Majid Jaberi-Douraki

Performance Assessment and Translation of Physiologically Based Pharmacokinetic Models From acslX to Berkeley Madonna, MATLAB, and R Language: Oxytetracycline and Gold Nanoparticles As Case Examples

Many physiologically based pharmacokinetic (PBPK) models for environmental chemicals, drugs, and nanomaterials have been developed to aid risk and safety assessments using acslX. However, acslX has been rendered sunset since November 2015. Alternative modeling tools and tutorials are needed for future PBPK applications. This forum article aimed to: (1) demonstrate the performance of 4 PBPK modeling software packages (acslX, Berkeley Madonna, MATLAB, and R language) tested using 2 existing models (oxytetracycline and gold nanoparticles); (2) provide a tutorial of PBPK model code conversion from acslX to Berkeley Madonna, MATLAB, and R language; (3) discuss the advantages and disadvantages of each software package in the implementation of PBPK models in toxicology, and (4) share our perspective about future direction in this field. Simulation results of plasma/tissue concentrations/amounts of oxytetracycline and gold from different models were compared visually and statistically with linear regression analyses. Simulation results from the original models were correlated well with results from the recoded models, with time-concentration/amount curves nearly superimposable and determination coefficients of 0.86-1.00. Step-by-step explanations of the recoding of the models in different software programs are provided in the Supplementary Data. In summary, this article presents a tutorial of PBPK model code conversion for a small molecule and a nanoparticle among 4 software packages, and a performance comparison of these software packages in PBPK model implementation. This tutorial helps beginners learn PBPK modeling, provides suggestions for selecting a suitable tool for future projects, and may lead to the transition from acslX to alternative modeling tools.

Bacterial endotoxin (lipopolysaccharide) binds to the surface of gold nanoparticles, interferes with biocorona formation and induces human monocyte inflammatory activation

Abstract Nanoparticles (NPs) are easily contaminated by bacterial endotoxin (lipopolysaccharide [LPS]). The presence of LPS can be responsible for many immune/inflammatory effects attributed to NPs. In this study, we examined the effects of LPS adsorption on the NP surface on the formation of a biocorona in biological fluids and on the subsequent inflammation-inducing activity of NPs. Different gold (Au) NPs with sizes ranging from 10 to 80 nm and with different surface functionalization (sodium citrate, lipoic acid, and branched polyethyleneimine (BPEI), or polyethylene glycol (PEG)) were exposed to E. coli LPS under different conditions. The binding capacity of LPS to the surface of AuNPs was dose- and time-dependent. LPS attached to sodium citrate and lipoic acid coatings, but did not adhere to BPEI- or PEG-coated NPs. By computational simulation, the binding of LPS to AuNPs seems to follow the Langmuir absorption isotherm. The presence of LPS on AuNP surface interfered and caused a decrease in the formation of the expected biomolecular corona upon incubation in human plasma. LPS-coated AuNPs, but not the LPS-free NPs, induced significant inflammatory responses in vitro. Notably, while free LPS did also induce an anti-inflammatory response, LPS bound to NPs appeared unable to do so. In conclusion, the unintentional adsorption of LPS onto the NP surface can affect the biocorona formation and the inflammatory properties of NPs. Thus, for an accurate interpretation of NP interactions with cells, it is extremely important to be able to distinguish the intrinsic NP biological effects from those caused by biologically active contaminants such as endotoxin.

Modulation of chemical dermal absorption by 14 natural products: a quantitative structure permeation analysis of components often found in topical preparations

Abstract A large number of cosmetics and topical pharmaceuticals contain compounds of natural origin. There is a rising concern if these compounds can interact with the activity of other topically applied components in these formulations. The current study demonstrates modulation of dermal absorption of model components often found in topical preparations (14C caffeine and 14C salicylic acid) by a set of 14 compounds of natural origin using a flow through in vitro porcine skin diffusion system. The parameters of flux and permeability were calculated and quantitative structure permeation relationship (QSPR) analysis conducted on different molecular descriptors of modulator compounds. Terpinyl acetate was the greatest permeability/flux enhancer for caffeine followed by s-perillyl acetate and limonene 1,2-epoxide. The permeability/flux of salicylic acid was highest with hydroxycitronellal followed by limonene 1,2-epoxide and s-perillyl acetate. The optimum descriptors using stepwise regression analysis for predicting additive modulation on penetrant permeability/flux were polar surface area, log P for caffeine and Henry’s Law constant, number of freely rotatable bonds, and water solubility for salicylic acid. In parallel with the experimental techniques, a novel mathematical model was developed to estimate the permeability coefficients and improve the stepwise regression analysis for assessing modulator effects. The r2 values significantly increased for multicomponent QSPR models. Notably, limonene 1,2-epoxide and s-perillyl acetate were excellent enhancers for both caffeine and salicylic acid. These results confirm that some natural products incorporated into topical formulations will enhance absorption of other components which could affect their safety and efficacy profiles.

