Innovation in Chemistry,Manufacturing, and Controls—A Regulatory Perspective From Industry

This review describes the landscape of novel modalities such as cell and gene therapies, viruses, other novel biologics, oligomers, and emerging technologies, including modern analytics. We summarize the regulatory history and recent landmark developments in some major markets and examine specific chemistry, manufacturing, and controls (CMC) challenges, including suggestions for exploration of potential science-based approaches in support of regulatory strategy development from an industry perspective. In addition, we evaluate the economic factors contributing to patient access to innovation and discuss the impact of regulation. There is a desperate need for a consistent form of regulation where global approaches to regulatory strategies can be harmonized, and specific CMC challenges can be dealt with using the appropriate science and risk-based tools. Although these tools are well described in current guidance documents, the specifics of applicability to complex novel modalities can still result in differing regulatory advice and outcomes. The future goals for efficiently regulating innovative modalities and technologies could be aided by more regulatory harmonization, regulatory education, and industry cooperation through consortia, enabling industry to supply key information to regulators in a transparent yet well-defined manner, and utilizing mutually understood risk-benefit analyses to produce drugs with appropriate safety, efficacy, and quality characteristics.     

注意缺陷多动障碍患儿药物治疗前后microRNA表达量与临床症状的关系

目的 探讨注意缺陷多动障碍（ADHD）儿童药物治疗前后microRNA表达量与临床症状的关系。方法 选取2017年5月至2018年10月初诊为ADHD儿童80例为研究对象，将愿意接受药物治疗的儿童随机分为盐酸哌甲酯治疗组（n=31）和盐酸托莫西汀治疗组（n=33），不愿接受治疗的作为未治疗组（n=16），随访中盐酸哌甲酯组脱落10例，盐酸托莫西汀组脱落13例。另随机选取同时期行健康体检儿童60例作为健康对照组。ADHD儿童在首诊、随访3个月、6个月时进行SNAP-V评分，并采集ADHD及健康对照组儿童血清样本以荧光定量PCR法检测miR-4655-3p和miR-7641的相对表达量。结果 重复测量方差分析结果显示，注意力不足症状SNAP-V评分在两治疗组和未治疗组中，以及两种miRNA相对表达量在两治疗组和健康对照组中均存在分组与时间因素差异，且分组与时间因素均存在交互作用（P < 0.05）。多动冲动症状SNAP-V评分在两治疗组和未治疗组中存在时间因素差异（P < 0.05），而分组因素差异无统计学意义，且时间因素与分组因素无交互作用（P > 0.05）。经药物治疗的ADHD儿童注意力不足症状SNAP-V评分与miRNA-4655-3p和miRNA-7641相对表达量均呈负相关（分别r=-0.314、-0.495，P < 0.05）。结论 药物治疗可显著改善ADHD儿童的临床症状；血清中miR-4655-3p和miR-7641的表达水平可能作为ADHD的诊断及疗效评估的分子指标。     

French Society of ENT (SFORL) guidelines. Management of acute Bell's palsy

AQFThe authors present the guidelines of the French Society of ENT and Head and Neck Surgery (SFORL) regarding the management of Bell's palsy in adults. After a literature review by a multidisciplinary workgroup, guidelines were drawn up based on retrieved articles and group-members’ experience, then read over by an independent group to edit the final version. Guidelines were graded A, B, C or “expert opinion” according to decreasing level of evidence. Thorough ENT and neurological clinical examination is recommended in all patients presenting with peripheral facial palsy to confirm diagnosis of Bell's palsy. MRI with gadolinium enhancement should explore the entire course of the facial nerve, if possible within the first month. ENMG should be performed to assess prognosis for recovery. In confirmed Bell's palsy, corticosteroid therapy should be implemented as early as possible (ideally within 72 h) at a dose of 1 mg/kg/day for 7–10 days. Antiviral therapy should be associated to steroids in patients with severe and early-onset disease and in Ramsay-Hunt syndrome. Isolated antiviral therapy is not recommended. To date, there is no evidence that surgical facial nerve decompression provides benefit.     

