A Comprehensive Scientific Survey of Excipients Used in Currently Marketed, Therapeutic Biological Drug Products.

PURPOSE: The steady development of biotechnology-derived therapeutic biologics over the last few decades has generated drugs that are now standard medical treatments for a range of indications. While the development of protein products has surged in recent years, the formulation and delivery of these complex molecules have relied on drug-specific studies and, in some instances, data from non-proteinaceous drug products. The commonalities, trends, and gaps in excipient technologies used to support the development of therapeutic proteins largely remain unexplored due to the drug-specific nature of many formulations. METHODS: Using a comprehensive and relational database approach, we aimed to provide a scientific survey of all approved or licensed biotechnology-derived drug products with the goal of providing evidence-based information on common attributes and trending features in protein product excipients. We examined 665 formulations, and 395 unique formulations based on having unique excipients within them, that supported 211 therapeutic proteins as of June 2020. RESULTS: We report the prevalence of each excipient class and excipient chemical used in eight different drug types including monoclonal antibodies, antibody conjugates, cytokines and growth factors, enzymes, polypeptide hormones, pulmonary surfactants, recombinant fusion proteins, and toxins. We also report the prevalence by excipient type among all therapeutic proteins, in the context of each drug's recommended pH range, concentration ranges for excipients, and route of administration. CONCLUSIONS: The results of our analyses indicate certain excipients common to monoclonal antibodies, cytokines, and polypeptide hormones. We also report on excipients unique to protein drug products, such as amino acids, solubilizers, and lyoprotectants. Overall, our report summarizes the current landscape of excipients used in marketed biotechnology-derived therapeutic biologic products.

Multifunctional TH1 cells define a correlate of vaccine-mediated protection against Leishmania major.

CD4+ T cells have a crucial role in mediating protection against a variety of pathogens through production of specific cytokines. However, substantial heterogeneity in CD4+ T-cell cytokine responses has limited the ability to define an immune correlate of protection after vaccination. Here, using multiparameter flow cytometry to assess the immune responses after immunization, we show that the degree of protection against Leishmania major infection in mice is predicted by the frequency of CD4+ T cells simultaneously producing interferon-gamma, interleukin-2 and tumor necrosis factor. Notably, multifunctional effector cells generated by all vaccines tested are unique in their capacity to produce high amounts of interferon-gamma. These data show that the quality of a CD4+ T-cell cytokine response can be a crucial determinant in whether a vaccine is protective, and may provide a new and useful prospective immune correlate of protection for vaccines based on T-helper type 1 (TH1) cells.

Reduction and selective oxo group silylation of the uranyl dication.

Uranium occurs in the environment predominantly as the uranyl dication [UO2]2+. Its solubility renders this species a problematic contaminant which is, moreover, chemically extraordinarily robust owing to strongly covalent U-O bonds. This feature manifests itself in the uranyl dication showing little propensity to partake in the many oxo group functionalizations and redox reactions typically seen with [CrO2]2+, [MoO2]2+ and other transition metal analogues. As a result, only a few examples of [UO2]2+ with functionalized oxo groups are known. Similarly, it is only very recently that the isolation and characterization of the singly reduced, pentavalent uranyl cation [UO2]+ has been reported. Here we show that placing the uranyl dication within a rigid and well-defined molecular framework while keeping the environment anaerobic allows simultaneous single-electron reduction and selective covalent bond formation at one of the two uranyl oxo groups. The product of this reaction is a pentavalent and monofunctionalized [O = U...OR]+ cation that can be isolated in the presence of transition metal cations. This finding demonstrates that under appropriate reaction conditions, the uranyl oxo group will readily undergo radical reactions commonly associated only with transition metal oxo groups. We expect that this work might also prove useful in probing the chemistry of the related but highly radioactive plutonyl and neptunyl analogues found in nuclear waste.

"Exceptionally challenging time for all of us": Qualitative study of the COVID-19 experiences of partners of diplomatic personnel.

