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Colistin is a polypeptide antibiotic mainly used in porcine and poultry to treat gastrointestinal infections. It has been included by the World Health Organisation (WHO) in the list of critically important human antibiotics of high priority for antimicrobial resistance since 2017. Therefore, it is necessary to develop specific and sensitive screening methods for this molecule. Screening for colistin with immunoassays is an interesting alternative to LC-MS/MS screening methods. The performance of three commercially available ELISA kits was evaluated in poultry and porcine muscles for the detection of colistin in regards to its European maximum residue limit (MRL) (150 µg/kg). The applicability of the three ELISA kits to the detection of colistin at or below the MRL in porcine and poultry muscles was demonstrated. The detection capabilities (CCβ) of two kits were or lower than or equal to the MRL (150 µg/kg). The lowest detection capability (30 µg/kg) was achieved with the third ELISA kit. The specificity of the three kits was very satisfactory (false positive rates 0%). The three kits are very specific for the detection of colistin (colistin A and B) and polymyxin B.

The resurgence and changing epidemiology of pertussis in high-income countries, the high infant mortality caused by pertussis in low-income countries, and the increasing morbidity in all age groups worldwide call for a concerted effort to both improve the current vaccines and develop new vaccines and vaccination strategies against pertussis. In this Personal View, we identify several key obstacles on the path to developing a durable solution for global control of pertussis. To systematically address these obstacles, the PERtussIS Correlates Of Protection Europe (PERISCOPE) Consortium was established in March, 2016. The objectives of this consortium are to increase scientific understanding of immunity to pertussis in humans induced by vaccines and infections, to identify biomarkers of protective immunity, and to generate technologies and infrastructure for the future development of improved pertussis vaccines. By working towards the accelerated licensure and implementation of novel, well tolerated, and effective pertussis vaccines, we hope to strengthen and stimulate further collaboration and transparency between the key stakeholders, including the public, the scientific community, public health institutes, regulatory authorities, and vaccine manufacturers., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Compound screening in biological assays and subsequent optimization of hits is indispensable for the development of new molecular research tools and drug candidates. To facilitate such discoveries, the European Research Infrastructure EU-OPENSCREEN was founded recently with the support of its member countries and the European Commission. Its distributed character harnesses complementary knowledge, expertise, and instrumentation in the discipline of chemical biology from 20 European partners, and its open working model ensures that academia and industry can readily access EU-OPENSCREEN's compound collection, equipment, and generated data. To demonstrate the power of this collaborative approach, this perspective article highlights recent projects from EU-OPENSCREEN partner institutions. These studies yielded (1) 2-aminoquinazolin-4(3 H)-ones as potential lead structures for new antimalarial drugs, (2) a novel lipodepsipeptide specifically inducing apoptosis in cells deficient for the pVHL tumor suppressor, (3) small-molecule-based ROCK inhibitors that induce definitive endoderm formation and can potentially be used for regenerative medicine, (4) potential pharmacological chaperones for inborn errors of metabolism and a familiar form of acute myeloid leukemia (AML), and (5) novel tankyrase inhibitors that entered a lead-to-candidate program. Collectively, these findings highlight the benefits of small-molecule screening, the plethora of assay designs, and the close connection between screening and medicinal chemistry within EU-OPENSCREEN.

Background: Juvenile animal testing has become an established part of drug development to support safe clinical use in the human pediatric population and for eventual drug product label use., Methods and Results: A review of European Paediatric Investigation Plan decisions showed that from 2007 to mid-2017, 229 drugs had juvenile animal work requested, almost exclusively incorporating general toxicology study designs, in rat (57.5%), dog (8%), mouse (4.5%), monkey (4%), pig (2%), sheep (1%), rabbit (1%), hamster (0.5%), and species not specified (21.5%). A range of therapeutic areas were found, but the most common areas were infectious diseases (15%), endocrinology (13.5%), oncology (13%), neurology (11%), and cardiovascular diseases (10%). Examination of major clinical indications within these therapeutic areas showed some level of consistency in the species of choice for testing and the pediatric age that required support. Examination of juvenile animal study findings presented in product labels raises questions around how useful the data are to allow prescribing the drug to a child., Conclusion: It is hopeful that the new ICH S11 guideline "Nonclinical Safety Testing in Support of Development of Pediatric Medicines" currently in preparation will aid drug developers in clarifying the need for juvenile animal studies as well as in promoting a move away from toxicology studies with a conventional design. This would permit more focused testing to examine identified areas of toxicity or safety concerns and clarify the presentation/interpretation of juvenile animal study findings for proper risk assessment by a drug prescriber.

