The Brighton collaboration standardized module for vaccine benefit-risk assessment.

Vaccine Benefit-Risk (B-R) assessment consists of evaluating the benefits and risks of a vaccine and making a judgment whether the expected key benefits outweigh the potential key risks associated with its expected use. B-R supports regulatory and public health decision-making throughout the vaccine's lifecycle. In August 2021, the Brighton Collaboration's Benefit-Risk Assessment of VAccines by TechnolOgy (BRAVATO) Benefit-Risk Assessment Module working group was established to develop a standard module to support the planning, conduct and evaluation of structured B-R assessments for vaccines from different platforms, based on data from clinical trials, post-marketing studies and real-world evidence. It enables sharing of relevant information via value trees, effects tables and graphical depictions of B-R trade-offs. It is intended to support vaccine developers, funders, regulators and policy makers in high-, middle- or low-income countries to help inform decision-making and facilitate transparent communication concerning development, licensure, deployment and other lifecycle decisions.

Virtual reality for biochemistry education: the cellular factory.

Virtual Reality (VR) involves the coupling of visual communication hardware and software. The technology is capable of offering transformative educational practice and is increasingly being adopted within the biochemistry domain to better understand complex biochemical processes. This article documents a pilot study for the efficacy of VR in biochemistry education at undergraduate university level, focusing on the citric acid cycle: a central process for extracting energy in most cellular life forms. 10 participants were equipped with a VR headset and electrodermal activity (EDA) sensors, then immersed within a digital environment where they were able to learn the 8 main steps of the citric acid cycle within a virtual lab by completing 8 levels of activity. Post and pre surveys were taken, along with EDA readings throughout the students' interaction with VR. Research findings support the hypothesis that VR increase students' understanding, particularly if students feel engaged, stimulated and intend to use the technology. Moreover, EDA analysis indicated that the majority of participants demonstrate enhanced engagement in the education-based VR-experience as measured by elevated levels of skin conductance, a marker for autonomic arousal and a measure of engagement in an activity.

A Toolkit for Co-Designing towards Community-Based Active Ageing: Lessons Learned during Development.

It is increasingly recognized that community-based interventions for active ageing are more lasting and effective, yet the tools and methods for developing these interventions are lacking. This study investigates how to co-design community-based active ageing with older adults via the development of a toolkit to support this goal. Rapid reviews were conducted to understand (i) the effective behavioural change techniques for older adults, (ii) how to co-design with older adults for community-based interventions, and (iii) how to design tools for behaviour change that are easy to use. These reviews served as the foundation for developing a toolkit to support the co-design of community-based active ageing, which was evaluated during an interdisciplinary hackathon with older adults. Quantitative data from the surveys suggested that the confidence levels of students in developing interventions for health behaviour change and in co-designing with older adults increased after the hackathon, and the enjoyment of participating in the hackathon and of using the toolkit were statistically significant factors influencing this increase. Qualitative data from interviews and observations revealed how the toolkit was (un)used by the participants and what aspects of the toolkit can be improved. We encourage future researchers and practitioners to apply and adapt our research findings to the communities of older adults that they are working with.

Virtual conference design: features and obstacles.

The Covid-19 pandemic has forced a change in the way people work, and the location that they work from. The impact has caused significant disruption to education, the work environment and how social interactions take place. Online user habits have also changed due to lockdown restrictions and virtual conferencing software has become a vital cog in team communication. In result, a spate in software solutions have emerged in order to support the challenges of remote learning and working. The conferencing software landscape is now a core communication solution for company-wide interaction, team discussions, screen sharing and face-to-face contact. Yet the number of existing platforms is diverse. In this article, a systematic literature review investigation on virtual conferencing is presented. As output from the analysis, 67 key features and 74 obstacles users experience when interacting with virtual conferencing technologies are identified from 60 related open-source journal articles from 5 digital library repositories.

Structured benefit-risk evaluation for medicinal products: review of quantitative benefit-risk assessment findings in the literature.