BACKGROUND: Although the romantic partners of diplomatic personnel frequently accompany their spouses to overseas postings and face the challenges of having to adjust to new cultures and separation from friends and family, they have rarely been the focus of academic research. This study explores the lived experiences of the partners/spouses of diplomatic personnel from the United Kingdom's Foreign, Commonwealth and Development Office (FCDO) during the COVID-19 pandemic. METHODS: Partners of FCDO staff took part in semi-structured interviews about how COVID-19 had affected their lives and their perceptions of the organisation's response to the pandemic. Thematic analysis was used to analyse the data. RESULTS: Eleven partners of FCDO staff took part, who between them had lived in 14 different countries during the pandemic. The analysis identified six key themes: deployment-specific challenges such as travel restrictions, quarantine and evacuation; children; impacts of the pandemic including financial and psychological; perceptions of the organisational response to COVID-19; support and help-seeking; and suggestions for the future. Overall participants reported experiencing a number of challenges, many of which left them feeling powerless and not in control of their own lives. Participants frequently described a lack of clarity around policies and support. Social support appeared to be valuable, but many participants wanted more support from the organisation and from informal networks. CONCLUSIONS: Diplomatic (and similar) organisations could enhance the wellbeing of the partners of their staff through improved communication and support. Keeping families informed about restrictions, requirements, policies and available help during a crisis, and reaching out to them to offer advice and support, would likely be beneficial. It is important that lessons are learned from the COVID-19 crisis in order for organisations to be able to support their employees and families if another prolonged crisis were to occur.

Genetic mapping of the p47 L.3.2 mutation in Drosophilamelanogaster.

An EMS-based forward genetic screen was conducted in an apoptotic null background to identify genetic aberrations that contribute to regulation of cell growth in Drosophila melanogaster . The current work maps the genomic location of one of the identified mutants, L.3.2 . Genetic crosses conducted through the Fly-CURE consortium determined that the gene locus for the L.3.2 mutation is p47 on chromosome 2R.

Acetate and hypertonic stress stimulate vacuole membrane fission using distinct mechanisms.

Vacuoles in plants and fungi play critical roles in cell metabolism and osmoregulation. To support these functions, vacuoles change their morphology, e.g. they fragment when these organisms are challenged with draught, high salinity or metabolic stress (e.g. acetate accumulation). In turn, morphology reflects an equilibrium between membrane fusion and fission that determines size, shape and copy number. By studying Saccharomyces cerevisiae and its vacuole as models, conserved molecular mechanisms responsible for fusion have been revealed. However, a detailed understanding of vacuole fission and how these opposing processes respond to metabolism or osmoregulation remain elusive. Herein we describe a new fluorometric assay to measure yeast vacuole fission in vitro. For proof-of-concept, we use this assay to confirm that acetate, a metabolic stressor, triggers vacuole fission and show it blocks homotypic vacuole fusion in vitro. Similarly, hypertonic stress induced by sorbitol or glucose caused robust vacuole fission in vitro whilst inhibiting fusion. Using wortmannin to inhibit phosphatidylinositol (PI) -kinases or rGyp1-46 to inactivate Rab-GTPases, we show that acetate stress likely targets PI signaling, whereas osmotic stress affects Rab signaling on vacuole membranes to stimulate fission. This study sets the stage for further investigation into the mechanisms that change vacuole morphology to support cell metabolism and osmoregulation.

"In the office nine to five, five days a week those days are gone": qualitative exploration of diplomatic personnel's experiences of remote working during the COVID-19 pandemic.

