An AI-powered patient triage platform for future viral outbreaks using COVID-19 as a disease model

Over the last century, outbreaks and pandemics have occurred with disturbing regularity, necessitating advance preparation and large-scale, coordinated response. Here, we developed a machine learning predictive model of disease severity and length of hospitalization for COVID-19, which can be utilized as a platform for future unknown viral outbreaks. We combined untargeted metabolomics on plasma data obtained from COVID-19 patients (n = 111) during hospitalization and healthy controls (n = 342), clinical and comorbidity data (n = 508) to build this patient triage platform, which consists of three parts: (i) the clinical decision tree, which amongst other biomarkers showed that patients with increased eosinophils have worse disease prognosis and can serve as a new potential biomarker with high accuracy (AUC = 0.974), (ii) the estimation of patient hospitalization length with ± 5 days error (R2 = 0.9765) and (iii) the prediction of the disease severity and the need of patient transfer to the intensive care unit. We report a significant decrease in serotonin levels in patients who needed positive airway pressure oxygen and/or were intubated. Furthermore, 5-hydroxy tryptophan, allantoin, and glucuronic acid metabolites were increased in COVID-19 patients and collectively they can serve as biomarkers to predict disease progression. The ability to quickly identify which patients will develop life-threatening illness would allow the efficient allocation of medical resources and implementation of the most effective medical interventions. We would advocate that the same approach could be utilized in future viral outbreaks to help hospitals triage patients more effectively and improve patient outcomes while optimizing healthcare resources

From Supersaturated Drug Delivery Systems to the Rising Era of Pediatric Formulations

The number of options available to drug discovery scientists to enhance the solubility of poorly soluble compounds by conventional formulation approaches is limited. In most cases, drug formulation is oriented toward the creation of a supersaturated solution upon contact with aqueous environment, often combined with solubilizing agents and precipitation inhibitors. The most popular formulations for achieving this target are the lipid-based formulations called self-emulsifying and self-microemulsifying drug delivery systems, SEDDS and SMEDDS, respectively. They offer enhanced absorption and hence enhanced oral bioavailability of lipophilic drugs, presenting the drug in solubilized form in vivo, avoiding dissolution, which can be the rate limiting step in drug absorption for sparingly soluble drugs. The production of high energy or rapid dissolving solid state formulations using drug particle engineering to enhance drug solubility and bioavailability is also applied. These formulations include solid dispersions, nanoparticles, co-ground mixtures etc. Furthermore, the development of prodrugs is also a useful strategy to improve the physicochemical, biopharmaceutical or pharmacokinetic properties of pharmacologically potent compounds, and thereby increase the developability and usefulness of a potential drug. Up to now, most medications were made for adults and children’s requirements were not taken into account. Since the recent adoption of Paediatric Regulations in the U.S. and E.U., there is a greater demand for age-appropriate medicines for children. The challenges in paediatric formulation development are mostly associated with the difficulty in defining design requirements for the intended dosage form that is most appropriate for the target patient population, due to the diversity of the paediatric population (range of ages, physical size and capabilities) that varies significantly from birth to age 12 yrs old along with the dosage flexibility. The last years there has been an effort to develop solid paediatric formulations that deliver the appropriate dose in a “user friendly” way and to find alternative drug delivery vehicles, such as mini-tablets, dairy products, and new taste masking techniques in order to improve drug acceptability. In addition, alternative routes of administration have been proposed such as inhalation and nasal administration

Supersaturated dissolution data and their interpretation: The TPGS-carbamazepine model case

Objectives: This study was undertaken to investigate the effect of d-alpha-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) on the dissolution of carbamazepine (CBZ) commercial tablets (Tegretol®) as a function of temperature and to modify the reaction-limited model of dissolution for the description of classical supersaturated dissolution data. Methods: Solubility studies were performed using various concentrations of (i) TPGS and (ii) silicon dioxide and microcrystalline cellulose, which are excipients of Tegretol® at 10, 25 and 37°C. Dissolution studies were carried out using Tegretol® tablets, 200 mg/tab. Key findings: The solubility of CBZ in the presence of TPGS was found to increase in a concentration-dependent manner at all temperatures studied. Classical supersaturated dissolution curves with concentration maxima higher than the corresponding solubility values in the presence of TPGS were observed only at 10°C. The model developed was based on a time-dependant expression for the forward microconstant of the CBZ-TPGS reaction at the solid-liquid interface and it was fitted successfully to the dissolution data of CBZ in the presence of TPGS at 10°C. Conclusions: Vitamin E TPGS increased the solubility of CBZ at all temperatures studied. The modification of the reaction-limited model of dissolution allowed us to describe classical supersaturated dissolution curves. © 2010 The Authors JPP © 2010 Royal Pharmaceutical Society