The widespread use and patent expiration of many biologics have led to global interest in development of biosimilar products. Because the manufacture of biologics, including biosimilars, is a complex process involving living systems, the development of a biosimilar is more rigorous than the development of a generic small molecule drug. Several regulatory agencies have established or are proposing guidelines that recommend a stepwise process to ensure the efficacy and safety of a biosimilar are highly similar to the reference product. This article also explores the early clinical phase of biosimilar development, which is particularly important to resolving any uncertainties that might remain following in vitro and in vivo evaluations and to enable a selective and targeted approach to Phase III clinical efficacy and safety investigation., (Copyright © 2015. Published by Elsevier Ltd.)

With the release of Regulation 1394/2007, a new framework for gene and cell therapy medicinal products and tissue-engineered products was established in the European Union. For all three product classes, called advanced therapy medicinal products, a centralised marketing authorisation became mandatory. The European Medicines Agency (EMA) together with its Committee for Advanced Therapies, Committee for Human Medicinal Products and the network of national agencies is responsible for scientific evaluation of the marketing authorisation applications. For a new application, data and information relating to manufacturing processes and quality control of the active substance and the final product have to be submitted for evaluation together with data from non-clinical and clinical safety and efficacy studies. Technical requirements for ATMPs are defined in the legislation, and guidance for different products is available through several EMA/CAT guidelines. Due to the diversity of ATMPs, a tailored approach for regulating these products is considered necessary. Thus, a risk-based approach has been introduced for ATMPs allowing flexibility for the regulatory requirements. Since the regulatory framework for ATMPs was established, five products have been licenced in the European Union. However, the pipeline of new ATMPs is much bigger, as seen from the significant numbers of different products discussed by the CAT in scientific advice and classification procedures. In 2013, a public consultation on the ATMP Regulation was conducted by the European Commission, and the results were published in 2014. The report proposes several improvements for the current framework and established procedures for the regulation of ATMPs.

Drug-induced vascular injury (DIVI) is a common preclinical toxicity usually characterized by hemorrhage, vascular endothelial and smooth muscle damage, and inflammation. DIVI findings can cause delays or termination of drug candidates due to low safety margins. The situation is complicated by the absence of sensitive, noninvasive biomarkers for monitoring vascular injury and the uncertain relevance to humans. The Safer And Faster Evidence-based Translation (SAFE-T) consortium is a public-private partnership funded within the European Commission's Innovative Medicines Initiative (IMI) aiming to accelerate drug development by qualifying biomarkers for drug-induced organ injuries, including DIVI. The group is using patients with vascular diseases that have key histomorphologic features (endothelial damage, smooth muscle damage, and inflammation) in common with those observed in DIVI, and has selected candidate biomarkers associated with these features. Studied populations include healthy volunteers, patients with spontaneous vasculitides and other vascular disorders. Initial results from studies with healthy volunteers and patients with vasculitides show that a panel of biomarkers can successfully discriminate the population groups. The SAFE-T group plans to seek endorsement from health authorities (European Medicines Agency and Food and Drug Administration) to qualify the biomarkers for use in regulatory decision-making processes., (© 2014 by The Author(s).)

In January 2007, the Paediatric Regulation entered into force and established the Paediatric Committee (PDCO) within the European Medicines Agency. The goal of the PDCO is to improve the health of the children of Europe by increasing high-quality research for medicinal products and promoting the development and authorization of such medicines at the EU level. A major function of the PDCO is to formulate and authorize Paediatric Investigation Plans and Paediatric Use Marketing Authorisations. The EU's Seventh Framework Programme for Research has facilitated the establishment of consortia whose ultimate goal is to answer important clinical questions involving medicines commonly used "off-label", in children. The benefits of these consortia include enhanced collaboration amongst paediatricians, scientists and small to medium enterprises whose ultimate goal is to obtain an authorization for a new indication or formulation for use in the paediatric population. It will be interesting in a number of years time to measure the success of this very important European initiative.