A favorable benefit-risk profile remains an essential requirement for marketing authorization of medicinal drugs and devices. Furthermore, prior subjective, implicit and inconsistent ad hoc benefit-risk assessment methods have rightly evolved towards more systematic, explicit or "structured" approaches. Contemporary structured benefit-risk evaluation aims at providing an objective assessment of the benefit-risk profile of medicinal products and a higher transparency for decision making purposes. The use of a descriptive framework should be the preferred starting point for a structured benefit-risk assessment. In support of more precise assessments, quantitative and semi-quantitative methodologies have been developed and utilized to complement descriptive or qualitative frameworks in order to facilitate the structured evaluation of the benefit-risk profile of medicinal products. In addition, quantitative structured benefit-risk analysis allows integration of patient preference data. Collecting patient perspectives throughout the medical product development process has become increasingly important and key to the regulatory decision-making process. Both industry and regulatory authorities increasingly rely on descriptive structured benefit-risk evaluation and frameworks in drug, vaccine and device evaluation and comparison. Although varied qualitative methods are more commonplace, quantitative approaches have recently been emphasized. However, it is unclear how frequently these quantitative frameworks have been used by pharmaceutical companies to support submission dossiers for drug approvals or to respond to the health authorities' requests. The objective of this study has been to identify and review, for the first time, currently available, published, structured, quantitative benefit-risk evaluations which may have informed health care professionals and/or payor as well as contributed to decision making purposes in the regulatory setting for drug, vaccine and/or device approval. PLAIN LANGUAGE SUMMARY: Quantitative evaluation of the benefit-risk balance for medicinal products The review of the benefits and the risks associated with a medicinal product is called benefit-risk assessment. One of the conditions for a medicinal product to receive marketing authorization is to demonstrate a positive benefit-risk balance in which the benefits outweigh the risks. In order to enhance the transparency and consistency in the assessment of benefit-risk balance, frameworks and quantitative methods have been developed for decision making purposes and regulatory approvals of medicinal products. This article considers published quantitative benefit-risk evaluations which may have informed health care professionals and/or payor as well as contributed to decision making purposes in the regulatory setting for drug, vaccine and/or device approval.

Isolation of 1-(3',4'-Dihydroxyphenyl)-3-(2″,4″,6″-trihydroxyphenyl)-propan-2-ol from Grape Seed Extract and Evaluation of its Antioxidant and Antispasmodic Potential.

HPLC profiling of phenolics in grape seed extracts revealed a prominent peak of an unknown substance with concentrations up to 5.3%. Spectroscopic data allowed the identification of the compound 1 as 1-(3',4'-dihydroxyphenyl)-3-(2″,4″,6″-trihydroxyphenyl)-propan-2-ol. 1 is known to be produced from catechin and epicatechin through anaerobic bacteria from human, as well as the rat, intestines. It was hypothesized that the marc remaining after expression of juice from grapes became infested during storage, resulting in the production of 1. Because compound 1 is infrequently found in nature and has never been found in grape seeds, its presence may be considered a marker of an unwanted anaerobic bacterial process occurring during production. The antioxidant potential of 1 was determined by DPPH, ABTS, and FRAP (ferric reducing antioxidant power) assays and compared to the potential of the following compounds: phloroglucine, pyrogallol, gallic acid, catechin, and epicatechin. Furthermore, it was established that 1 significantly reduced guinea pig ileum contraction induced by histamine.

Impact of lixisenatide dose range on clinical outcomes with fixed-ratio combination iGlarLixi in patients with type 2 diabetes.

OBJECTIVE: To evaluate the lixisenatide dose range delivered by the iGlarLixi SoloSTAR pen (5-20 µg), alone or in fixed-ratio combination with insulin glargine (iGlar; iGlarLixi). METHODS: Data from three clinical studies were analyzed to assess lixisenatide efficacy and safety: a phase 2a trial assessing gastric emptying effects (ACT6011); a phase 2b dose-ranging trial (DRI6012); and a randomized controlled phase 3 trial comparing iGlarLixi with its components of iGlar and lixisenatide (LixiLan-O). Efficacy metrics included glycated hemoglobin A1c (A1C), post-prandial glucose (PPG) values following a standardized breakfast, fasting plasma glucose (FPG), and weight change. Occurrence of gastrointestinal adverse events was also assessed. RESULTS: ACT6011: lixisenatide doses from 5-20 µg once daily (QD) suppressed PPG; maximal reductions in mean PPG area under the curve were achieved with doses ≥12.5 µg QD, but doses as low as 5 µg achieved 44% of maximal reduction. DRI6012: lixisenatide doses 5-20 µg QD resulted in significant, dose-dependent decreases in A1C, percentage of patients achieving A1C <7.0%, and 2-h PPG levels; doses of 20 µg achieved complete suppression of PPG. LixiLan-O: iGlarLixi decreased 2-h PPG across the entire dose range. Lixisenatide dose was unrelated to reductions in FPG with iGlarLixi. Similar reductions in A1C were seen with iGlarLixi across all lixisenatide doses. CONCLUSIONS: This analysis demonstrates the clinical benefit of lixisenatide alone or in the formulation of iGlarLixi over the entire dose range of lixisenatide contained in iGlarLixi (5-20 µg), supporting the selection of the lixisenatide dose range delivered by the iGlarLixi SoloSTAR pen.