Clinical and infection dynamics of foot-and-mouth disease in beef feedlot cattle: An expert survey

Parameterizing mathematical models of foot-and-mouth disease virus (FMDv) transmission is challenging due to knowledge gaps on the variable dynamics in susceptible populations. Expert opinion surveys are an approach to gather data on topics where no data have been reported. The objective of this study was to collect-via an expert-opinion survey-key parameter values of the potential FMD natural history and transmissibility in beef feedlot cattle in the U.S. Experts with experience working with FMD in endemic and non-endemic settings were targeted. Parameters surveyed were: duration of infection and disease stages, proportions of animals with specific clinical manifestations, duration and extent of the reduction in feed consumption, and probabilities of severe clinical disease and FMDv transmission. We surveyed the parameter values for infections by strains of different virulence, different infection doses, and routes of transmission. Twenty-seven experts from around the world agreed to participate and 16 (59%) completed the survey. The expert responses to individual questions were resampled via Monte Carlo simulations; to the resulting distributions, candidate theoretical distributions were fitted using the maximum likelihood method and the sought parameter values estimated based on the best-fit distributions. Of the infection stages, the estimates of the expected FMD latent period in beef feedlot ranged from 1.7 to 5.3 days and the infectious period from 5.6 to 10.9 days. Of the disease stages, the estimated incubation period ranged from 2.9 to 6.1 days, subclinical period from 1.2 to 2.8 days, and clinical period from 4.2 to 7.5 days. Probability of developing clinical disease after infection varied from 82% (IQ range 90-70%) with high-virulent to 63% (IQ range 89-60%) with low-virulent strains. Reduction in feed consumption was estimated to last 5 (SD ± 2) days in cattle infected by a low-virulent FMDv strain and 7 (SD ± 2) days for high virulent strains. The study results can be used in combination with experimental and outbreak investigation data to parameterize FMDv-transmission models to evaluate intervention responses during hypothetical FMD epidemics in beef feedlot populations in the U.S.

Modeling gold nanoparticle biodistribution after arterial infusion into perfused tissue: effects of surface coating, size and protein corona

Abstract A detailed understanding of the factors governing nanomaterial biodistribution is needed to rationally design safe nanomedicines. This research details the pharmacokinetics of gold nanoparticle (AuNP) biodistribution after arterial infusion of 40 or 80 nm AuNP (1 μg/ml) into the isolated perfused porcine skin flap (IPPSF). AuNP had surface coatings consisting of neutral polyethylene glycol (PEG), anionic lipoic acid (LA), or cationic branched polyethylenimine (BPEI). Effect of a porcine plasma corona (PPC) on 40 nm BPEI and PEG-AuNP were assessed in the IPPSF. Au concentrations were determined by ICP/MS and arterial to venous concentration-time profiles were analyzed over 8 hr (4 hr infusion, 4 hr washout) using a two-compartment pharmacokinetic model. IPPSF viability and vascular function were assessed by change in glucose utilization, vascular resistance, or weight gain after perfusion. All AuNP demonstrated some degree of AuNP arterial extraction and skin flap retention, as well as enhanced kinetic parameters of tissue uptake; with BPEI-AuNP consistently having the greatest biodistribution even with a PPC. Toxicological effects were not detected. Transmission electron microscopy confirmed intracellular uptake of AuNP. These studies paralleled previous in vitro cell culture studies using the same AuNP in human endothelial and renal proximal tubule cells, hepatocytes, keratinocytes, showing BPEI-AuNP having the greatest uptake, although the presence of a PPC did not reduce IPPSF biodistribution as in the cell culture studies. These findings clearly indicate arterial to the venous extraction of AuNP after infusion with the magnitude of extraction being greatest with the BPEI surface coating and provide data and model structure necessary to construct the whole body physiologically based pharmacokinetic models capable of utilizing available in vitro data.

