Phaseguide assisted liquid lamination for magnetic particle-based assays

We have developed a magnetic particle-based assay platform in which functionalised magnetic particles are transferred sequentially through laminated volumes of reagents and washing buffers. Lamination of aqueous liquids is achieved via the use of phaseguide technology; microstructures that control the advancing air–liquid interface of solutions as they enter a microfluidic chamber. This allows manual filling of the device, eliminating the need for external pumping systems, and preparation of the system requires only a few minutes. Here, we apply the platform to two on-chip strategies: (i) a one-step streptavidin–biotin binding assay, and (ii) a two-step C-reactive protein immunoassay. With these, we demonstrate how condensing multiple reaction and washing processes into a single step significantly reduces procedural times, with both assay procedures requiring less than 8 seconds

Biosimilar Pegfilgrastim: Improving Access and Optimising Practice to Supportive Care that Enables Cure

Febrile neutropenia (FN) is a serious complication of chemotherapy, which can cause significant morbidity and mortality, result in dose delays and reductions and, ultimately, reduce cancer survival. Over the past decade, the availability of biosimilar filgrastim (short-acting granulocyte colony-stimulating factor [G-CSF]) has transformed patient access, with clear evidence of clinical benefit at preventing FN at reduced costs. In 2019, seven biosimilar pegfilgrastims (long-acting G-CSFs) were licensed, creating optimal market conditions and choice for prescribers. FN affects up to 117 per 1000 cancer patients, with mortality rates in the range of 2–21%. By reducing FN incidence and improving chemotherapy relative dose intensity (RDI), G-CSF has been associated with a 3.2% absolute survival benefit. Guidelines recommend primary prophylaxis and that filgrastim be administered for 10–14 days, while pegfilgrastim is administered once per cycle. When taken according to the guidelines, pegfilgrastim and filgrastim are equally effective. However, in routine clinical practice, filgrastim is often under-dosed (< 7 days) and has been shown to be inferior to pegfilgrastim at reducing FN incidence, hospitalisations and maintaining RDI. Once-per-cycle administration with pegfilgrastim might also aid patient adherence. The introduction of biosimilar pegfilgrastim should instigate a rethink of neutropenia management. Biosimilar pegfilgrastim

Changes in antibiotic use in Dutch hospitals over a six-year period: 1997 to 2002

OBJECTIVE: To analyse trends in antibiotic use in Dutch hospitals over the period 1997 to 2002. METHODS: Data on the use of antibiotics and hospital resource indicators were obtained by distributing a questionnaire to all Dutch hospital pharmacies. Antibiotic use was expressed as the number of defined daily doses (DDD) per 100 patient-days and as DDD per 100 admissions. RESULTS: Between 1997 and 2002, the mean length of stay decreased by 18%. The mean number of admissions remained almost constant. Total antibiotic use significantly increased by 24%, from 47.2 in 1997 to 58.5 DDD per 100 patient-days in 2002 (p<0.01), whereas expressed as DDD per admissions it remained constant. Antibiotic use varied greatly between the hospitals. Moreover, the mean number of DDD per hospital of amoxicillin with clavulanic acid, clarithromycin, cefazolin, clindamycin and ciprofloxacin increased by 16, 38, 39, 50 and 52%, respectively. Total antibiotic use was higher in university hospitals than in general hospitals. CONCLUSIONS: Between 1997 and 2002, patients hospitalised in the Netherlands did not receive more antibiotics but, since they remained in the hospital for fewer days, the number of DDD per 100 patient-days increased. For macrolides, lincosamides and fluoroquinolones increases in both DDD per 100 patient-days and in DDD per 100 admissions were observed. It is arguable whether these trends result in an increase in selection pressure towards resistance in the hospitals. Continuous surveillance of antibiotic use and resistance is warranted to maintain efficacy and safety of antibiotic treatment

The market of biopharmaceutical medicines: A snapshot of a diverse industrial landscape

Background: Biopharmaceutical medicines represent a growing share of the global pharmaceutical market, and with many of these biopharmaceutical products facing loss of exclusivity rights, also biosimilars may now enter the biopharmaceutical market. Objectives: This study aims to identify and document which investment and development strategies are adopted by industrial players in the global biopharmaceutical market. Methods: A descriptive analysis was undertaken of the investment and development strategies of the top 25 pharmaceutical companies according to 2015 worldwide prescription drug sales. Strategies were documented by collecting data on manufacturing plans, development programs, acquisition and collaboration agreements, the portfolio and pipeline of biosimilar, originator and next-generation biopharmaceutical products. Data were extracted from publicly available sources. Results: Various investment and development strategies can be identified in the global biopharmaceutical market: (a) development of originator biopharmaceuticals, (b) investment in biotechnology, (c) development of next-generation biopharmaceuticals, (d) development of biosimilars, (e) investment in emerging countries, and (f) collaboration between companies. In the top 25 pharmaceutical companies almost every company invests in originator biopharmaceuticals and in biotechnology in general, but only half of them develops next-generation biopharmaceuticals. Furthermore, only half of them invest in development of biosimilars. The companies' biosimilar pipeline is mainly focused on development of biosimilar monoclonal antibodies and to some extent on biosimilar insulins. A common strategy is collaboration between companies and investment in emerging countries. Conclusions: A snapshot of investment and development strategies used by industrial players in the global biopharmaceutical market shows that all top 25 pharmaceutical companies are engaged in the biopharmaceutical market and that this industrial landscape is diverse. Companies do not focus on a single strategy, but are involved in multiple investment and development strategies. A common strategy to market biopharmaceuticals is collaboration between companies. These collaborations can as well be used to gain access in regions the company has less experience with. With patents expiring for some of the highest selling monoclonal antibodies, this snapshot highlights the interest of companies to invest in the development of these molecules and/or enter into collaborations to create access to these molecules