Reducing Antibiotic Exposure in Suspected Neonatal Sepsis.

Prolonged antibiotic therapy is associated with antimicrobial resistance and increased mortality in preterm infants. We evaluated the impact of an automatic stop order (ASO) and C-reactive protein (CRP) on the duration of antibiotics and level of intervention in infants screened for early-onset sepsis who had negative cultures. We introduced an ASO for low-risk infants, then, consequently, for all infants treated for suspected sepsis. We subsequently introduced a single CRP measurement at 36 hours. Between 2011 and 2014, 4 time periods were studied, at baseline and after each intervention. The proportion of infants receiving ≤48 hours of antibiotics increased from 19% to 72.5% ( P < .0001), whereas that of infants receiving avoidable doses (>48 hours and <5 days) fell from 50% to 0.8% ( P < .0001). The use of an ASO decreased the proportion receiving avoidable doses from 26/92 (28.3%) to 9/293 (3.1%); P < .0001. There was a reduction in lumbar punctures performed, from 35% to 20%; P = .015.

Positron Emission Tomography Assessment of the Intranasal Delivery Route for Orexin A.

Intranasal drug delivery is a noninvasive drug delivery route that can enhance systemic delivery of therapeutics with poor oral bioavailability by exploiting the rich microvasculature within the nasal cavity. The intranasal delivery route has also been targeted as a method for improved brain uptake of neurotherapeutics, with a goal of harnessing putative, direct nose-to-brain pathways. Studies in rodents, nonhuman primates, and humans have pointed to the efficacy of intranasally delivered neurotherapeutics, while radiolabeling studies have analyzed brain uptake following intranasal administration. In the present study, we employed carbon-11 radioactive methylation to assess the pharmacokinetic mechanism of intranasal delivery of Orexin A, a native neuropeptide and prospective antinarcoleptic drug that binds the orexin receptor 1. Using physicochemical and pharmacological analysis, we identified the methylation sites and confirmed the structure and function of methylated Orexin A (CH3-Orexin A) prior to monitoring its brain uptake following intranasal administration in rodent and nonhuman primate. Through positron emission tomography (PET) imaging of [11C]CH3-Orexin A, we determined that the brain exposure to Orexin A is poor after intranasal administration. Additional ex vivo analysis of brain uptake using [125I]Orexin A indicated intranasal administration of Orexin A affords similar brain uptake when compared to intravenous administration across most brain regions, with possible increased brain uptake localized to the olfactory bulbs.

Effects of the Adulteration Technique on the Near-Infrared Detection of Melamine in Milk Powder.

The United States Pharmacopeial Convention has led an international collaborative project to develop a toolbox of screening methods and reference standards for the detection of milk powder adulteration. During the development of adulterated milk powder reference standards, blending methods used to combine melamine and milk had unanticipated strong effects on the near-infrared (NIR) spectrum of melamine. The prominent absorbance band at 1468 nm of melamine was retained when it was dry-blended with skim milk powder but disappeared in wet-blended mixtures, where spray-dried milk powder samples were prepared from solution. Analyses using polarized light microscopy, Raman spectroscopy, dielectric relaxation spectroscopy, X-ray diffraction, and mass spectrometry indicated that wet blending promoted reversible and early Maillard reactions with lactose that are responsible for differences in melamine NIR spectra between wet- and dry-blended samples. Targeted detection estimates based solely on dry-blended reference standards are likely to overestimate NIR detection capabilities in wet-blended samples as a result of previously overlooked matrix effects arising from changes in melamine hydrogen-bonding status, covalent complexation with lactose, and the lower but more homogeneous melamine local concentration distribution produced in wet-blended samples. Techniques used to incorporate potential adulterants can determine the suitability of milk reference standards for use with rapid detection methods.

