临床药师干预药物治疗的消化科典型案例报告

文中通过对药师参与的4例消化科典型案例进行报告分析,探讨临床药师在药物治疗中的作用.临床药师应利用自己学到的知识,协助医护人员参与患者的药物治疗,有利于保障药物在临床使用过程中安全、有效.     

药物治疗管理服务对门诊慢病患者干预效果评价

目的:探讨药物治疗管理(MTM)服务对门诊老年慢病患者的干预效果.方法:选取上海市浦东新区公立医院2018年1月至2019年6月药学门诊收治的160名患有高血压或/和糖尿病老年慢病患者,随机分为干预组和对照组.对照组接受普通药物咨询,干预组至少在药学门诊实施1次完整MTM服务,随访时间不少于6个月.利用经济、临床和人文...     

Recent advancements in nanoparticle based drug delivery for gastrointestinal disorders

Introduction: The emergent field of nanoparticles has presented a wealth of opportunities for improving the treatment of human diseases. Recent advances have allowed for promising developments in drug delivery, diagnostics, and therapeutics. Modified delivery systems allow improved drug delivery over traditional pH, microbe, or receptor dependent models, while antibody association allows for more advanced imaging modalities. Nanoparticles have potential clinical application in the field of gastroenterology as they offer several advantages compared to the conventional treatment systems including target drug delivery, enhanced treatment efficacy, and reduced side effects.

Areas covered: The aim of this review article is to summarize the recent advancements in developing nanoparticle technologies to treat gastrointestinal diseases. We have covered the application of nanoparticles in various gastrointestinal disorders including inflammatory bowel disease and colorectal cancer. We also have discussed how the gut microbiota affects the nanoparticle based drug delivery in the gastrointestinal tract.

Expert opinion: Nanoparticles based drug delivery offers a great platform for targeted drug delivery for gastrointestinal disorders. However, it is influenced by the presence of microbiota, drug interaction with nanoparticles, and cytotoxicity of nanoparticles. With the advancements in nanoparticle technology, it may be possible to overcome these barriers leading to efficient drug delivery for gastrointestinal disorders based on nanoparticle platform.     

T型钙通道和心血管及神经系统疾病

低电压T型钙通道广泛分布在各种类型细胞中,包括心血管和神经元细胞中,与高电压钙通道不同,在接近膜静息电位的低度去极化时即能被激活,因而有利于心脏起博和神经元细胞在生理状态下接近静息时,对兴奋和电反应的调节。但对T型钙通道在疾病中的作用所知有限。近年来因为克隆出3种T型钙通道α1亚单位的基因,(Cav3.1,Cav3.2和Cav3.3),使深入研究实验动物及人体疾病时T型钙通道的性质、药理、体内分布、基因调节成为可能。并且为新药研发提供有力工具。转基因动物实验已证明T型钙通道不仅是治疗肾性高血压、心律失常也是治疗意识丧失型癫痫及神经性疼痛的重要药物靶点。此外,细胞内钙超载还与房颤、心衰、偏头痛、阿尔采末病、睡眠障碍等的发病有关,所以盼望有新的T型钙通道阻断剂出现。有报道Efonidipine能选择性地抑制低电压T型钙通道,有望成为选择性阻断剂。此外,近年来调控T型钙通道活性的分子机制的研究取得新的达展,对新药的开发有所启迪。作者建议,对治疗心血管及神经系统疾病的药物靶点T型钙通道及其阻断剂的研究给予更多的关注。     

Biodegradable polymers: an update on drug delivery in bone and cartilage diseases

ABSTRACT

Introduction: The unique structure of bone and cartilage makes the systemic delivery of free drugs to those connective tissues very challenging. Consequently, effective and targeted delivery for bone and cartilage is of utmost importance. Engineered biodegradable polymers enable designing carriers for a targeted and temporal controlled release of one or more drugs in concentrations within the therapeutic range. Also, tissue engineering strategies can allow drug delivery to advantageously promote the in situ tissue repair.