Introduction: Mirabegron is a new once-daily, oral treatment for management of overactive bladder (OAB) that is approved in USA, EU and Japan. It activates β3 adrenoceptor to facilitate bladder filling and reduce mean micturition frequency with better safety profile than current treatment of antimuscarinic drugs., Areas Covered: The following article reviews the information available from published randomized trials on the metabolism and pharmacokinetics mirabegron. The reader will gain better insight into the variability in plasma exposure of mirabegron due to various causes. Propensity for drug interactions with mirabegron is low as its clearance involves multiple metabolic and excretory pathways. Mirabegron is generally well tolerated, but its pharmacokinetics is altered by dose and gender with implications for cardiovascular toxicity., Expert Opinion: Mirabegron is a first-in-class of β3 adrenoceptor agonists that could offer an alternative to antimuscarinics for OAB patients. The marketed dose of 50 mg achieves primary efficacy endpoints but causes only modest improvement over placebo in terms of daily incontinence and voiding episodes. Involvement of saturable efflux transporters is indicated in oral bioavailability of mirabegron. It is well tolerated with hypertension, nasopharyngitis, urinary tract infection and headache being the most common side effects.

The single-laboratory validation (SLV) of an LC-MS/MS method for determination and confirmation of two ionophores, narasin and monensin, in animal tissues is described. The data demonstrated linearity of matrix-matched calibration curves using a weighted (1/x) regression and selectivity of the method for narasin and monensin in the presence of lasalocid, salinomycin, maduramycin, nicarbazin, and sulfadiazine. Recoveries varied from 86.2 to 103.5% for narasin and 89.1 to 105.1% for monensin. Intertrial repeatability precision [relative standard deviation of repeatability (RSDr)] varied from 3.9 to 13.8% for narasin and 3.3 to 16.3% for monensin in fortified tissue. Precision of the method was verified in incurred tissues. The LOQ of the method was validated and ranged from 0.45 ng/g in milk, to 4.0 ng/g in chicken fat, but was 0.75 ng/g for most tissues. Two confirmatory ions for each analyte were examined across all matrixes, resulting in estimated false-negative rates of 0.00% (95% confidence interval of 0.00-0.68%) for monensin ions (540 samples) compared to the U.S. and European Union (EU) acceptance criteria. The confirmatory ions for narasin demonstrated 0.00% false-negative rates (95% confidence interval of 0.00-0.58%) when compared to either the U.S. or EU criteria in 630 samples. The method was robust when small changes in method parameters were made and stability of fortified tissues, extracts, and calibration solutions were estimated. The data satisfy the requirements of the AOAC Stakeholder Panel on Veterinary Drug Residue for SLV studies, and the method was adopted Official Methods of Analysis First Action 2011.24 by the AOAC Expert Review Panel on Veterinary Drug Residues.

Following the explosion of the influenza A pandemic (H1N1) during the first semester of 2009, oseltamivir and zanamivir were used as the treatment of choice in the absence of rigorous clinical studies demonstrating their efficacy in the treatment and prophylaxis of this disease. Knowledge of seasonal influenza, flu pandemics and particularly the H1N1, which produces more severe infection and a higher mortality rate during pregnancy, led to the use of antiviral treatment despite the scarcity of clinical studies on their efficacy and effectiveness, mainly due to the influence of the media. This study reviewed the experimental and clinical studies performed on the safety of oseltamivir and zanamivir in pregnancy. Likewise, the recommendations made by the different health care and governmental authorities as well as other institutions and scientific and health care organizations on the therapeutic management and prophylaxis of influenza A 2009 in pregnant women were reviewed., (Copyright © 2010 Elsevier España, S.L. All rights reserved.)