BACKGROUND: Many employees had to work remotely during the COVID-19 pandemic. Literature suggests there are both challenges and benefits to remote working and that remote working can have detrimental effects on mental health. This study aimed to explore diplomatic personnel's perceptions and experiences of working from home during the pandemic. METHODS: Twenty-five employees of the Foreign, Commonwealth and Development Office took part in semi-structured interviews. Thematic analysis was carried out to extract recurring themes from the data. RESULTS: Seven main themes emerged from the data: impact of the pandemic on work; relationships with colleagues; benefits of working from home; challenges of working from home; family; moving posts during the pandemic; and perceptions and predictions of post-pandemic work. Participants provided mixed views on how remote working had affected productivity and relationships with colleagues. Benefits of working from home included greater freedom and flexibility; new opportunities; and inclusivity of remote meetings. Challenges included being in different time zones to the countries they were working for; unsuitable home ergonomics; technological issues; and difficulties finding appropriate work-life balance. Those with young children reported difficulties juggling work and childcare. Adjusting to new posts at a time when staff were working remotely appeared particularly challenging. However, most did not want or expect to return to entirely office-based work. They predicted a hybrid model of working in the future, involving both office work and remote work; they stressed the importance of flexibility and suggested there would not be a one-size-fits-all approach to returning to face-to-face work. CONCLUSIONS: Remote working during the COVID-19 pandemic has changed the ways in which employees work, showing them that they do not have to be in the office to successfully achieve their work goals and leaving many wanting flexibility to make their own decisions about working from home (or not). There are both benefits and challenges to remote working; managers can take steps to reduce some of the challenges by being available to support their employees, organising regular remote meetings and allowing employees autonomy in terms of when and where they work.

National review of reported Yellow fever vaccine incidents in the UK.

BACKGROUND: Yellow fever (YF) vaccination is the single most important preventative measure against YF infection, however the live attenuated vaccine has associated serious adverse events. All YF vaccinations in England, Wales and Northern Ireland (EWNI) are administered in YF Vaccination Centres and comply with National Travel Health Network and Centre (NaTHNaC) Conditions of Designation and Code of Practice, including reporting of vaccine incidents to NaTHNaC. In this study we evaluated the number and type of YF vaccine incidents in EWNI to identify areas for improvement. METHODS: NaTHNaC's telephone advice line database was retrospectively searched from 1st January 2016 to 31st December 2018 for YF vaccine incidents. Calls were categorised and analysed according to incident type. RESULTS: Seventy-eight YF vaccine incidents were reported from a total of 17250 calls. The commonest incident was incorrect timing of measles, mumps and rubella vaccine in relation to YF vaccine, where the recommended 28-day interval was not observed (n = 21). Other incidents included accidental partial vaccination (n = 11), inappropriate vaccination (n = 5) and invalid vaccination due to expiry or cold chain breach (n = 4). Inadvertent vaccination in contraindicated individuals occurred in two travellers with thymectomies (resulting in one death), and five immunocompromised travellers. CONCLUSIONS: YF vaccine incidents represent a small proportion of total calls. Similar incidents likely occur with other vaccines, but YF vaccine incidents are of particular concern; whilst most incidents were not harmful, vaccination in contraindicated individuals resulted in one death. These findings helped to inform new guidance and update training for staff in YF vaccination centres.

Role of nanocellulose in industrial and pharmaceutical sectors - A review.

Lignocellulosic biomass from agricultural residues serves as the critical component to replace synthetic polymeric materials in the coming future. Agricultural residues can be used to obtain cellulose by delignification followed by bleaching. Further, cellulose is converted into nanocellulose by various methods. Nanocellulose is used in multiple pharmaceutical applications as a polymer in hydrogels, transdermal drug delivery systems, aerogels, wound healing dressing materials, as superdisintegrants in fast dissolving tablets, emulgel, microparticles, gels, foams, thickening agents, stabilizers, cosmetics, medical implants, tissue engineering, liposomes, food and composites, etc. This review provides detailed knowledge about the nature of nanocellulose regarding its high surface area, high polymerization, loading, and binding capacity of hydrophilic and hydrophobic active pharmaceutical ingredients and significance of various applications of nanocellulose. Biocompatible and non-toxic, it makes it an ideal material for applications in the biomedical field. A significant advantage is a biocompatibility, which is non-toxic for many biomedical applications.

The nature of unsupported uranium-ruthenium bonds: a combined experimental and theoretical study.