Areas covered: This review article highlights various drug delivery systems (DDS) based on biodegradable biomaterials to treat bone and/or cartilage diseases. We will review their applications in osteoporosis, inflammatory arthritis (namely osteoarthritis and rheumatoid arthritis), cancer and bone and cartilage tissue engineering.

Expert opinion: The increased knowledge about biomaterials science and of the pathophysiology of diseases, biomarkers, and targets as well as the development of innovative tools has led to the design of high value-added DDS. However, some challenges persist and are mainly related to an appropriate residence time and a controlled and sustained release over a prolonged period of time of the therapeutic agents. Additionally, the poor prediction value of some preclinical animal models hinders the translation of many formulations into the clinical practice.     

The hippo kinases MST1/2 in cardiovascular and metabolic diseases: A promising therapeutic target option for pharmacotherapy

Cardiovascular diseases (CVDs) and metabolic disorders are major components of noncommunicable diseases, causing an enormous health and economic burden worldwide. There are common risk factors and developmental mechanisms among them, indicating the far-reaching significance in exploring the corresponding therapeutic targets. MST1/2 kinases are well-established proapoptotic effectors that also bidirectionally regulate autophagic activity. Recent studies have demonstrated that MST1/2 influence the outcome of cardiovascular and metabolic diseases by regulating immune inflammation. In addition, drug development against them is in full swing. In this review, we mainly describe the roles and mechanisms of MST1/2 in apoptosis and autophagy in cardiovascular and metabolic events as well as emphasis on the existing evidence for their involvement in immune inflammation. Moreover, we summarize the latest progress of pharmacotherapy targeting MST1/2 and propose a new mode of drug combination therapy, which may be beneficial to seek more effective strategies to prevent and treat CVDs and metabolic disorders.     

精准药学:从转化医学到精准医学探讨新药发展

自1960年以来,美国FDA推出的基础研究-发现-设计-临床前开发-临床研究等过程的新药研发的转化研究,这种"转化研究"的"万里挑一"的模式,可以说是最早的"转化研究",对近50年的新药发展起了积极作用。随着生命科学研究的发展及成果的应用,转化研究得到快速发展,转换医学模式成为国际医学健康领域的新概念和研究模式。在美国2010年提出"精准医学"概念之后,奥巴马在他的国情咨文中提出了"精确医学"计划,希望更接近治愈癌症和糖尿病等疾病,希望将以基因为特点的大数据信息用于精准个体化药物治疗。"精准医学"作为医学的未来是人类医学的变革,长期目标是为实现多种疾病的治愈提供有价值的信息。基于精准医疗四要素中"精确、准时、共享、个体化",笔者提出"精准药学"的概念,希望它在实现"精准医疗"中发挥重要的作用,而且具有不同于"精准医学"的研究目标和研究特征。"精准药物"治疗只有实现"精准诊断"的基础上,医疗应用相关的"精准药物"才能提出"精准治疗方案",才能实现精准的个体化治疗。在"大数据"时代,基因组学是精准医学和精准药学的共同基础。但药物研发中可以认为与健康人和病人的基因有关,更与疾病的病因有关,但有些功能性疾病和病毒、细菌、寄生虫等感染性疾病的治疗还与它们的感染、复制及其酶和蛋白等生化过程有关,也与药物的制剂技术和组合有关。因此需要更广阔的知识和视野去认识研发的难度和治疗的精准性,才能开发出疗效更好、更安全、更便利、更经济的新药。     

Clinical utility of therapeutic drug monitoring in biological disease modifying anti-rheumatic drug treatment of rheumatic disorders: a systematic narrative review

Introduction: Biological Disease Modifying Anti-Rheumatic Drugs (bDMARDs) have improved the treatment outcomes of inflammatory rheumatic diseases including Rheumatoid Arthritis and spondyloarthropathies. Inter-individual variation exists in (maintenance of) response to bDMARDs. Therapeutic Drug Monitoring (TDM) of bDMARDs could potentially help in optimizing treatment for the individual patient.

