An Ontology-Based Artificial Intelligence Model for Medicine Side-Effect Prediction: Taking Traditional Chinese Medicine as An Example

In this work, an ontology-based model for AI-assisted medicine side-effect (SE) prediction is developed, where three main components, including the drug model, the treatment model, and the AI-assisted prediction model, of proposed model are presented. To validate the proposed model, an ANN structure is established and trained by two hundred and forty-two TCM prescriptions. These data are gathered and classified from the most famous ancient TCM book and more than one thousand SE reports, in which two ontology-based attributions, hot and cold, are introduced to evaluate whether the prescription will cause SE or not. The results preliminarily reveal that it is a relationship between the ontology-based attributions and the corresponding predicted indicator that can be learnt by AI for predicting the SE, which suggests the proposed model has a potential in AI-assisted SE prediction. However, it should be noted that, the proposed model highly depends on the sufficient clinic data, and hereby, much deeper exploration is important for enhancing the accuracy of the prediction

A rapid stability-indicating, fused-core HPLC method for simultaneous determination of β-artemether and lumefantrine in anti-malarial fixed dose combination products

Background: Artemisinin-based fixed dose combination (FDC) products are recommended by World Health Organization (WHO) as a first-line treatment. However, the current artemisinin FDC products, such as beta-artemether and lumefantrine, are inherently unstable and require controlled distribution and storage conditions, which are not always available in resource-limited settings. Moreover, quality control is hampered by lack of suitable analytical methods. Thus, there is a need for a rapid and simple, but stability-indicating method for the simultaneous assay of beta-artemether and lumefantrine FDC products. Methods: Three reversed-phase fused-core HPLC columns (Halo RP-Amide, Halo C18 and Halo Phenyl-hexyl), all thermostated at 30 degrees C, were evaluated. beta-artemether and lumefantrine (unstressed and stressed), and reference-related impurities were injected and chromatographic parameters were assessed. Optimal chromatographic parameters were obtained using Halo RP-Amide column and an isocratic mobile phase composed of acetonitrile and 1mM phosphate buffer pH 3.0 (52:48; V/V) at a flow of 1.0 ml/min and 3 mu l injection volume. Quantification was performed at 210 nm and 335 nm for beta-artemether and for lumefantrine, respectively. In-silico toxicological evaluation of the related impurities was made using Derek Nexus v2.0 (R). Results: Both beta-artemether and lumefantrine were separated from each other as well as from the specified and unspecified related impurities including degradants. A complete chromatographic run only took four minutes. Evaluation of the method, including a Plackett-Burman robustness verification within analytical QbD-principles, and real-life samples showed the method is suitable for quantitative assay purposes of both active pharmaceutical ingredients, with a mean recovery relative standard deviation (+/- RSD) of 99.7 % (+/- 0.7%) for beta-artemether and 99.7 % (+/- 0.6%) for lumefantrine. All identified beta-artemether-related impurities were predicted in Derek Nexus v2.0 (R) to have toxicity risks similar to beta-artemether active pharmaceutical ingredient (API) itself. Conclusions: A rapid, robust, precise and accurate stability-indicating, quantitative fused-core isocratic HPLC method was developed for simultaneous assay of beta-artemether and lumefantrine. This method can be applied in the routine regulatory quality control of FDC products. The in-silico toxicological investigation using Derek Nexus (R) indicated that the overall toxicity risk for beta-artemether-related impurities is comparable to that of beta-artemether API