Novel milk-based oral formulations: Proof of concept

The aim of this study is to develop milk-based formulations for ionized and unionized lipophilic drugs. Solubility studies of the following non-steroidal anti-inflammatory drugs (NSAIDs): mefenamic acid, tolfenamic acid, ketoprofen, meloxicam, tenoxicam and nimesulide in phosphate- and glycine-NaOH buffers at nominal pH 8-12, were performed. The solubilities of cyclosporine and danazol in water-ethanol solutions were studied. NSAIDs-, cyclosporine-, danazol-, aspirin-milk oral liquid formulations were prepared by adding the appropriate volume of (i) NSAIDs-alkaline buffer solutions, (ii) water-ethanol solutions of cyclosporine and danazol and (iii) aspirin aqueous solution to 150-200. ml of milk. All the non-steroidal anti-inflammatory drugs exhibited increased solubility in the alkaline buffers. The actual pH values (range 6.7-7.7) of the final NSAIDs-milk formulations were very close to milk pH. The higher ethanol content in ethanol-water mixtures increased the solubility of danazol and cyclosporine. A 15. mg meloxicam-, a 100. mg cyclosporine- and a 500. mg aspirin-milk formulation was administered orally to healthy volunteers. All these formulations showed a satisfactory in vivo performance. The strong buffering capacity of milk that was observed and the high solubility of unionized drugs in ethanol allow the preparation of drug-milk formulations with enhanced pharmacokinetic properties. © 2010 Elsevier B.V

Biopharmaceutical classification based on solubility and dissolution: A reappraisal of criteria for hypothesis models in the light of the experimental observations

The diffusion layer model of drug dissolution is used for the simulation of oral drug absorption as well as for the analysis of experimental data. The governing role of saturation solubility in the rate of dissolution makes this parameter predominant for biopharmaceutical classification purposes. The hypothesis models and criteria associated with the use of solubility and dissolution for the biopharmaceutical classification of compounds and marketed drugs are reviewed in this article. The complex hydrodynamics in the in vitro dissolution apparatuses as well as the motility in the gastrointestinal tract do not allow the application of the diffusion layer model in these systems, as this has been built and verified in the rotating disk device. The solubilizing capacity of gastrointestinal fluids media is higher than the aqueous saturation solubility usually reported and used for biopharmaceutical purposes. Emphasis is given on the reaction-limited model of dissolution which provides a useful alternative not based on diffusion principles. Model independent dissolution parameters are more useful for regulators as our knowledge for the dissolution mechanism(s) under in vivo conditions is limited. © 2009 Nordic Pharmacological Society

Population pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide metabolite in patients with autoimmune glomerulonephritis

OBJECTIVES: To develop a simultaneous population pharmacokinetic model of cyclophosphamide (CY) and 4-hydroxycyclophosphamide (4-OH) in patients with glomerulonephritis. METHODS: In total, 23 patients participated in a pharmacokinetic evaluation using dense plasma sampling. A population pharmacokinetic model was developed in Monolix Suite 2020R1 that simultaneously describes the kinetics of CY and 4-OH. Several structural and residual error models were evaluated and patient variables were tested as potential covariates. The final model was selected based on visual predictive check and bootstrap. Simulations of plasma concentrations for various doses were conducted. KEY FINDINGS: A model including two compartments for CY and one for 4-OH was found to best describe the data. A proportional error model for both compounds was chosen. The following estimates were found for the main CY pharmacokinetic parameters: total clearance, 13.3 l/h with inter-individual variability (IIV) 32%, and central volume of distribution, 59.8 l with IIV 12%. The metabolite elimination rate constant was 4.3 h-1 with IIV 36% and the proportion of metabolism 64%. Sex was a significant covariate on the central volume of CY, with females exhibiting 25% lower value than males. CONCLUSIONS: A population pharmacokinetic model was developed for CY and 4-OH in patients with autoimmune glomerulonephritis. Simulations using various dose regimens allow for informed dosing before the initiation of therapy. © The Author(s) 2021. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: [email protected]

Review of the Third Conference of the Imaging Mass Spectrometry Society (IMSS 3): Accounts of a Hybrid Virtual and In-Person Meeting and the State and Future of the Field

The third annual conference of the Imaging Mass Spectrometry Society (IMSS3) was held October 3-6, 2021 in a hybrid format that included virtual and in-person attendance (Colorado Springs, CO). Here, we highlight many of the methods and applications presented, the state of the field, and some insights into the emerging areas in the field of imaging mass spectrometry. We also reflect upon the processes behind planning a hybrid conference and discuss the successes and challenges of the event in retrospect

Stability and physicochemical characterization of novel milk-based oral formulations

Purpose: The purpose of this work was to assess the colloidal stability of novel milk-based formulations. Methods: Milk-based formulations were prepared in situ by adding into milk alkaline- or ethanolic-drug solutions containing an array of drugs namely; ketoprofen, tolfenamic acid, meloxicam, tenoxicam and nimesulide, mefenamic acid, cyclosporine A, danazol and clopidogrel besylate. The produced formulations were characterized by means of dynamic lightscattering, ζ-potential studies, atomic force microscopy, fluorescence spectroscopy, Raman spectroscopy complemented with ab initio calculations and stability studies. Results: The presence of the drugs did not induce significant changes in most cases to the particle size and ζ-potential values of the emulsions pointing to the colloidal stability of these formulations. Raman spectroscopy studies revealed interactions of the drugs and the milk at the intermolecular level. Complementary analysis with ab initio calculations confirmed the experimental observations obtained by Raman spectroscopy. Finally the produced drug containing alkaline/ethanolic solutions exhibited stability over a period of up to 12 months. Conclusions: The current data demonstrate that milk is a promising drug carrier. © 2013 Elsevier B.V. All rights reserved