Model-Informed Drug Development of a Sustained Release Formulation of Flucytosine in the Treatment of Cryptococcal Meningitis: A Case Study Using Physiologically Based Pharmacokinetic Modeling.

This paper presents a case study demonstrating the application of model-informed drug development (MIDD) and early modeling integration in the development of a sustained release (SR) formulation of flucytosine for cryptococcal meningoencephalitis (CM) in HIV-infected patients. The study aimed to showcase the value of physiologically based pharmacokinetic (PBPK) modeling and physiologically based biopharmaceutics modeling (PBBM) in guiding decisions and optimizing therapeutic strategies throughout drug development. The MIDD strategy started with a PBPK model based on limited literature data, iteratively refined informed by data from two Phase 1 clinical studies with various flucytosine formulations under different prandial conditions in healthy participants, enhancing model reliability.

Multimodal Interaction in Collaborative Design of a Healthcare Space: A Social Semiotic Approach.

In professional interactive practices, space, time, human bodies, and material objects as well as written and oral language are dynamically implicated in a multimodal co-construction of meaning. A healthcare space - an operating room - is a typical example of such a social-semiotic, multimodal arrangement of communication modes which impacts the practices that are played out therein. Therefore, in designing healthcare spaces, it is important to allow for proactive inclusion and engagement of the categories of professionals who carry out their daily work in these spaces.

Observations from the first 100 cases of intraoperative MRI - experiences, trends and short-term outcomes.

Background: We sought to analyze, in well-defined clinical setting, the first 100 patients treated at the intraoperative MRI (iMRI) hybrid surgical theatre at our facility in a population-based setting to evaluate which pathologies are best approached with iMRI assisted surgeries, as this is not yet clearly defined.

Methods: Patients undergoing surgery in the 3T iMRI hybrid surgical theatre at our neurosurgical department between December 2017 to May 2021 were included after informed consent. Demographic, clinical, surgical, histological, radiological and outcome parameters, as well as variables related to iMRI, were retrospectively collected and analyzed.

Bioavailability of a novel sustained-release pellet formulation of 5-flucytosine in healthy-fed participants for use in patients with cryptococcal meningitis.

Cryptococcal meningoencephalitis (CM) is an opportunistic fungal infection and a major cause of death among people living with human immunodeficiency virus in sub-Saharan Africa. 5-flucytosine (5-FC) is a unique, brain-permeable antifungal agent used to reduce mortality from CM and to prevent disease in individuals carrying cryptococcal antigen. 5-FC has a short plasma half-life, requiring 6-hourly oral dosing with an immediate-release (IR) formulation, a significant challenge in hospital and outpatient settings, risking a lack of compliance.

Bioavailability of three novel oral, sustained-release pellets, relative to an immediate-release tablet containing 500 mg flucytosine: A randomized, open-label, crossover study in healthy volunteers.

The opportunistic fungal infection cryptococcal meningoencephalitis is a major cause of death among people living with HIV in sub-Saharan Africa. We report pharmacokinetic (PK) and safety data from a randomized, four-period crossover phase I trial of three sustained-release (SR) oral pellet formulations of 5-flucytosine conducted in South Africa. These formulations were developed to require less frequent administration, to provide a convenient alternative to the current immediate release (IR) formulation, A.

Tracing back primed resistance in cancer via sister cells.

Exploring non-genetic evolution of cell states during cancer treatments has become attainable by recent advances in lineage-tracing methods. However, transcriptional changes that drive cells into resistant fates may be subtle, necessitating high resolution analysis. Here, we present ReSisTrace that uses shared transcriptomic features of sister cells to predict the states priming treatment resistance.

Bipartite network models to design combination therapies in acute myeloid leukaemia.

Combination therapy is preferred over single-targeted monotherapies for cancer treatment due to its efficiency and safety. However, identifying effective drug combinations costs time and resources. We propose a method for identifying potential drug combinations by bipartite network modelling of patient-related drug response data, specifically the Beat AML dataset.

patient experiences of using an Activity Board after abdominal cancer surgery.