Four new uranium-ruthenium complexes, [(Tren(TMS))URu(η(5)-C(5)H(5))(CO)(2)] (9), [(Tren(DMSB))URu(η(5)-C(5)H(5))(CO)(2)] (10), [(Ts(Tolyl))(THF)URu(η(5)-C(5)H(5))(CO)(2)] (11), and [(Ts(Xylyl))(THF)URu(η(5)-C(5)H(5))(CO)(2)] (12) [Tren(TMS)=N(CH(2)CH(2)NSiMe(3))(3); Tren(DMSB)=N(CH(2)CH(2)NSiMe(2)tBu)(3)]; Ts(Tolyl)=HC(SiMe(2)NC(6)H(4)-4-Me)(3); Ts(Xylyl)=HC(SiMe(2)NC(6)H(3)-3,5-Me(2))(3)], were prepared by a salt-elimination strategy. Structural, spectroscopic, and computational analyses of 9-12 shows: i) the formation of unsupported uranium-ruthenium bonds with no isocarbonyl linkages in the solid state; ii) ruthenium-carbonyl backbonding in the [Ru(η(5)-C(5)H(5))(CO)(2)](-) ions that is tempered by polarization of charge within the ruthenium fragments towards uranium; iii) closed-shell uranium-ruthenium interactions that can be classified as predominantly ionic with little covalent character. Comparison of the calculated U-Ru bond interaction energies (BIEs) of 9-12 with the BIE of [(η(5)-C(5)H(5))(3)URu(η(5)-C(5)H(5))(CO)(2)], for which an experimentally determined U-Ru bond disruption enthalpy (BDE) has been reported, suggests BDEs of approximately 150 kJ mol(-1) for 9-12.

Air travel and COVID-19 prevention in the pandemic and peri-pandemic period: A narrative review.

Air travel during the COVID-19 pandemic is challenging for travellers, airlines, airports, health authorities, and governments. We reviewed multiple aspects of COVID peri-pandemic air travel, including data on traveller numbers, peri-flight prevention, and testing recommendations and in-flight SARS-CoV-2 transmission, photo-epidemiology of mask use, the pausing of air travel to mass gathering events, and quarantine measures and their effectiveness. Flights are reduced by 43% compared to 2019. Hygiene measures, mask use, and distancing are effective, while temperature screening has been shown to be unreliable. Although the risk of in-flight transmission is considered to be very low, estimated at one case per 27 million travellers, confirmed in-flight cases have been published. Some models exist and predict minimal risk but fail to consider human behavior and airline procedures variations. Despite aircraft high-efficiency filtering, there is some evidence that passengers within two rows of an index case are at higher risk. Air travel to mass gatherings should be avoided. Antigen testing is useful but impaired by time lag to results. Widespread application of solutions such as saliva-based, rapid testing or even detection with the help of "sniffer dogs" might be the way forward. The "traffic light system" for traveling, recently introduced by the Council of the European Union is a first step towards normalization of air travel. Quarantine of travellers may delay introduction or re-introduction of the virus, or may delay the peak of transmission, but the effect is small and there is limited evidence. New protocols detailing on-arrival, rapid testing and tracing are indicated to ensure that restricted movement is pragmatically implemented. Guidelines from airlines are non-transparent. Most airlines disinfect their flights and enforce wearing masks and social distancing to a certain degree. A layered approach of non-pharmaceutical interventions, screening and testing procedures, implementation and adherence to distancing, hygiene measures and mask use at airports, in-flight and throughout the entire journey together with pragmatic post-flight testing and tracing are all effective measures that can be implemented. Ongoing research and systematic review are indicated to provide evidence on the utility of preventive measures and to help answer the question "is it safe to fly?".

Stability-indicating RP-HPLC method development and validation for duloxetine hydrochloride in tablets.