Areas covered: Evidence of clinical utility of TDM in bDMARD treatment is reviewed. Different clinical scenarios will be discussed, including: prediction of response after start of treatment, prediction of response to a next bDMARD in case of treatment failure of the first, prediction of successful dose reduction or discontinuation in case of low disease activity, prediction of response to dose-escalation in case of active disease and prediction of response to bDMARD in case of flare in disease activity.

Expert opinion: The limited available evidence does often not report important outcomes for diagnostic studies, such as sensitivity and specificity. In most clinical relevant scenarios, predictive value of serum (anti-) drug levels is absent, therefore the use of TDM of bDMARDs cannot be advocated. Well-designed prospective studies should be done to further investigate the promising scenarios to determine the place of TDM in clinical practice.     

布瓦西坦致儿童不良反应的文献分析

目的 分析布瓦西坦致儿童不良反应(ADR)的一般规律及特点,为临床安全用药提供参考。方法 以"布瓦西坦" "布立西坦" "不良反应"和"副作用"等为中文检索词,以"Brivaracetam" "adverse reaction" "adverseeffects"ADR "和" side effect"等为英文检索词,对中国学术期刊全文数据库(CNKI)、万方数据库(Wanfang Data)、维普生物医学数据库(VIP)、PubMed、Web of Sciene和Embase等数据库进行文献检索,检索时限均为数据库建库起至2024年1月31日。对纳入研究患者性别、年龄、用药情况、联合用药、ADR临床表现等进行统计分析。结果 共纳入文献13篇,纳入病例849例,其中男性458例(53.9 %)、女性391例(46.1 %),ADR共累及6个系统/器官,以神经系统(39.22 %)和精神疾病(31.86 %)为主,包括嗜睡、癫痫发作恶化、抽搐、易怒、攻击性、精神运动机能亢进、行为问题等。大多数ADR是可逆且预后良好的,但仍有部分患者在进行干预治疗后产生了不良结局,甚至死亡。结论 布瓦西坦可致儿童严重ADR的发生,临床应关注该药的合理使用,加强用药监护和随访,以确保患者临床用药安全。     

Predicting effects of kinase inhibitor in therapy for myeloid malignancies – the challenges in capturing disease heterogeneity

Protein kinase inhibitors have proved to be effective and well tolerated in special form of malignant diseases in which targeted kinases play a central role in the development and progression of the malignant clone. In addition, the development of acquired drug resistance, due to new mutations or clonal evolution, during treatment is common. Methods for measuring the activity and predicting the efficacy of such compounds are warranted for evaluating individual responses to treatment, particularly in a context of widespread preclinical and clinical studies of protein kinase inhibitors in patients with heterogeneous myeloid malignancies.     

Pharmacokinetic drug–drug interactions with methotrexate in oncology

Methotrexate is an antifolate agent used in the treatment of various cancers and some autoimmune diseases. In oncology, methotrexate is frequently administered at a high dose (>1 g/m²) and comes with various procedures to reduce the occurrence of toxicity and particularly to ensure optimal renal elimination. Drug–drug interactions involving methotrexate are the origin of severe side effects owing to delayed elimination of the antifolate and, more rarely, of decreased efficacy in relation to suboptimal exposure. Most of these interactions are driven by membrane drug transporters whose activity/expression can be inhibited by the interacting medication. In the last 10 years, research on drug transporters has permitted retrospective identification of the molecular mechanisms underlying drug–drug interactions with methotrexate. This article summarizes reported drug–drug interactions involving methotrexate in clinical oncology with reference to the role of drug transporters that control the disposition of the antifolate agent.     

