From Serendipity to Mitochondria-Targeted Nanocarriers

This review illustrates how a random observation at the laboratory bench has helped pave the way towards the development of organelle-targeted pharmaceutical nanocarriers. A fortuitous discovery in the mid 1990s involving the self-assembly of a molecule, known to accumulate inside mitochondria, has lead to the development of subcellular nanocarriers suited for the selective delivery of biologically active molecules to mitochondria inside living mammalian cells. Applications for mitochondria-specific drug and DNA delivery are described, the current state-of-the-art of mitochondrial drug targeting technology is reviewed, and its future perspectives are discussed.     

Biologics against cancer-specific receptors - challenges to personalised medicine from early trial results

Understanding molecular mechanisms of tumourigenesis underlies new therapeutic strategies that specifically target tumours. This has led to the evolution of personalised therapy that was first used in breast cancer when hormone receptor status was determined. More recently in colorectal cancer treatment the Epidermal Growth Factor receptor and its tumourigenic role has led to its targeting by using Cetuximab and Panitumumab. Addition of these drugs to existing drug regimes (FOLFOX and FOLFIRI) showed improved respectability rates in patients with liver metastasis. Most recently the Endothelin receptor has been implicated in multiple tumourigenic processes. Interest has grown in using Endothelin A receptor antagonists as adjuvant or combination therapy as suggested by the FOLFERA and FOLFIRI trials currently on-going.     

Serendipity and pharmaceutical research

So far as pharmaceutical research in concerned, serendipity plays a significant part even in the genesis of rigorous research. Quite often, scientific discoveries occur by chance, without searching anything or when searching something else. Unforseen discoveries win the medicines of the central nervous system, as well as the side effects of some medicines which received then new indications. Aspirin, iproniazide, reserpine, phenothiazine... Serendipity played its part in drug discovery as well as in any human activity.     

Biologics for tendon repair

Tendon injuries are common and present a clinical challenge to orthopedic surgery mainly because these injuries often respond poorly to treatment and require prolonged rehabilitation. Therapeutic options used to repair ruptured tendons have consisted of suture, autografts, allografts, and synthetic prostheses. To date, none of these alternatives has provided a successful long-term solution, and often the restored tendons do not recover their complete strength and functionality. Unfortunately, our understanding of tendon biology lags far behind that of other musculoskeletal tissues, thus impeding the development of new treatment options for tendon conditions. Hence, in this review, after introducing the clinical significance of tendon diseases and the present understanding of tendon biology, we describe and critically assess the current strategies for enhancing tendon repair by biological means. These consist mainly of applying growth factors, stem cells, natural biomaterials and genes, alone or in combination, to the site of tendon damage. A deeper understanding of how tendon tissue and cells operate, combined with practical applications of modern molecular and cellular tools could provide the long awaited breakthrough in designing effective tendon-specific therapeutics and overall improvement of tendon disease management.     

生物制剂治疗风湿免疫病的临床疗效分析

目的探析生物制剂治疗风湿免疫病的临床效果。方法将我院2012年3月至2013年4月收治的40例风湿免疫病患者作为研究对象,随机分为两组,其中给予对照组常规治疗,而观察组则运用生物制剂治疗,对比分析两组治疗效果。结果观察组10例显效,8例有效,2例无效,治疗总有效率为90.0%,而对照组5例显效,10例有效,5例无效,治疗总有效率为75.0%,两组临床治疗效果差异明显,具有统计学意义(P<0.05)。结论临床上运用生物制剂对风湿免疫病患者进行治疗,不仅不良反应小、安全性高,在一定程度上还能有效提高治疗效果,改善患者预后生活质量。     

Biosimilarity for Follow-on Biologics

With dramatic increased spending on biologics and approaching patent expirations for existing biological products, there is a need to consolidate thinking on the regulatory approval pathway of biosimilars. However, biologics have much greater complexity by nature. The traditional paradigm currently used for generic chemical drugs, where bioequivalence is the focus, cannot be extrapolated to biologics. In the biosimilars scenario, the comparability of pharmacokinetic and pharmacodynamic parameters, and the comparability of efficacy and safety from clinical trials are the keys for the success of follow-on biologics. Developing sensitive bioanalytical methods to detect small, meaningful differences is critical. This article proposes a novel reference-scaled method to evaluate the comparability of pharmacokinetics parameters, and illustrates the method using a study comparing a test drug to a reference drug in a cancer study.     

生物仿制药整装待发

生物制药和仿制药食业纷纷瞄准生物仿制药领域,随着2013年一些重量级治疗性蛋白质药物的专利到期,生物仿制药将迎来巨人的市场机遇.     