Serosurvey of Human Antibodies Recognizing Aedes aegypti D7 Salivary Proteins in Colombia

Background Dengue is one of the most geographically significant mosquito-borne viral diseases transmitted by Aedes mosquitoes. During blood feeding, mosquitoes deposit salivary proteins that induce antibody responses. These can be related to the intensity of exposure to bites. Some mosquito salivary proteins, such as D7 proteins, are known as potent allergens. The antibody response to D7 proteins can be used as a marker to evaluate the risk of exposure and disease transmission and provide critical information for understanding the dynamics of vector–host interactions. Methods The study was conducted at the Los Patios Hospital, Cucuta, Norte de Santander, Colombia. A total of 63 participants were enrolled in the study. Participants were categorized into three disease status groups, age groups, and socioeconomic strata. The level of IgG antibodies against D7 Aedes proteins was determined by ELISA. We used a statistical approach to determine if there is an association between antibody levels and factors such as age, living conditions, and dengue virus (DENV) infection. Results We found that IgG antibodies against D7 proteins were higher in non-DENV infected individuals in comparison to DENV-infected participants. Also, the age factor showed a significant positive correlation with IgG antibodies against D7 proteins, and the living conditions (socioeconomic stratification), in people aged 20 years or older, are a statistically significant factor in the variability of IgG antibodies against D7 proteins. Conclusion This pilot study represents the first approximation to elucidate any correlation between the antibody response against mosquito D7 salivary proteins and its correlation with age, living conditions, and DENV infection in a dengue endemic area.

Establishing Statistical Equivalence of Data from Different Sampling Approaches for Assessment of Bacterial Phenotypic Antimicrobial Resistance

ABSTRACT To assess phenotypic bacterial antimicrobial resistance (AMR) in different strata (e.g., host populations, environmental areas, manure, or sewage effluents) for epidemiological purposes, isolates of target bacteria can be obtained from a stratum using various sample types. Also, different sample processing methods can be applied. The MIC of each target antimicrobial drug for each isolate is measured. Statistical equivalence testing of the MIC data for the isolates allows evaluation of whether different sample types or sample processing methods yield equivalent estimates of the bacterial antimicrobial susceptibility in the stratum. We demonstrate this approach on the antimicrobial susceptibility estimates for (i) nontyphoidal Salmonella spp. from ground or trimmed meat versus cecal content samples of cattle in processing plants in 2013-2014 and (ii) nontyphoidal Salmonella spp. from urine, fecal, and blood human samples in 2015 (U.S. National Antimicrobial Resistance Monitoring System data). We found that the sample types for cattle yielded nonequivalent susceptibility estimates for several antimicrobial drug classes and thus may gauge distinct subpopulations of salmonellae. The quinolone and fluoroquinolone susceptibility estimates for nontyphoidal salmonellae from human blood are nonequivalent to those from urine or feces, conjecturally due to the fluoroquinolone (ciprofloxacin) use to treat infections caused by nontyphoidal salmonellae. We also demonstrate statistical equivalence testing for comparing sample processing methods for fecal samples (culturing one versus multiple aliquots per sample) to assess AMR in fecal Escherichia coli. These methods yield equivalent results, except for tetracyclines. Importantly, statistical equivalence testing provides the MIC difference at which the data from two sample types or sample processing methods differ statistically. Data users (e.g., microbiologists and epidemiologists) may then interpret practical relevance of the difference. IMPORTANCE Bacterial antimicrobial resistance (AMR) needs to be assessed in different populations or strata for the purposes of surveillance and determination of the efficacy of interventions to halt AMR dissemination. To assess phenotypic antimicrobial susceptibility, isolates of target bacteria can be obtained from a stratum using different sample types or employing different sample processing methods in the laboratory. The MIC of each target antimicrobial drug for each of the isolates is measured, yielding the MIC distribution across the isolates from each sample type or sample processing method. We describe statistical equivalence testing for the MIC data for evaluating whether two sample types or sample processing methods yield equivalent estimates of the bacterial phenotypic antimicrobial susceptibility in the stratum. This includes estimating the MIC difference at which the data from the two approaches differ statistically. Data users (e.g., microbiologists, epidemiologists, and public health professionals) can then interpret whether that present difference is practically relevant.