The risk of overanticoagulation in patients with heart failure on coumarin anticoagulants

Heart failure has been identified as a risk factor for increased coumarin anticoagulant responsiveness in several small-scale experiments. Epidemiological studies quantifying the risk of overanticoagulation by heart failure in a non-selected population on coumarins are scarce. Therefore, we investigated whether patients with heart failure have an increased risk of overanticoagulation and determined the effect of incidental heart failure on coumarin dose requirements. A cohort study of all patients was performed from an outpatient anticoagulation clinic treated with acenocoumarol or phenprocoumon between 1 January 1990 and 1 January 2000. All cohort members were followed until the first occurrence of an international normalized ratio (INR) ≥6.0, the last INR assessment, death, loss to follow-up, or end of the study period. Of the 1077 patients in the cohort, 396 developed an INR ≥6.0. The risk of overanticoag

Healthy and diseased placental barrier on-a-chip models suitable for standardized studies

Pathologies associated with uteroplacental hypoxia, such as preeclampsia are among the leading causes of maternal and perinatal morbidity in the world. Its fundamental mechanisms are yet poorly understood due to a lack of good experimental models. Here we report an in vitro model of the placental barrier, based on co-culture of trophoblasts and endothelial cells against a collagen extracellular matrix in a microfluidic platform. The model yields a functional syncytium with barrier properties, polarization, secretion of relevant extracellular membrane components, thinning of the materno-fetal space, hormone secretion, and transporter function. The model is exposed to low oxygen conditions and perfusion flow is modulated to induce a pathological environment. This results in reduced barrier function, hormone secretion, and microvilli as well as an increased nuclei count, characteristics of preeclamptic placentas. The model is implemented in a titer plate-based microfluidic platform fully amenable to high-throughput screening. We thus believe this model could aid mechanistic understanding of preeclampsia and other placental pathologies associated with hypoxia/ischemia, as well as support future development of effective therapies through target and compound screening campaigns.Statement of Significance: The human placenta is a unique organ sustaining fetus growth but is also the source of severe pathologies, such as Preeclampsia. Though leading cause of perinatal mortality in the world, preeclampsia remains untreatable due to a lack of relevant in vitro placenta models. To better understand the pathology, we have developed 3D placental barrier models in a microfluidic device. The platform allows parallel culture of 40 perfused physiological miniaturized placental barriers, comprising a differentiated syncytium and endothelium that have been validated for transporter functions. Exposure to a hypoxic and ischemic environment enabled the mimicking of preeclamptic characteristics in high-throughput, which we believe could lead to a better understanding of the pathology as well as support future effective therapies development.</p

The arrival of biosimilar monoclonal antibodies in oncology: clinical studies for trastuzumab biosimilars

The monoclonal antibody trastuzumab (Herceptin®), which targets the human epidermal growth factor receptor 2 (HER2), is approved for the treatment of early breast and advanced breast and gastric cancer in which HER2 is overexpressed. Several biosimilar versions of trastuzumab are expected to enter the European market over the course of 2018 and 2019. The biosimilar development pathway consists of a comprehensive comparability exercise between the biosimilar candidate and the reference product, primarily focussing on data from analytical studies. Clinical studies for biosimilar candidates follow a different design to those for a new biological, as the aim is not to independently establish clinical benefit, but to confirm biosimilarity between the two agents. The different trastuzumab biosimilar candidates have followed diverse pathways in their clinical development, with differences in clinical trial design (equivalence or non-inferiority design), patient population (those with metastatic or early breast cancer) and endpoint (overall response rate or pathological complete response). These differences in approach in phase 3 testing must be viewed in the totality of evidence demonstrating biosimilarity. Adequate information on the biosimilar approval pathway, the nature of the biosimilarity exercise and how the clinical development of a biosimilar is tailored to meet the licensing requirements can help informed decision making in clinical practice

Automated micro uidic cell culture of stem cell derived dopaminergic neurons in Parkinson's disease

AbstractParkinson’s disease is a slowly progressive neurodegenerative disease characterised by dysfunction and death of selectively vulnerable midbrain dopaminergic neurons leading mainly to motor dysfunction, but also other non-motor symptoms. The development of human in vitro cellular models with similar phenotypic characteristics to selectively vulnerable neurons is a major challenge in Parkinson’s disease research. We constructed a fully automated cell culture platform optimised for long-term maintenance and monitoring of induced pluripotent stem cell derived neurons in three dimensional microfluidic cell culture devices. The system can be flexibly adapted to various experimental protocols and features time-lapse imaging microscopy for quality control and electrophysiology monitoring to assess neuronal activity. Using this system, we continuously monitored the differentiation of Parkinson’s disease patient derived human neuroepithelial stem cells into midbrain specific dopaminergic neurons. Calcium imaging confirmed the electrophysiological activity of differentiated neurons and immunostaining confirmed the efficiency of the differentiation protocol. This system is the first example of a fully automated Organ-on-a-Chip culture and enables a versatile array of in vitro experiments for patient-specific disease modelling.</jats:p