Biologics in development for rheumatoid arthritis: relevance to osteoarthritis

The osteoarthritis disease process affects not only the cartilage but also the entire joint structure, including the synovium, bone and periarticular muscles. Characteristically, abnormal biomechanical forces result in an imbalance between chondrocyte anabolic and catabolic pathways, which ultimately leads to progressive joint destruction. Within cartilage and synovium, pro-inflammatory cytokines, particularly IL-1b and TNF-a, auto-catalytically stimulate their own production and induce chondrocytes to produce additional catabolic mediators, including proteases, chemokines, nitric oxide, and prostaglandins. The success of targeted biological therapy in rheumatoid arthritis has taught that the blockade of a single dominant cytokine can lead to remarkable clinical benefit, even in complex disease. The effectiveness of biologicals in inflammatory arthritides as disease modifying agents has increased the likelihood that similar strategies can be developed to target specific molecular mechanisms in osteoarthritis (OA). However, since the clinical development program for disease-modifying OA drugs (DMOADs) is complicated by the slow progression of disease in many patients, the introduction of DMOADs will be greatly enhanced by advances in imaging and biomarkers that serve as validated surrogate endpoints for meaningful clinical outcomes.     

A Tolerance Interval Approach to Assessing the Biosimilarity of Follow-On Biologics

With many important biologic products due to lose patent protection in the next few years, the development of follow-on biologics has received much attention from both sponsors and regulatory authorities. Biologics are often produced in living systems. The living systems used to produce biologics are highly complex and could be sensitive to very minor changes in the manufacturing process. According to the guideline published by the European Medicines Agency, biosimilar products are similar, not identical, to the innovator products they seek to copy. Therefore, in developing a biosimilar, it is important to assess the similarity between it and the innovator product. In this article, we consider a two-arm, parallel design with a reference biological product and a biosimilar. Then, we construct a biosimilarity index for assessing the degree of similarity based on the tolerance limits. The acceptance criterion is proposed to judge whether the biosimilar is similar to the reference product. We also address the determination of the number of subjects to ensure that the occurring probability of biosimilarity criterion is maintained at a desired level, say 80% or 90%. Supplementary materials for this article are available online.     

鼻用生物制品的进展与挑战

生物制品发展迅猛,在应对多类疾病的治疗时展现出其独特的优势与潜力。然而目前常用的口服、注射等给药方式中,生物制品常存在稳定性差、体内半衰期短、中枢神经系统利用度差等问题,限制了生物制品的应用范围与发展。通过鼻腔对生物制剂进行给药的鼻用生物制品,充分利用鼻腔中天然存在的鼻脑通路、黏膜免疫淋巴组织等功能组分递送药物分子,具有高效递送、提高药物利用度的潜力,成为一种很有前景的策略。本文通过已发表文献、临床试验数据库、相关产品信息等公开资料,从作用机制、应用现状、发展前景等方面对鼻用大分子治疗药物、鼻用疫苗及鼻用细胞疗法等鼻用生物制品主要类别的研究现状进行总结,进一步对鼻用生物制品的发展提出建议。     

Biologics Safety Preclinical,Clinical and Regulatory

Biologicals offer particular challenges for all concerned, whether they be scientific researchers, profit-oriented companies (including not yet profit-producing start-ups), public health-focused regulators, physicians, or, most importantly, patients. One of the most important of these challenges is safety. Hence, this conference was organised by Vision in Business (the trading name of Analysis and Networking Ltd) to provide practical solutions and advice for comprehensive, effective safety testing. It provided a wide spectrum of presentations, ranging from the usefulness of animal models for biologicals safety predictions, to an FDA perspective on implications of its recent restructuring, to a real-life case study on erythropoietin and pure red cell anaemia. For anyone seriously interested in the safety of biologicals, this was a very good opportunity to gain an overview of all major aspects of biologicals safety, broaden existing expertise and to network with those concerned with these issues.     

Biologics in the treatment of pustular psoriasis

ABSTRACT

Introduction

Pustular psoriasis is a group of skin diseases characterized by neutrophil infiltration in the epidermis and formation of sterile pustules. Conventional treatments, such as retinoids and immunosuppressive drugs, have improved the clinical manifestations; however, many patients suffer from drug-related toxicity or are resistant to therapy.     

Biologics safety preclinical, clinical and regulatory

Biologicals offer particular challenges for all concerned, whether they be scientific researchers, profit-oriented companies (including not yet profit-producing start-ups), public health-focused regulators, physicians, or, most importantly, patients. One of the most important of these challenges is safety. Hence, this conference was organised by Vision in Business (the trading name of Analysis and Networking Ltd) to provide practical solutions and advice for comprehensive, effective safety testing. It provided a wide spectrum of presentations, ranging from the usefulness of animal models for biologicals safety predictions, to an FDA perspective on implications of its recent restructuring, to a real-life case study on erythropoietin and pure red cell anaemia. For anyone seriously interested in the safety of biologicals, this was a very good opportunity to gain an overview of all major aspects of biologicals safety, broaden existing expertise and to network with those concerned with these issues.     

Transfer of Methods Supporting Biologics and Vaccines

The transfer of analytical methods supporting biologics and vaccines is complicated by the complexity and variability of biological systems. Many of these assays may be linked to clinical performance, and thus subject to specifications established from materials that were tested in the development laboratory. Thus, transfer must account for the risk that the method characteristics have changed, and may generate results for commercial lots that either earmarks a satisfactory lot as failing, or an unsatisfactory lot as passing specification. Transfer study strategies have been proposed based on method parameters or on tolerance intervals. This article describes a framework for establishing the equivalence between two laboratories with emphasis on the associated risks, and compares and contrasts the parametric and tolerance approaches.