AMERICANS AND GM FOOD: KNOWLEDGE, OPINION AND INTEREST IN 2004

This report presents the results from the third in a series of studies examining public perception of genetically modified (GM) food in the United States. All three studies were based on survey results of separate, nationally representative samples of approximately 1,200 Americans taken in 2001, 2003, and 2004. While the survey instrument on which the current report is based maintained many of the same measures of awareness and attitude as its two predecessors, it also included several new queries that assess the ability of respondents to recall specific news stories related to GM food, their interest in the topic, and where they would go to look for new information. Many questions that were repeated from previous years have changed considerably in the current survey. Some of the classic measures of awareness and opinion now incorporate an "unsure" response as choice supplied by the interviewer. While respondents were allowed to volunteer this response in the past, explicitly providing this option to respondents reduced guessing on knowledge-based questions and encouraged a more accurate representation of opinion than in the past. The report begins with an investigation of Americans' awareness and knowledge about the topic in general, their ability to recall related news stories, familiarity with laws and regulations as well as other questions designed to get at highly specific knowledge about agricultural biotechnology. Next, it details the effect of the new survey methodology on reported opinions about plant-based and animal-based GM food. Finally, it delves into a number of novel findings about interest in hypothetical television shows about GM food, desire for information on food labels, and reported behavior with regards to information seeking. Consistent with results from our previous studies and others, these findings suggest that the American public is generally unaware of GM food. Most Americans have heard or read little about it, are not aware of its prevalence in their lives, and are confused as to which type of GM products are available. Respondents struggled with factual questions related to GM food and the science behind it, could not recall news stories related to the topic, and were not very knowledgeable about laws regarding the labeling and testing of GM food. Americans are also unsure of their opinions about GM food and split in their assessments of the technology when forced to take a position. Americans say they are interested in the topic of GM food, specifically those topics related to human health. Respondents say they desire more information on food labels and report that they would like to see GM foods labeled as such. The majority of Americans admit they have never looked for information about GM food and most say they will search the Internet should the need arise.Research and Development/Tech Change/Emerging Technologies,

Accurate and efficient description of protein vibrational dynamics: comparing molecular dynamics and Gaussian models

Current all-atom potential based molecular dynamics (MD) allow the identification of a protein's functional motions on a wide-range of time-scales, up to few tens of ns. However, functional large scale motions of proteins may occur on a time-scale currently not accessible by all-atom potential based molecular dynamics. To avoid the massive computational effort required by this approach several simplified schemes have been introduced. One of the most satisfactory is the Gaussian Network approach based on the energy expansion in terms of the deviation of the protein backbone from its native configuration. Here we consider an extension of this model which captures in a more realistic way the distribution of native interactions due to the introduction of effective sidechain centroids. Since their location is entirely determined by the protein backbone, the model is amenable to the same exact and computationally efficient treatment as previous simpler models. The ability of the model to describe the correlated motion of protein residues in thermodynamic equilibrium is established through a series of successful comparisons with an extensive (14 ns) MD simulation based on the AMBER potential of HIV-1 protease in complex with a peptide substrate. Thus, the model presented here emerges as a powerful tool to provide preliminary, fast yet accurate characterizations of proteins near-native motion.Comment: 14 pages 7 figure

Emerging technologies for the non-invasive characterization of physical-mechanical properties of tablets

The density, porosity, breaking force, viscoelastic properties, and the presence or absence of any structural defects or irregularities are important physical-mechanical quality attributes of popular solid dosage forms like tablets. The irregularities associated with these attributes may influence the drug product functionality. Thus, an accurate and efficient characterization of these properties is critical for successful development and manufacturing of a robust tablets. These properties are mainly analyzed and monitored with traditional pharmacopeial and non-pharmacopeial methods. Such methods are associated with several challenges such as lack of spatial resolution, efficiency, or sample-sparing attributes. Recent advances in technology, design, instrumentation, and software have led to the emergence of newer techniques for non-invasive characterization of physical-mechanical properties of tablets. These techniques include near infrared spectroscopy, Raman spectroscopy, X-ray microtomography, nuclear magnetic resonance (NMR) imaging, terahertz pulsed imaging, laser-induced breakdown spectroscopy, and various acoustic- and thermal-based techniques. Such state-of-the-art techniques are currently applied at various stages of development and manufacturing of tablets at industrial scale. Each technique has specific advantages or challenges with respect to operational efficiency and cost, compared to traditional analytical methods. Currently, most of these techniques are used as secondary analytical tools to support the traditional methods in characterizing or monitoring tablet quality attributes. Therefore, further development in the instrumentation and software, and studies on the applications are necessary for their adoption in routine analysis and monitoring of tablet physical-mechanical properties