Clinical significance of the sparteine/debrisoquine oxidation polymorphism

Summary The sparteine/debrisoquine oxidation polymorphism results from differences in the activity of one isozyme of cytochrome P450, the P450db1 (P450 IID1). The oxidation of more than 20 clinically useful drugs has now been shown to be under similar genetic control to that of sparteine/debrisoquine. The clinical significance of this polymorphism may be defined by the value of phenotyping patients before treatment. The clinical significance of such polymorphic elimination of a particular drug can be analyzed in three steps: first, does the kinetics of active principle of a drug depend significantly on P450db1?; second, is the resulting pharmacokinetic variability of any clinical importance?; and third, can the variation in response be assessed by direct clinical or paraclinical measurements? It is concluded from such an analysis that, in general, the sparteine/debrisoquine oxidation polymorphism is of significance in patient management only for those drugs for which plasma concentration measurements are considered useful and for which the elimination of the drug and/or its active metabolite is mainly determined by P450db1. At present, this applies to tricyclic antidepressants and to certain neuroleptics (e.g. perphenazine and thioridazine) and antiarrhythmics (e.g. propafenone and flecainide). Phenotyping should be introduced in to clinical routine under strictly controlled conditions to afford a better understanding of its potentials and limitations. The increasing knowledge of specific substrates and inhibitors of P450db1 allows precise predictions of drug-drug interactions. At present, the strong inhibitory effect of neuroleptics on the metabolism of tricyclic antidepressants represents the best clinically documented and most relevant example of such an interaction.     

Role of single nucleotide polymorphisms in pharmacogenomics and their association with human diseases

Global statistical data shed light on an alarming trend that every year thousands of people die due to adverse drug reactions as each individual responds in a different way to the same drug. Pharmacogenomics has come up as a promising field in drug development and clinical medication in the past few decades. It has emerged as a ray of hope in preventing patients from developing potentially fatal complications due to adverse drug reactions. Pharmacogenomics also minimizes the exposure to drugs that are less/non-effective and sometimes even found toxic for patients. It is well reported that drugs elicit different responses in different individuals due to variations in the nucleotide sequences of genes encoding for biologically important molecules (drug-metabolizing enzymes, drug targets and drug transporters). Single nucleotide polymorphisms (SNPs), the most common type of polymorphism found in the human genome is believed to be the main reason behind 90% of all types of genetic variations among the individuals. Therefore, pharmacogenomics may be helpful in answering the question as to how inherited differences in a single gene have a profound effect on the mobilization and biological action of a drug. In the present review, we have discussed clinically relevant examples of SNP in associated diseases that can be utilized as markers for “better management of complex diseases” and attempted to correlate the drug response with genetic variations. Attention is also given towards the therapeutic consequences of inherited differences at the chromosomal level and how associated drug disposition and/or drug targets differ in various diseases as well as among the individuals.     

呼吸系统疾病治疗用雾化吸入抗菌药物的研究进展

传统的抗菌药物给药方式(口服或静脉注射)由于药物的理化性质和宿主解剖学特点,感染部位往往达不到有效的抗菌浓度,导致了治疗的失败。雾化吸入疗法因药物直接作用于靶器官,具有起效迅速、疗效佳、全身不良反应少、不需要患者刻意配合等优势,成为治疗呼吸系统相关疾病较为理想的给药方法。目前抗菌药物吸入制剂只有妥布霉素、氨曲南和多黏菌素,正在研制的有环丙沙星、左氧氟沙星、阿米卡星、两性霉素B、万古霉素等。国外在20世纪40年代开始对吸入抗菌药物进行研究,相对国外的研究,国内的相关报道还较少,因此,为给呼吸系统疾病的防治带来临床新路径,对近年来国内外雾化吸入抗菌药物的药效/药动学研究进展进行综述。     

Utility of measuring serum concentrations of anti-TNF agents and anti-drug antibodies in inflammatory bowel disease