The Innovative Medicine Initiative (IMI) is a joint technology initiative jointly implemented by the European Commission and by the European Federation of Pharmaceutical Industries and Associations (EFPIA). The objective of IMI, officially launched on April 30th 2008, is to identify and address the bottlenecks of the drug discovery and development process. IMI will reinforce the public-private partnerships and will be focused towards critical nodes of the drug discovery such as efficacy predictivity, safety predictivity, knowledge management and education and training. This initiative will also reinforce the attractivity of Europe for biomedical science and will then lead to the discovery of novel therapeutic strategies for the patients.

New drug development is a long, expensive and hazardous process especially regarding the final outcome. During the first non-clinical steps, molecules identified as potential candidates are screened for their toxicological profile, which allows to eliminate some but also to identify possible "target" organs. Then clinical trials are conducted, where tolerance profile knowledge is increased through the development with the detection of the most frequent adverse effects (between 1% and 1 per thousand). At marketing authorization, because of the limited number and of the selectivity of patients enrolled in clinical trials, the drug safety profile is based on the more frequent adverse effects. In Europe, since November 2005, a new regulation - the Risk Management system - has been added to Pharmacovigilance. These are designed to better anticipate and even minimize important identified or potential risks or to better inform on populations not studied during the clinical trials. This concept is based on risk reduction throughout drug's life cycle with specific strategic actions in addition to the product information, in order to optimise the drug benefit/risk ratio. Pharmaceutical companies will therefore invest significantly in post-marketing, allowing proper and safety use of their products. As they played a major role in the clinical development few years ago, they could from now on, be recognised as the key player towards this new paradigm defined as the post-approval development.

The mycobactericidal and tuberculocidal activities of Korsolex AF against Mycobacterium tuberculosis, Mycobacterium avium-Mycobacterium intracellulare (MAI), Mycobacterium kansasii and Mycobacterium chelonae were determined using quantitative suspension and carrier tests. The effects of organic load and hard water were also considered. A clinical isolate of MAI was the most resistant of the four test organisms. A 2% solution had good mycobactericidal and tuberculocidal activities after 30 min of exposure. Although further evaluation using European standard tests is necessary, we conclude that Korsolex AF appears to be a promising product for the disinfection of hospital instruments contaminated with mycobacteria.

Background and Objectives: Individuals with primary or secondary immune-deficiency diseases may be at risk for vaccinia infection if widespread smallpox-immunization programmes are implemented in the United States of America (USA) for bioterrorism preparedness. The objective of this study was to determine whether commercial immune globulin (intravenous, human) products contain biologically active antibodies to vaccinia that have the potential to protect people, with immune deficiencies, from complications of vaccinia., Materials and Methods: Eight currently United States (US)-licensed and two European intravenous immunoglobulin (IVIG) products were tested in a vaccinia plaque-reduction neutralization assay. The in vivo activity of five of these lots was assessed in severely immune-deficient mice., Results: All tested products contained neutralizing anti-vaccinia activity, in vitro and in vivo., Conclusions: The use of IVIG by individuals with inherited or acquired humoral immune deficiencies may provide some protection if they are inadvertently exposed to vaccinia.

Despite the growing demand for combination vaccines, many challenges have been encountered in developing them. It is difficult to predict the physical compatibility and stability of antigens in combination, because these characteristics are highly dependent on vaccine excipients. Clinical evaluation of potential modifications of efficacy of antigens in combination may be alleviated by use of appropriate animal models. Manufacturing issues, such as batch-release testing, storage of intermediate products, and the shift to preservative-free products, are of particular concern because they have the potential to affect the supply chain. Managing changes in the manufacture of one antigen that is a component of several different combination vaccines is also difficult. However, most potential issues can be resolved through the simplification of regulatory processes and harmonization of requirements, such as the acceptance of comparability protocols and antigen master files. Continued collaboration between industry and authorities is necessary to develop effective means of handling all submissions pertaining to combination vaccines.