Direct renin inhibition: an evaluation of the safety and tolerability of aliskiren

ABSTRACT

Background: Aliskiren, an antihypertensive drug approved in the United States and Europe, is the first in a new class known as direct renin inhibitors. Aliskiren has been evaluated for safety and tolerability in more than 6400 patients. It has demonstrated a favorable safety and tolerability profile alone or in combination with other drugs.

Objective: This article reviews the currently available safety and tolerability data for aliskiren.

Methodology: Using the search term aliskiren, MEDLINE (no timeframe set) and major cardiovascular congresses (2005–2008) were searched. Articles and abstracts with safety and drug interaction data were included.

Findings: Aliskiren may share common adverse effects observed with angiotensin-converting enzyme (ACE)-inhibitor and angiotensin receptor blocker (ARB) therapy. In placebo-controlled trials, those commonly reported for aliskiren at the approved dosage were headache, diarrhea, and fatigue, with incidences similar to those of placebo. Aliskiren has been well tolerated in black, geriatric, diabetic, or obese patients and patients with renal or hepatic impairment. Aliskiren neither inhibits nor induces the cytochrome P450 system; it does not inhibit P-glycoprotein, but is a substrate for this drug transporter. Adding a direct renin inhibitor to another renin–angiotensin–aldosterone system (RAAS) inhibitor may further improve cardiovascular outcomes, renal outcomes, or both, without increasing the incidence of adverse effects.

Conclusions: Aliskiren is well tolerated, has an adverse effect profile comparable to that of placebo, and has a low potential for drug interactions. Data from ongoing trials evaluating the effects of aliskiren on surrogate markers, morbidity, and mortality will further define the role of direct renin inhibition in the antihypertensive armamentarium.     

Sustained release bioadhesive effervescent ketoconazole microcapsules tabletted for vaginal delivery

Microcapsules of ketoconazole with 1:1 and 1:2 core-wall ratios were prepared by means of the phase separation technique using sodium carboxymethylcellulose as a coating material. The microcapsules were mixed with effervescent granules and were tabletted. Dissolution studies of microcapsules, tabletted microcapsules and commercial ovules were carried out with a new basket method (horizontal rotating basket). A good sustained action was obtained with tablets. Micromeritic investigations were carried out on microcapsules in order to standardize the microcapsule product and to optimize the pilot production of the dosage forms prepared with these microcapsules. Bulk volume and weight, tapping volume and weight, fluidity, angle of repose, weight deviation, relative deviation, particle size distribution, density and porosity values of the microcapsules were determined. In addition, to evaluate whether some kind of glidant will be needed during tabletting of microcapsules, the Hausner ratio and consolidation index were also calculated and it may be concluded that microcapsules do not need any glidant.     

Announcements

Rotating head-to-head agglutinates of human spermatozoa were always observed to turn counterclockwise. The phenomenon seems to suggest a unidirectional rotatory component in the tail movement that may be related to the substructure of the axoneme.     

Radioactive Antibodies: A Historical Review of Selective Targeting and Treatment of Cancer

Abstract

Radioactive antibodies have served as imaging and therapeutic agents for several decades, but recent developments raise enthusiasm that a new generation of cancer therapeutics and diverse molecular imaging agents for various cancers are more likely than ever before. This article traces the development of tumor-targeting antibodies labeled with diagnostic or therapeutic radionuclides, and describes the problems encountered and the clinical advances made. We also emphasize recent attempts to improve both molecular imaging and radioimmunotherapy with multistep pretargeting methods that separate the delivery of the tumor-binding, bispecific antibody given in the first step from the radionuclide carrier, which, in the second step, will localize to the “anti-carrier” binding arm of the pretargeted bispecific antibody.     

Kinetics of biomolecular interactions

Recent advances in instrumentation, in particular the development of biosensors, have greatly simplified the measurement of the kinetics of molecular interactions. Previously, while it was realised that the kinetics of biomolecular interactions were important factors in the successful design of molecules for clinical, industrial or scientific purposes, the difficulties in measuring the kinetics of these interactions meant that, in most cases, they were ignored. This review will briefly explain the principles behind kinetic interactions (more fully reviewed in [1-5]), then summarise the nature of optical biosensors used to measure kinetic interactions and, finally, give some selected and limited case studies to illustrate why measuring these interactions can be important in drug development.