Tumor necrosis factor alpha (TNFα) is a cytokine with a critical role in the pathogenesis of some chronic inflammatory diseases, such as inflammatory bowel diseases. Anti-TNF agents, which neutralize the biological activity of TNFα, are widely used among the different therapeutic options for the treatment of patients with inflammatory bowel diseases. These drugs are very useful in clinical practice, but some patients experience lack and loss of response during the treatment. Drug serum concentration, antibodies against anti-TNF agents, clearance of the drug, formation of immune complexes, a more severe disease and probably other unknown factors can influence the treatment's efficacy. Nowadays, the management of patients with lack or loss of response is empirical. The measurement of drug concentrations and antibodies against anti-TNF agents might be useful for improving the selection of patients that will benefit from the maintenance treatment. In clinical practice, these methods may help us decide which strategy will be used in cases of loss of response: treatment intensification, shortening the infusion interval, increasing the dose, switching to another anti-TNF agent or to a drug with another mechanism of action. The optimal strategy in the future may be comprised of an early detection of loss of response to the treatment by assessing clinical symptoms and finding evidence of activity of the disease on endoscopic or radiological examinations when necessary, as well as a better management of anti-TNF treatment aided by measuring the serum concentration of the drug and antibodies against the drug.     

Deprescribing: An Application to Medication Management in Older Adults

Polypharmacy has been found to have potentially negative consequences for patients due to use of potentially inappropriate medications, as well as increased risk of drug interactions and adverse effects. Deprescribing has been proposed as a method of improving medication use throughout a patient's course of care. This article reviews the process of deprescribing and applies the process to medication classes commonly encountered by clinical pharmacists. This review of therapeutics included studies identified through a PubMed search and by review of the reference list of included studies. Relevant studies known to the author were also included. Previous studies have identified several classes of medications as a high priority for construction of evidence‐based deprescribing guidelines. In the absence of currently available evidence‐based clinical practice guidelines, this articles reviews applicable evidence and applies the deprescribing process to three high‐priority medication classes: statins, cholinesterase inhibitors and bisphosphonates. Available evidence can be used to apply the deprescribing process to preventive medications for chronic diseases commonly encountered by clinical pharmacists.     

Delivery to mitochondria: a narrower approach for broader therapeutics

Introduction: Research has revealed a relationship between mitochondrial dysfunction and diseases such as diabetes, ischemia–reperfusion injury, cancer and many more. As a result, mitochondria have gained attention as a target organelle for the treatment of many diseases. Successful delivery of the drug molecule to the mitochondria could be achieved by keeping in mind the normal intracellular trafficking fate of molecules in cell as well as through the mitochondria and exploring the new possibilities to reach the target in an efficient manner.

Areas covered: This review covers important areas such as structure and physiology of mitochondria, mitochondrial genome and its role in the diseases led by mitochondrial dysfunction, generation of reactive oxygen species and its disbalance in pathophysiological conditions and apoptosis. Further, the review focuses on various human mitochondrial diseases, particularly cancer, and strategies and methods of targeting drug and genetic materials to mitochondria. Novel nanotechnology-based carriers for mitochondria delivery are discussed with an attempt of providing readers with a current and future prospective of mitochondrial therapeutics.

Expert opinion: Numerous investigators have attempted to establish a mitochondrial drug delivery system; still, many hurdles yet remain to be overcome before mitochondrial medicine reaches clinical applications. We need to develop a delivery system to encapsulate drugs, proteins and genes that would be practically viable for scale-up and strategies to target and regulate drug release to the cytosol after endosomal escape, and thereafter to deliver the released drug to the mitochondria. Current innovations in the nanotechnology could be effectively utilized with mitochondrial medicine for designing optimal nanoparticle drug delivery system for mitochondrial diseases on clinical setting.     