Influence of Degree-of-Polymerization and Linkage on the Quantification of Proanthocyanidins using 4-Dimethylaminocinnamaldehyde (DMAC) Assay.

Proanthocyanidins (PACs) are naturally occurring flavonoids possessing health beneficial bioactivities. Their quantification often utilizes the 4-dimethylaminocinnamaldehyde (DMAC) spectrophotometric assay with the assumption that molar absorption coefficients (MACs) are similar across the various PAC species. To assess the validity of this assumption, individual PAC monomers and oligomers were examined for their absorbance response with DMAC. Our results have shown that PAC dimers and trimers with interflavan linkage variations exhibited differential absorbance response. Absence of A-type linkage between the terminal and second units in PAC molecule not only impacts absorbance intensity at 640 nm but also elicits a prominent secondary 440 nm absorbance peak. Cranberry (A-type) and cocoa (B-type) oligomeric PACs exhibited differential absorbance (MACs) relationship with degree-of-polymerization. Thus, PAC structural variations have considerable impact on the resulting MAC. The use of DMAC assay in PAC quantification, especially in comparing across specific oligomers and compositions, should not assume MACs are similar.

Design and synthesis of a novel series of histamine H3 receptor antagonists through a scaffold hopping strategy.

Lead compounds 5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-benzamide (1), tetrahydro-pyran-4-carboxylic acid [((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-amide (2), and 3,5-dimethyl-isoxazole-4-carboxylic acid [((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-amide (3) discovered in our laboratory, displayed high histamine H3 receptor (H3R) affinity, good selectivity and weak human Ether-à-go-go-Related Gene (hERG) channel affinity with desirable overall physico-chemical and pharmacokinetic (PK) profiles. Herein, we describe the design and synthesis of a novel series of H3R antagonists utilizing a scaffold hopping strategy. Further structure-activity relationship (SAR) studies of the series culminated in the identification of ((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-naphthalene-2-carboxylic acid (tetrahydro-pyran-4-yl)-amide (4c) and -[4-((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-N-(tetrahydro-pyran-4-yl)-acetamide (4d), which exhibited good H3R affinity in vitro, good selectivity, and desirable PK properties. Compounds 4c and 4d were also assessed in cardiac safety experiments. In particular, the effects of the compounds on action potentials recorded from ventricular myocytes isolated from guinea pigs were used to screen compounds that not only displayed a low affinity towards hERG channel, but also had lower interference with other cardiac ion channels. Compound 4c did not alter the major parameters in this model system at ⩽10 µM, and no significant induction of any major haemodynamic effect when intravenously administered at 3mg/kg dose to anaesthetized mongrel dogs. Compound 4c is a new promising lead as orally potent and selective H3R antagonist belonging to a distinct structural class.

Cocoa extracts reduce oligomerization of amyloid-ß: implications for cognitive improvement in Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder, characterized by pathological aggregates of amyloid peptide-ß (Aß) and tau protein. Currently available therapies mediate AD symptoms without modifying disease progression. Polyphenol-rich diets are reported to reduce the risk for AD. OBJECTIVE: In the present study, we investigated the AD disease-modifying effects of cocoa, a rich source of flavanols, which are a class of polyphenols. We hypothesized that cocoa extracts interfere with amyloid-ß oligomerization to prevent synaptic deficits. METHODS: We tested the effects of three different cocoa extracts, viz. Natural, Dutched, and Lavado extracts, on Aß42 and Aß40 oligomerization, using photo-induced cross-linking of unmodified proteins technique. To assess the effects of cocoa extracts on synaptic function, we measured long term potentiation in mouse brain hippocampal slices exposed to oligomeric Aß. RESULTS: Our results indicate that cocoa extracts are effective in preventing the oligomerization of Aß, with Lavado extract being most effective. Lavado extract, but not Dutched extract, was effective in restoring the long term potentiation response reduced by oligomeric Aß. CONCLUSION: Our findings indicate that cocoa extracts have multiple disease-modifying properties in AD and present a promising route of therapeutic and/or preventative initiatives.