This paper describes the development of a stability-indicating RP-HPLC method for duloxetine hydrochloride (DLX) in the presence of its degradation products generated from forced decomposition studies. The drug substance was found to be susceptible to stress conditions of acid, base, oxidation, wet heat, dry heat, and photodegradation. The drug was found to be stable to the dry heat condition attempted. Successful separation of the drug from the degradation products formed under stress conditions was achieved on a Phenomenex C18 column (250 x 4.6 mm id, 5 microm particle size) using acetonitrile-methanol-0.032 M ammonium acetate buffer (55 + 05 + 40, v/v/v) as the mobile phase at a flow rate of 1.0 mL/min at 40 degrees C temperature. Quantification was achieved with photodiode array detection at 290 nm over the concentration range 0.2-5 microg/mL with mean recovery of 101.048 +/- 0.53% for DLX by the RP-HPLC method. Statistical analysis proved the method is repeatable, specific, and accurate for estimation of DLX. Because the method could effectively separate the drug from its degradation products, it can be used as a stability-indicating method.

Reprint of: Air travel and COVID-19 prevention in the pandemic and peri-pandemic period: A narrative review.

Air travel during the COVID-19 pandemic is challenging for travellers, airlines, airports, health authorities, and governments. We reviewed multiple aspects of COVID peri-pandemic air travel, including data on traveller numbers, peri-flight prevention, and testing recommendations and in-flight SARS-CoV-2 transmission, photo-epidemiology of mask use, the pausing of air travel to mass gathering events, and quarantine measures and their effectiveness. Flights are reduced by 43% compared to 2019. Hygiene measures, mask use, and distancing are effective, while temperature screening has been shown to be unreliable. Although the risk of in-flight transmission is considered to be very low, estimated at one case per 27 million travellers, confirmed in-flight cases have been published. Some models exist and predict minimal risk but fail to consider human behavior and airline procedures variations. Despite aircraft high-efficiency filtering, there is some evidence that passengers within two rows of an index case are at higher risk. Air travel to mass gatherings should be avoided. Antigen testing is useful but impaired by time lag to results. Widespread application of solutions such as saliva-based, rapid testing or even detection with the help of "sniffer dogs" might be the way forward. The "traffic light system" for traveling, recently introduced by the Council of the European Union is a first step towards normalization of air travel. Quarantine of travellers may delay introduction or re-introduction of the virus, or may delay the peak of transmission, but the effect is small and there is limited evidence. New protocols detailing on-arrival, rapid testing and tracing are indicated to ensure that restricted movement is pragmatically implemented. Guidelines from airlines are non-transparent. Most airlines disinfect their flights and enforce wearing masks and social distancing to a certain degree. A layered approach of non-pharmaceutical interventions, screening and testing procedures, implementation and adherence to distancing, hygiene measures and mask use at airports, in-flight and throughout the entire journey together with pragmatic post-flight testing and tracing are all effective measures that can be implemented. Ongoing research and systematic review are indicated to provide evidence on the utility of preventive measures and to help answer the question "is it safe to fly?".

To err is human: Clinical incident calls to a national travel health advice line.

The National Travel Health Network and Centre (NaTHNaC) offers a telephone advice line for travel health practitioners in the UK. In this study we review clinical incidents concerning vaccines or malaria prophylaxis reported between 2016 and 2018. Two-hundred-and-fifty-one clinical incident calls were recorded, and commonly concerned scheduling or dosing errors. Vaccine scheduling errors accounted for 103 calls (41%), predominantly due to hepatitis A or hepatitis B vaccination either alone or in combination (65/103, 63%). Administration of yellow fever vaccine within 28 days of measles, mumps and rubella accounted for a further 15 (15%) calls. Twenty-six (10%) calls reported administration of a vaccine that was not recommended either for the destination or contraindicated in the traveller. Yellow fever was the commonest single vaccine discussed in 28.4% of vaccine clinical incidents reported. By highlighting common mistakes, we hope to raise awareness of common issues and improve practice in travel health.

Pre-travel malaria enquiries to the United Kingdom national travel advice line 2016: Advice mainly needed on malaria maps and risk groups.