Tissue factor pathway inhibitor: an update of potential implications in the treatment of cardiovascular disorders

Tissue factor (TF) plays a crucial role in the pathogenesis of thrombotic, vascular and inflammatory disorders. Thus, the inhibition of this membrane protein provides a unique therapeutic approach for prophylaxis and/or treatment of various diseases. Tissue factor pathway inhibitor (TFPI), the only endogenous inhibitor of the TF/Factor VIIa (FVIIa) complex, has recently been characterised biochemically and pharmacologically. Studies in patients demonstrated that both TF and TFPI may be indicators for the course and the outcome of cardiovascular and other diseases. Based on experimental and clinical data, TFPI might become an important drug for several clinical indications. TFPI is expected to inhibit the development of post-injury intimal hyperplasia and thrombotic occlusion in atherosclerotic vessels as well as to be effective in acute coronary syndromes, such as unstable angina and myocardial infarction. Of special interest is the inhibition of TF-mediated processes in sepsis and disseminated intravascular coagulation (DIC), which are associated with the activation of various inflammatory pathways as well as of the coagulation system. A Phase II trial of the efficacy of TFPI in patients with severe sepsis showed a mortality reduction in TFPI- compared to placebo-treated patients and an improvement of organ dysfunctions. TFPI can be administered exogenously in high doses to suppress TF-mediated effects, alternatively high amounts of TFPI can be released from intravascular stores by other drugs, such as heparin and low molecular weight heparins (LMWH). Using this method high concentrations of the inhibitor are provided at sites of tissue damage and ongoing thrombosis. At present, clinical studies with TFPI are rather limited so that the clinical potential of the drug cannot be assessed properly. However, TFPI and its variants are expected to undergo further development and to find indications in various clinical states.     

Approaches for discovering anti-prion compounds: lessons learned and challenges ahead

Introduction: Recent years have witnessed major advances in our understanding of the molecular bases of prion diseases. These studies not only highlight the protein misfolding as a potential initiator of a neurodegenerative process, they also provide a foundation for considering whether such a process can be common to many neurodegenerative diseases, including Alzheimer’s disease. This makes prion diseases a sort of prototype of neurodegenerative disease, endowed with some intrinsic positive features in terms of drug development. Thanks to the fact that disappearance of the scrapie protein can serve as a clear readout of drug efficiency, phenotypic approaches have high potential for prion disease drug discovery.

Areas covered: In this review, the authors discuss phenotypic screening and how it lends itself to drug repositioning. Furthermore, they discuss the advantages of working with a molecule with proven safety, tolerability and drug-like properties in combination with a reliable phenotypic screening and how it could improve the success rate for prion drug development. They also provide examples of several interesting candidates that have been identified using this approach, including quinacrine, astemizole, guanabenz and doxycycline.

Expert opinion: The availability of persistently scrapie-infected murine neuroblastoma cells has greatly helped to identify compounds that inhibit prion formation. However, a human neuronal model infected with the human isoform would ultimately serve as the ideal disease model toward the discovery of effective drugs.     

Lipid nanoparticles for intranasal administration: application to nose-to-brain delivery

Introduction: The blood brain barrier is a functional barrier allowing the entry into the brain of only essential nutrients, excluding other molecules. Its structure, although essential to keep the harmful entities out, is also a major roadblock for pharmacological treatment of brain diseases. Several alternative invasive drug delivery approaches, such as transcranial drug delivery and disruption of blood brain barrier have been explored, with limited success and several challenges. Intranasal delivery is a non-invasive methodology, which bypasses the systemic circulation, and, through the intra- and extra- neuronal pathways, provides direct brain drug delivery. Colloidal drug delivery systems, particularly lipidic nanoparticles offer several unique advantages for this goal .

Areas covered: This review focuses on key brain diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis, and provide a detailed overview of the current lipid nanoparticle based treatment options explored thus far. The review also delves into basic preparation, challenges and evaluation methods of lipid drug delivery systems.

Expert opinion: Brain diseases present complex pathophysiology, in addition to the practically inaccessible brain tissues, hence according to the authors, a two-pronged approach utilizing new target discovery coupled with new drug delivery systems such as lipid carriers must be adopted.