Identification and profiling of 3,5-dimethyl-isoxazole-4-carboxylic acid [2-methyl-4-((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)phenyl] amide as histamine H(3) receptor antagonist for the treatment of depression.

Lead optimization guided by histamine H3 receptor (H3R) affinity and calculated physico-chemical properties enabled simultaneous improvement in potency and PK properties leading to the identification of a potent, selective, devoid of hERG issues, orally bioavailable, and CNS penetrable H3R antagonist/inverse agonist 3h. The compound was active in forced-swimming tests suggesting its potential therapeutic utility as an anti-depressive agent. This Letter further includes its cardiovascular and neuropsychological/behavioral safety assessments.

Discovery of a potent, selective, and orally bioavailable histamine H3 receptor antagonist SAR110068 for the treatment of sleep-wake disorders.

Previous studies have shown that compound 1 displayed high affinity towards histamine H3 receptor (H3R), (human (h-H3R), K(i)=8.6 nM, rhesus monkey (rh-H3R), K(i)=1.2 nM, and rat (r-H3R), K(i)=16.5 nM), but exhibited high affinity for hERG channel. Herein, we report the discovery of a novel, potent, and highly selective H3R antagonist/inverse agonist 5a(SS) (SAR110068) with acceptable hERG channel selectivity and desirable pharmacological and pharmacokinetic properties through lead optimization sequence. The significant awakening effects of 5a(SS) on sleep-wake cycles studied by using EEG recording in rats during their light phase support its potential therapeutic utility in human sleep-wake disorders.

Synthesis, characterization, and biological assessment of the four stereoisomers of the H(3) receptor antagonist 5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl[1,3']bipyrrolidinyl-1'-yl)phenyl]benzamide.

This Letter describes the asymmetric synthesis of the four stereoisomers (8a-8d) of a potent and highly selective histamine H3 receptor (H3R) antagonist, 5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl[1,3']bipyrrolidinyl-1'-yl) phenyl]benzamide (1). The physico-chemical properties, in vitro H3R affinities and ADME of 8a-8d were determined. Stereoisomer 8c (2S,3'S) displayed superior in vitro H3R affinity over other three stereoisomers and was selected for further profiling in in vivo PK and drug safety. Compound 8c exhibited excellent PK properties with high exposure, desired brain to plasma ratio and reasonable brain half life. However, all stereoisomers showed similar unwanted hERG affinities.

Gap-freezing approach for shortening the lyophilization cycle time of pharmaceutical formulations-demonstration of the concept.

During gap freezing, vials are placed on a metal tray, which is separated from the shelf surface with a small air gap that eliminates significant conductive heat transfer from the shelf to the bottom of the vial. The purpose of this freezing approach is to reduce the lyophilization cycle time of various amorphous formulations by nearly isothermal freezing. Such isothermal freezing promotes the formation of large ice crystals, and thus large pores throughout the cake, which subsequently accelerates the primary drying rate. The nucleation temperature using gap freezing, for the experimental conditions tested, was in the range of -1°C to -6°C, much higher than the range of -10°C to -14°C found using conventional shelf freezing. Isothermal freezing becomes effective when the gap is greater than 3 mm. The pore sizes and cake resistance during primary drying for various formulations were determined using the pore diffusion model developed by Kuu et al. (Pharm Dev Technol, 2011, 16(4): 343-357). Reductions in primary drying time were 42% (for 10% sucrose), 45% (for 10% trehalose), and 33% (for 5% sucrose).

Discovery of aryl ureas and aryl amides as potent and selective histamine H3 receptor antagonists for the treatment of obesity (part I).

A series of structurally novel aryl ureas was derived from optimization of the HTS lead as selective histamine H3 receptor (H3R) antagonists. The SAR was explored and the data obtained set up the starting point and foundation for further optimization. The most potent tool compounds, as exemplified by compounds 2l, 5b, 5d, and 5e, displayed antagonism potencies in the subnanomolar range in in vitro human-H3R FLIPR assays and rhesus monkey H3R binding assays.