Chemical screening in the United States is often conducted using scoring and ranking methodologies. Linked models accounting for chemical fate, exposure, and toxicological effects are generally preferred in Europe and in product Life Cycle Assessment. For the first time, a comparison is presented in this article of two of the prominent, but structurally different methodologies adopted to help screen and rank chemicals and chemical emissions data. Results for 250 chemicals are presented, with a focus on 12 chemicals of interest in the United Nations Environment Programme's Persistent Organic Pollutants global treaty negotiations. These results help to illustrate the significance of described structural differences and to assess the correlation between the methodologies. The scope of the comparison was restricted here to human health, although the insights would be equally useful in the context of the health of ecosystems. Illustrating the current types of chemical screening and emissions comparison approaches, the relative significance of the scenario and structural differences of the Waste Minimization Prioritization Tool (WMPT) and the Toxic Equivalency Potential (TEP) methodologies are analyzed. The WMPT facilitates comparison in terms of key physical-chemical properties. Measures for Persistence, Bioaccumulation, and Toxicity (PBT) are calculated. Each PBT measure is scored and then these scores are added to provide a single measure of relative concern. TEPs account for chemical fate, multipathway exposure, and toxicity using a model-based approach. This model structure is sometimes considered to provide a less subjective representation of environmental mechanisms, and, hence, an improved basis for screening. Nevertheless, a strong relationship exists between the two approaches and both have their limitations.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has shown high clinical antitumor activity in several tumor types, including ovarian, breast, and lung carcinoma. Preclinical studies have shown that paclitaxel has an additive effect when combined with platinum compounds. Early clinical trials confirmed these data and established the dose range for both drugs. In recent years, several studies were developed in Europe using the combination of paclitaxel and platinum in non-small cell lung cancer, and four large randomized trials have been completed in Europe. The first study compared paclitaxel/cisplatin with teniposide/cisplatin, which was the control arm of the European Organization for Research and Treatment of Cancer at that time. The second study evaluated the benefit of the addition of paclitaxel to cisplatin. The third study compared paclitaxel/cisplatin with paclitaxel/carboplatin, and the fourth compared two doses of paclitaxel combined with carboplatin. Another large randomized study is currently being performed by the European Organization for Research and Treatment of Cancer. Combinations using paclitaxel-based regimens in the preoperative setting are under investigation. An ongoing European Organization for Research and Treatment of Cancer trial compares surgery with radiotherapy following various induction chemotherapy combinations, among which paclitaxel/platinum is one of the most frequently used. Another induction regimen is currently being evaluated by the University Medical School of Essen and Institut Gustave Roussy in Villejuif, France. In this trial, paclitaxel/cisplatin is delivered before etoposide/cisplatin and concurrent radiotherapy followed by surgery in locally advanced non-small cell lung cancer. Preclinical studies underline the radiosensitizing effect of paclitaxel, and many clinical studies are being conducted with radiotherapy in association with paclitaxel alone or in combination with platinum compounds. The use of paclitaxel in regimens without platinum and in triplet combinations is also being studied, and the optimal manner in which to administer this active agent clearly is of interest., (Copyright 2001 by W.B. Saunders Company.)

Study Objectives: Widow spiders of the genus Latrodectus are found worldwide and produce similar clinical envenomation syndromes. In Australia, red-back spider antivenom (RBS-AV) is effective therapy for Latrodectus hasselti envenomation and it has been reported to reverse envenomation by other widow spiders. This study assessed the efficacy of RBS-AV in preventing in vitro and in vivo toxicity of widow spider venoms of North America and Europe., Methods: The binding of RBS-AV to alpha-latrotoxin and Latrodectus venoms (Latrodectus spp mactans, hesperus, lugubris, tredecimguttatus, hasselti) was assayed using Western blotting. Prevention of in vitro toxicity to alpha-latrotoxin and the same venoms was tested by pretreating an isolated chick biventer cervicis nerve-muscle preparation with RBS-AV. Prevention of in vivo toxicity was determined by a lethality study in male Balb/c mice (2.5 to 5x median lethal dose [LD50]) or alpha-latrotoxin (10x LD50) preincubated with antivenom or without RBS-AV (control)., Results: In Western blots, RBS-AV bound to alpha-latrotoxin and similar widow spider proteins in all venoms tested, indicating antigenic similarity with proteins found in RBS venom. Antivenom prevented the typical in vitro muscle contracture and loss of twitch tension seen with alpha-latrotoxin and the venoms tested. Control mice rapidly developed signs of envenomation, but mice treated with RBS-AV remained free of signs of envenomation., Conclusion: RBS-AV prevented both in vitro and in vivo toxicity from Latrodectus venoms and alpha-latrotoxin in mice. These data suggest that RBS-AV may be clinically effective in the treatment of envenomation resulting from the bite of other widow spiders.