BACKGROUND: Malaria prevention in travellers can be complex and requires consideration of a number of factors. UK healthcare professionals providing pre-travel malaria advice can access specialist support from the National Travel Health Network and Centre (NaTHNaC) telephone advice line. The aim of this study is to characterise queries to the NaTHNaC telephone advice line regarding pre-travel malaria advice. METHOD: Telephone calls received to NaTHNaC's advice line are recorded using an online data capture form. All calls relating to malaria advice during 2016 were selected and data extracted. Analysis was undertaken using Microsoft Excel and STATA. RESULTS: During 2016, 1803 malaria-related calls were received; the majority from general practice and calls were from across the UK. The most common type of pre-travel malaria query was country-specific followed by travellers with special health needs. Many queries related to pregnant and breastfeeding travellers, children under 5 years and travellers over 60 years. CONCLUSIONS: This review presents a large and exceptional dataset and reflects the ambiguity amongst some healthcare professionals regarding malaria advice. We have identified potential knowledge gaps, and as a result will strengthen future guidance, enhance existing malaria maps, and inform the development of future clinical educational activity.

Biodistribution and toxicological evaluation of micron- and nano-sized erythrocyte-derived optical particles in healthy Swiss Webster mice.

Particle-based systems provide a capability for the delivery of imaging and/or therapeutic payloads. We have engineered constructs derived from erythrocytes, and doped with the FDA-approved near infrared dye, indocyanine green (ICG). We refer to these optical particles as NIR erythrocyte-mimicking transducers (NETs). A particular feature of NETs is that their diameters can be tuned from micron- to nano-scale. Herein, we investigated the effects of micron- (≈2.6 µm diameter), and nano- (≈145 nm diameter) sized NETs on their biodistribution, and evaluated their acute toxicity in healthy Swiss Webster mice. Following tail vein injection of free ICG and NETs, animals were euthanized at various time points up to 48 hours. Fluorescence analysis of blood showed that nearly 11% of the injected amount of nano-sized NETs (nNETs) remained in blood at 48 hours post-injection as compared to ≈5% for micron-sized NETs (µNETs). Similarly, at this time point, higher levels of nNETs were present in various organs including the lungs, liver, and spleen. Histological analyses of various organs, extracted at 24 hours post-injection of NETs, did not show pathological alterations. Serum biochemistry profiles, in general, did not show elevated levels of the various analyzed biomarkers associated with liver and kidney functions. Values of various hematological profiles remained within the normal ranges following the administration of µNETs and nNETs. Results of this study suggest that erythrocyte-derived particles can potentially provide a non-toxic platform for delivery of ICG.

Computational density functional study of polypyrrolic macrocycles: analysis of actinyl-oxo to 3d transition metal bonding.

Density functional theoretical methods are used to study heterobimetallic compounds of a new form of binucleating Schiff-base polypyrrolic macrocycle, denoted [An(VI)O(2)(1)H(2)L], [An(V)O(2)(1)H(2)L](-), [An(VI)O(2)(TM)L] and [An(V)O(2)(TM)L](-), and containing actinyl ions AnO(2)(n+) (An = U, Np, Pu; n = 1, 2) and 3d transition metals (TM): no TM = 1, Mn = 2, Fe = 3, Co = 4, and Zn = 5. Calculated bond orders (TM-O2 = 0.36 to 0.81) provide evidence for partial bond formation between the transition metal (TM) and the actinyl-endo-oxygen for all 24 cases studied. Redox potentials for [An(VI)O(2)(1)H(2)L]/[An(V)O(2)(1)H(2)L](-) couples were found to have the same Np(VI/V) > Pu(VI/V) > U(VI/V) trend as previously studied for the [AnO(2)(H(2)O)(5)](2+/1+) couples, where Np(VI) is the most easily reduced to Np(V). Extrapolation from the earlier penta-aqua actinyl results is used to predict [An(VI)O(2)(1)H(2)L]/[An(V)O(2)(1)H(2)L](-) redox couples of U = -1.10 eV, Np = 0.25 eV, and Pu = 0.01 eV. The calculated redox potential for [U(VI)O(2)(1)H(2)L]/[U(V)O(2)(1)H(2)L](-) is within 0.08 eV of the value found by cyclic voltammetry (-1.18 eV, in THF/NBu(n)(4)BF(4) solvent).