Determining Particle Size of Polymeric Micelles in Thermothickening Aqueous Solutions

Many active pharmaceutical ingredients (APIs) are poorly soluble and cause inadequate drug absorption. Soluplus®, a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, is a commercial excipient (BASF Corp) that enhances the solubility and bioavailability of many APIs. The mechanism of enhancement is related to the ability to form polymeric micelles in solution. These micelles store insoluble APIs in their hydrophobic interior and transport them to targeted sites in the body. An important characteristic of solubility enhancers is the particle size exhibited in solution before and after loading with APIs. This is most commonly determined by dynamic light scattering (DLS) methods. However, DLS measurements involving thermothickening polymer solutions can be complicated by the temperature dependence of viscosity and refractive index, solution properties that directly impact the size analysis algorithms in DLS. In this project, the temperature dependence of viscosity for Soluplus® solutions were evaluated and used as a correction to particle size measurements by DLS. Solution concentrations ranging 1.0% to 30.0% (w/w) of Soluplus® were studied from 5.0 °C to 40.0 °C using a cone-and-plate rheometer. Refractive index of Soluplus® solutions were also studied and used in the correction of particle size. It was found that correcting viscosity and refractive index data drastically affected hydrodynamic effective diameter, where viscosity was more highly weighted. The corrected particle size of Soluplus® solutions was inversely proportional to concentration with the 0.1% and 10.0% solutions showing effective diameters of 63.13 ± 0.76 nm and 24.98 ± 0.30 nm at 25.0 °C, respectively. By properly accounting for these variables in DLS algorithms, particle size of thermoresponsive polymer solutions can be more accurately characterized

Dynamics of aerosol size during inhalation : Hygroscopic growth of commercial nebulizer formulations

We thank the Elizabeth Blackwell Institute (EBI) for financial support through the EBI Early Career Research Fellowship awarded to AEH, and the EPSRC for financial support through a Leadership Fellowship awarded to JPR (grant reference EP/G007713/1). This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are creditedThe size of aerosol particles prior to, and during, inhalation influences the site of deposition within the lung. As such, a detailed understanding of the hygroscopic growth of an aerosol during inhalation is necessary to accurately model the deposited dose. In the first part of this study, it is demonstrated that the aerosol produced by a nebulizer, depending on the airflows rates, may experience a (predictable) wide range of relative humidity prior to inhalation and undergo dramatic changes in both size and solute concentration. A series of sensitive single aerosol analysis techniques are then used to make measurements of the relative humidity dependent thermodynamic equilibrium properties of aerosol generated from four common nebulizer formulations. Measurements are also reported of the kinetics of mass transport during the evaporation or condensation of water from the aerosol. Combined, these measurements allow accurate prediction of the temporal response of the aerosol size prior to and during inhalation. Specifically, we compare aerosol composed of pure saline (150 mM sodium chloride solution in ultrapure water) with two commercially available nebulizer products containing relatively low compound doses: Breath, consisting of a simple salbutamol sulfate solution (5 mg/2.5 mL; 1.7 mM) in saline, and Flixotide Nebules, consisting of a more complex stabilized fluticasone propionate suspension (0.25 mg/mL; 0.5 mM in saline. A mimic of the commercial product Tobi (60 mg/mL tobramycin and 2.25 mg/mL NaC1, pH 5.5-6.5) is also studied, which was prepared in house. In all cases, the presence of the pharmaceutical was shown to have a profound effect on the magnitude, and in some cases the rate, of the mass flux of water to and from the aerosol as compared to saline. These findings provide physical chemical evidence supporting observations from human inhalation studies, and suggest that using the growth dynamics of a pure saline aerosol in a lung inhalation model to represent nebulizer formulations may not be representative of the actual behavior of the aerosolized drug solutions. (C) 2014 Published by Elsevier B.V.Peer reviewe