Tick-borne encephalitis is usually caused by infection with one of two flaviviruses: Russian spring summer encephalitis virus (RSSEV) or Central European encephalitis virus (CEEV). We previously demonstrated that gene gun inoculation of mice with naked DNA vaccines expressing the prM and E genes of these viruses resulted in long-lived homologous and heterologous protective immunity (Schmaljohn et al., 1997). To further evaluate these vaccines, we inoculated rhesus macaques by gene gun with the RSSEV or CEEV vaccines or with both DNA vaccines and compared resulting antibody titers with those obtained by vaccination with a commercial, formalin-inactivated vaccine administered at the human dose. Vaccinations were given at days 0, 30, and 70. All of the vaccines elicited antibodies detected by ELISA and by plaque-reduction neutralization tests. The neutralizing antibody responses persisted for at least 15 weeks after the final vaccination. Because monkeys are not uniformly susceptible to tick-borne encephalitis, the protective properties of the vaccines were assessed by passive transfer of monkey sera to mice and subsequent challenge of the mice with RSSEV or CEEV. One hour after transfer, mice that received 50 microl of sera from monkeys vaccinated with both DNA vaccines had circulating neutralizing antibody levels <20-80. All of these mice were protected from challenge with RSSEV or CEEV. Mice that received 10 microl of sera from monkeys vaccinated with the individual DNA vaccines, both DNA vaccines, or a commercial vaccine were partially to completely protected from RSSEV or CEEV challenge. These data suggest that DNA vaccines may offer protective immunity to primates similar to that obtained with a commercial inactivated-virus vaccine., (Copyright 1999 Academic Press.)

For 41 toothpastes available to European consumers in 1995, the cleaning efficacy was evaluated in comparison with abrasivity on dentin (RDA value). For cleaning power assessment, a modified pellicle cleaning ratio (PCR) measurement method was developed. The method is characterized by a five-day tea-staining procedure on bovine front teeth slabs on a rotating wheel, standardized brushing of the slabs in a V8 cross-brushing machine, and brightness measurement by a chromametric technique. All tested products were in accordance with the new DIN/ISO standard 11,609 for toothpastes in terms of dentin abrasivity. Not a single product exceeded an RDA value of 200. The majority of toothpastes (80%) had an RDA value below 100. Only three products surpassed the reference in cleaning power. Most products (73%) had a cleaning power (PCR value) between 20 and 80. The correlation between cleaning power and dentin abrasion was low (r = 0.66), which can be explained with the different influence on dentin and stains by factors like abrasive type, particle surface and size, as well as the chemical influence of other toothpaste ingredients. Some major trends could be shown on the basis of abrasive types. The ratio PCR to RDA was rather good in most silica-based toothpastes. A lower ratio was found in some products containing calcium carbonate or aluminum trihydrate as the only abrasive. The addition of other abrasives, such as polishing alumina, showed improved cleaning power. Some active ingredients, especially sequenstrants such as sodium tripolyphosphate or AHBP, also improve the PCR/RDA ratio by stain-dissolving action without being abrasive. The data for some special anti-stain products did not differ significantly from standard products. Compared with data measured in 1988, a general trend toward reduced abrasivity without loss of cleaning efficacy could be noticed on the European toothpaste market. This may be mostly due to the increased use of high-performance abrasives such as hydrated silica.

The problem of a juridical and administrative regulation for therapeutic drugs is analyzed. There are 3 concurring factors of public interest: 1. protection of the patient against dangerous side-effects, 2. promotion of new effective therapies. 3. position and responsibility of the physician. Risks and problems of control are discussed in the light of development of a new preparation. A scheme of functions in the clinical trial under auspices of medico-ethical postulations is mentioned. Restrictive facts on behalf of a quick development of drug therapy are discussed. The necessity of intensifying biological basic research is emphasized.