Purpose: Most patients treated in a hospital setting are fully or partially immobilised. The Activity Board (Träningstavlan Phystec) is a useful tool to enhance mobilisation after major abdominal cancer surgery. Knowledge of patient experiences of the mobilisation tool is crucial in implementing the Activity Board in health care.

Pesticide-induced multigenerational effects on amphibian reproduction and metabolism.

Underlying drivers of species extinctions need to be better understood for effective conservation of biodiversity. Nearly half of all amphibian species are at risk of extinction, and pollution may be a significant threat as seasonal high-level agrochemical use overlaps with critical windows of larval development. The potential of environmental chemicals to reduce the fitness of future generations may have profound ecological and evolutionary implications.

Correction to: Drug Absorption Parameters Obtained Using the Isolated Perfused Rat Lung Model Are Predictive of Rat In Vivo Lung Absorption.

A Correction to sthis paper has been published: https://doi.org/10.1208/s12248-020-00545-x.

Pulmonary drug absorption and systemic exposure in human: Predictions using physiologically based biopharmaceutics modeling.

Systemic exposure of inhaled drugs is used to estimate the local lung exposure and assess systemic side effects for drugs with local pharmacological targets. Predicting systemic exposure is therefore central for successful development of drugs intended to be inhaled. Currently, these predictions are based mainly on data from in vitro experiments, but the accuracy of these predictions might be improved if they were based on data with higher physiological relevance.

Drug Absorption Parameters Obtained Using the Isolated Perfused Rat Lung Model Are Predictive of Rat In Vivo Lung Absorption.

The ex vivo isolated perfused rat lung (IPL) model has been demonstrated to be a useful tool during drug development for studying pulmonary drug absorption. This study aims to investigate the potential use of IPL data to predict rat in vivo lung absorption. Absorption parameters determined from IPL data (ex vivo input parameters) in combination with intravenously determined pharmacokinetic data were used in a biopharmaceutics model to predict experimental rat in vivo plasma concentration-time profiles and lung amount after inhalation of five different inhalation compounds.

Prolyl 4-hydroxylase subunit alpha 1 (P4HA1) is a biomarker of poor prognosis in primary melanomas, and its depletion inhibits melanoma cell invasion and disrupts tumor blood vessel walls.

Melanoma is an unpredictable, highly metastatic malignancy, and treatment of advanced melanoma remains challenging. Novel molecular markers based on the alterations in gene expression and the molecular pathways activated or deactivated during melanoma progression are needed for predicting the course of the disease already in primary tumors and for providing new targets for therapy. Here, we sought to identify genes whose expression in primary melanomas correlate with patient disease-specific survival using global gene expression profiling.

Pulmonary Dissolution of Poorly Soluble Compounds Studied in an ex Vivo Rat Lung Model.

Many inhaled drugs are poorly water soluble, and the dissolution rate is often the rate-limiting step in the overall absorption process. To improve understanding of pulmonary drug dissolution, four poorly soluble inhalation compounds (AZD5423 (a developmental nonsteroidal glucocorticoid), budesonide, fluticasone furoate (FF), and fluticasone propionate (FP)) were administered as suspensions or dry powders to the well-established isolated perfused rat lung (IPL) model. Two particle size distributions (d50 = 1.

Pulmonary absorption - estimation of effective pulmonary permeability and tissue retention of ten drugs using an ex vivo rat model and computational analysis.

Permeation of inhaled drugs across the pulmonary epithelium can regulate the rate and extent of local drug absorption and hence the pulmonary tissue concentration. Therefore, understanding pulmonary epithelial transport could be important for successful design of novel inhaled medicines. To enhance understanding of pulmonary epithelial transport, drug transport data were generated for a set of inhaled compounds (n = 10) in the single-pass, isolated perfused rat lung model.

Excised segments of rat small intestine in Ussing chamber studies: A comparison of native and stripped tissue viability and permeability to drugs.

Excised rat intestinal tissue mounted in an Ussing chamber can be used for intestinal permeability assessments in drug development. The outer layer of the intestine, the serosa and part of the muscle layer, is traditionally removed since it is considered a barrier to the diffusion of nutrients and oxygen as well as to that of pharmaceutical substances. However, the procedure for removing the serosal-muscle layer, i.