and use of emergency healthcare services.ResultsQuestionnaires at baseline and endpoint were available for 83 patients (median age 77 years; median of 7 drugs) of 24 pharmacies. The Living with Medicines Questionnaire showed low medication burden at baseline (84.8/205) which increased to 85.7 three weeks later (n = 57; p = 0.219). Scores significantly reduced to 81.9 at twelve weeks (p = 0.031). The Probabilistic Medication Adherence Scale (n = 67) showed high median adherence scores at baseline (14/18) which remained unaltered (p = 0.974). The patient activation measure found low self-management in one third of the sample at baseline and endpoint (35.5% and 37.1% respectively; p = 0.243). The Patient Satisfaction with Pharmacist Services Questionnaire (n = 66) demonstrated high patient satisfaction. The number of patients with a hospitalization in the last three months decreased non-significantly from 14.8% to 11.1% in the post-measurement after 12 weeks (p = 0.227). No effect was observed on emergency room visits and falls.ConclusionsThe medication use review reduced medication burden but did not impact the patient's adherence and self-management. However, adherence scores were high, medication burden was low at baseline and the sample size was limited. The Living with Medicines instrument is a promising instrument for future research to assess medication-related quality of life in older polymedicated patients.     

Development of a tool to assess the completeness of drug information sources for health care professionals: A Delphi study

The aim of this study was to create a standard set of essential drug information items as a tool to assess the completeness of any type of drug information source, regardless of its length, using a Delphi consensus panel of European health care professionals. A compilation of drug-related information items was performed by searching several resources for health care professionals and a final list of 162 items was obtained. Fifty-seven experts in drug information from 23 different European countries were invited to participate in a three-round Delphi technique to obtain consensus on items considered essential and non-essential content of information. Consensus for the first, second, and third rounds was defined as ≥90%, ≥80%, and ≥75% agreement, respectively. Of the 57 experts invited, 32 completed the first round, 27 the second, and 29 the third. Consensus was achieved for 28.3% of the items in the first round, 49.3% in the second, and 58.3% in the third. The final cumulative consensus was 67.7% (n = 126) for items considered essential and 16.1% (n = 30) for items considered non-essential. The final tool obtained to assess the completeness of drug information sources was composed by 126 essential items grouped into 11 sections. This tool allows for the comparison of different information sources for the same medicine and the information content for different medicines in the same source.     

三苯氧胺治疗乳腺增生的疗效及安全性分析

目的：探讨三苯氧胺治疗乳腺增生的疗效及安全性。方法选取2010年12月—2013年12月泸州医学院附属中医医院收治的乳腺增生患者156例,采用随机数字表法将患者分为治疗组与对照组,各78例。治疗组患者予以三苯氧胺治疗,对照组患者予以乳癖消治疗。观察两组患者临床疗效、血清雌二醇（E2）水平及不良反应发生情况。结果治疗组患者总有效率高于对照组,差异有统计学意义（P ＜0.05）;治疗组患者血清 E2水平低于对照组（P ＜0.05）;治疗组患者不良反应发生率低于对照组（P ＜0.05）。结论三苯氧胺治疗乳腺增生的疗效显著,不良反应少,安全性高。     

Characteristics of opiate users presenting for a new treatment episode: Baseline data from the national drug treatment outcome study in Ireland (ROSIE)

Aim: The Research Outcome Study in Ireland (ROSIE) is the first large-scale, prospective, multi-site, drug treatment outcome study in Ireland.

Method: Using a structured questionnaire, the substance use, health, crime and social problems of 404 opiate users were assessed at treatment intake (6 months, 1 year and 3 years later).

Findings: While the majority of study participants were opiate users, poly-drug use was the norm (76%, n = 308). Most participants had a history of injecting drug use (77%, n = 308), however only 42% (n = 170) reported injecting in the preceding 90 days. Participants reported a range of mental and physical health complaints and extensive contact with social care services. High crime rates were observed. Analysis revealed differences in the characteristics and substance use of participants across treatment modality.

Conclusions: The range and severity of problems affecting individuals commencing treatment for their problem drug use highlights the complex needs of the cohort. These problems create substantial costs for providers of social care services in Ireland and can affect treatment outcomes.     

Implications of salivary proteomics in drug discovery and development: a focus on cancer drug discovery

Human saliva proteomics has proven to be a novel approach in the search for protein biomarkers for non-invasive detection of human cancers. This approach may also have implications within the process of anti-cancer drug discovery. Information from saliva proteomic measurements may contribute to the target discovery and validation, assessment of efficacy and toxicity of candidate drugs, identification of disease subgroups, and prediction of responses of individual patients. In this article, we aim to give a brief overview on human saliva proteome analysis, as well as its applications to cancer biomarker discovery. Potential applications of saliva proteomics in anticancer drug discovery and development will also be discussed.     

喹硫平单药治疗伴强迫症状精神分裂症的开放性研究

目的:探讨喹硫平单药治疗伴强迫症状精神分裂症患者的疗效和安全性。方法:采用多中心、自身前后对照研究,选择58例符合ICD-10诊断标准的精神分裂症患者,接受可变剂量的喹硫平(思瑞康()治疗8周。疗效评定用耶鲁-布朗强迫症状量表(Y-BOCS)、阳性及阴性症状量表(PANSS)量表。安全性评价用不良事件和严重不良事件记录表等。结果:采用独立样本t检验、重复测量方差检验显示,完成治疗患者的Y-BOCS量表评分[(21.31±7.33)vs.(9.29±6.09),F=102.36,P<0.01]和PANSS量表评分[(88.47±16.39)vs.(52.92±14.92),F=134.98,P<0.01]在治疗前后均差异有统计学意义,两两比较发现Y-BOCS量表和PANSS量表评分,基线期、2周末、4周末、6周末和8周末之间均两两差异有统计学意义(均P<0.01)。8周末强迫症状的有效率为63.3%;精神病性症状有效率为65.3%。相关分析显示强迫症状在基线期与阳性因子呈弱相关(r=0.264,P<0.05),而治疗到6周末,与阳性因子(r=0.403,P<0.05)、阴性因子分(r=0.340,P<0.05)...     

Loratadine versus levocetirizine in chronic idiopathic urticaria: A comparative study of efficacy and safety

Background:

Treatment of chronic idiopathic urticaria (CIU) is challenging because of its unpredictable course and negative influence on the quality of life. New treatments are being developed, but antihistaminics remain the cornerstone of the therapeutic approach. Newer generation antihistaminics such as loratadine and levocetirizine have already proved to be safe and efficacious for CIU.

Objective:

To choose the better drug between loratadine and levocetirizine for CIU, by comparing their efficacy and safety.

Methods:

A randomized, open, outdoor-based clinical study was conducted on 60 patients of CIU, to compare the two drugs. After initial clinical assessment and baseline investigations, loratadine was prescribed to 30 patients and levocetirizine to another 30 patients for four weeks. At follow-up, the patients were re-evaluated and then compared using different statistical tools.

Result:

The comparative study showed that the changes in differential eosinophil count (P = 0.006) and absolute eosinophil count (P = 0.003) in the levocetirizine group was statistically significant. The results of the Total Symptom Score showed better symptomatic improvement of CIU with levocetirizine as compared to loratadine. The overall incidence of adverse drug reactions was also found to be less in the levocetirizine group.

Conclusion:

An analysis of the results of all the parameters of safety and efficacy proves the superiority of levocetirizine over loratadine for CIU.     

Davunetide: a review of safety and efficacy data with a focus on neurodegenerative diseases

Davunetide is the first neuroprotective peptide in its class, and has preclinical evidence for neuroprotective, neurotrophic and cognitive protective properties. Davunetide has also been shown to prevent apoptosis or programmed-cell death in a range of in vitro and in vivo models by promoting microtubule stabilization. Potential clinical uses of davunetide include neurodegenerative disorders such as Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), frontotemporal dementia (FTD) or cognitive impairment in other diseases such as schizophrenia where microtubule structure and function is known to be impaired. The nonclinical and clinical safety of davunetide is reviewed here in detail. Pre-clinical toxicology studies in rats and dogs using the maximum feasible dose of davunetide provide strong evidence that davunetide is well-tolerated. Similarly, data from 10 separate clinical trials of davunetide, investigating safety and efficacy provide evidence that davunetide is generally safe and well-tolerated, and has shown some signs of clinical efficacy.     

Serological biochemical markers of surrogate efficacy and safety as a novel approach to drug repositioning

How do pharmaceutical companies find new uses for old or failed drugs? Is there a way to 'manage serendipity' at the very first stage of identifying compounds that could be developed into new drugs? Several approaches are now being pursued by various companies that are dedicated to drug repositioning cross a spectrum of technologies and scientific bases. Biochemical markers could provide significant shortcuts for drug development. In this review, we introduce drug repositioning, approaches to it and their associated challenges. We also highlight a novel class of serological biomarkers, namely neo-epitopes, which have proven successful in repositioning drugs in clinical settings.