Publications by authors named "Stephan Schmidt"

230 Publications

Indication of Liver Transplantation for Hepatocellular Carcinoma Should Be Reconsidered in Case of Microvascular Invasion and Multilocular Tumor Occurrence.

J Clin Med 2021 Mar 10;10(6). Epub 2021 Mar 10.

Department of General, Visceral-, Thoracic-, Transplantation- and Pediatric Surgery, Campus Kiel, University Medical Center Schleswig-Holstein (UKSH), Arnold-Heller-Strasse 3, 24105 Kiel, Germany.

Liver transplantation (LT) is routinely performed for hepatocellular carcinoma (HCC) in cirrhosis without major vascular invasion. Although the adverse influence of microvascular invasion is recognized, its occurrence does not contraindicate LT. We retrospectively analyzed in our LT cohort the significance of microvascular invasion on survival and demonstrate bridging procedures. At our hospital, 346 patients were diagnosed with HCC, 171 patients were evaluated for LT, and 153 were listed at Eurotransplant during a period of 11 years. Among these, 112 patients received LT and were included in this study. Overall survival after 1, 3 and 5 years was 86.3%, 73.9%, and 67.9%, respectively. Microvascular invasion led to significantly reduced overall ( = 0.030) and disease-free survival ( = 0.002). Five-year disease-free survival with microvascular invasion was 10.5%. Multilocular tumor occurrence with simultaneous microvascular invasion revealed the worst prognosis. In our LT cohort, predominant bridging treatment was transarterial chemoembolization (TACE) and the number of TACE significantly correlated with poorer overall survival after LT ( = 0.028), which was confirmed in multiple Cox regression analysis for overall and disease-free survival ( = 0.015 and = 0.011). Microvascular tumor invasion is significantly associated with reduced prognosis after LT, which is aggravated by simultaneous occurrence of multiple lesions. Therefore, indication strategies for LT should be reconsidered.
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http://dx.doi.org/10.3390/jcm10061155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998779PMC
March 2021

In Vitro Synergistic Interactions of Isavuconazole and Echinocandins against .

Antibiotics (Basel) 2021 Mar 28;10(4). Epub 2021 Mar 28.

Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain.

is an emergent fungal pathogen that causes severe infectious outbreaks globally. The public health concern when dealing with this pathogen is mainly due to reduced susceptibility to current antifungal drugs. A valuable alternative to overcome this problem is to investigate the efficacy of combination therapy. The aim of this study was to determine the in vitro interactions of isavuconazole with echinocandins against . Interactions were determined using a checkerboard method, and absorbance data were analyzed with different approaches: the fractional inhibitory concentration index (FICI), Greco universal response surface approach, and Bliss interaction model. All models were in accordance and showed that combinations of isavuconazole with echinocandins resulted in an overall synergistic interaction. A wide range of concentrations within the therapeutic range were selected to perform time-kill curves. These confirmed that isavuconazole-echinocandin combinations were more effective than monotherapy regimens. Synergism and fungistatic activity were achieved with combinations that included isavuconazole in low concentrations (≥0.125 mg/L) and ≥1 mg/L of echinocandin. Time-kill curves revealed that once synergy was achieved, combinations of higher drug concentrations did not improve the antifungal activity. This work launches promising results regarding the combination of isavuconazole with echinocandins for the treatment of infections.
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http://dx.doi.org/10.3390/antibiotics10040355DOI Listing
March 2021

Descriptive Analysis of Real-World Data on Fingolimod Long-Term Treatment of Young Adult RRMS Patients.

Front Neurol 2021 3;12:637107. Epub 2021 Mar 3.

Novartis Pharma GmbH, Nuremberg, Germany.

Fingolimod (Gilenya®) is approved for adult and pediatric patients with highly active relapsing-remitting multiple sclerosis (RRMS). The objective was to describe the effectiveness of fingolimod in young adults compared to older patients in clinical practice. PANGAEA is the largest prospective, multi-center, non-interventional, long-term study evaluating fingolimod in RRMS. We descriptively analyzed demographics, MS characteristics, and severity in two subgroups of young adults (≤20 and >20 to ≤30 years) and older patients (>30 years). Young adults had lower Expanded Disability Status Scale (EDSS) scores compared to older patients (1.8 and 2.3 vs. 3.2) at baseline. The mean EDSS scores remained stable over 5 years in all subgroups. Young adults had higher annual relapse rates (2.0 and 1.7 vs. 1.4) at study entry, which were reduced by approximately 80% in all subgroups over 5 years. The proportion of patients with no clinical disease activity in year 4 was 52.6 and 73.4 vs. 66.9% in patients ≤20, >20 to ≤30 years and >30 years, respectively. The symbol digit modalities test score increased by 15.25 ± 8.3 and 8.3 ± 11.3 (mean ± SD) from baseline in patients >20 to ≤30 and >30 years. Real-world evidence suggests a long-term treatment benefit of fingolimod in young RRMS patients.
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http://dx.doi.org/10.3389/fneur.2021.637107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982917PMC
March 2021

Tribute to Professor Hartmut Derendorf - 1953 to 2020: Driving force in Clinical Pharmacology and Mentor Extraordinaire.

Clin Pharmacol Ther 2021 Apr 5;109(4):805-809. Epub 2021 Mar 5.

Department of Pharmaceutics and Center for Pharmacometrics and Systems Pharmacology, University of Florida College of Pharmacy, Gainesville, Florida, USA.

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http://dx.doi.org/10.1002/cpt.2193DOI Listing
April 2021

Temperature-Controlled Adhesion to Carbohydrate Functionalized Microgel Films: An E. coli and Lectin Binding Study.

Macromol Biosci 2021 Feb 19:e2000386. Epub 2021 Feb 19.

Institute of Organic and Macromolecular Chemistry, Heinrich-Heine-University Düsseldorf, Universitätsstraße 1, Düsseldorf, 40225, Germany.

The preparation of thermoresponsive mannose functionalized monolayers of poly(N-isopropylacrylamide) microgels and the analysis of the specific binding of concanavalin A (ConA) and E. coli above and below the lower critical solution temperature (LCST) are shown. Via inhibition and direct binding assays it is found that ConA binding is time-dependent, where at short incubation times binding is stronger above the LCST. Given larger incubation times, the interaction of ConA to the microgel network is increased below the LCST when compared to temperatures above the LCST, possibly due to increased ConA diffusion and multivalent binding in the more open microgel network below the LCST. For E. coli, which presents only monovalent lectins and is too large to diffuse into the network, binding is always enhanced above the LCST. This is due to the larger mannose density of the microgel layer above the LCST increasing the interaction to E. coli. Once bound to the microgel layer above the LCST, E. coli cannot be released by cooling down below the LCST. Overall, this suggests that the carbohydrate presenting microgel layers enable specific binding where the temperature-induced transition between swollen and collapsed microgels may increase or decrease binding depending on the receptor size.
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http://dx.doi.org/10.1002/mabi.202000386DOI Listing
February 2021

Dose Fractionation of Moxifloxacin for Treatment of Tuberculosis: Impact of Dosing Interval and Elimination Half-Life on Microbial Kill and Resistance Suppression.

Antimicrob Agents Chemother 2021 03 18;65(4). Epub 2021 Mar 18.

Institute for Therapeutic Innovation, College of Medicine, University of Florida, Orlando, Florida, USA.

The repurposed agent moxifloxacin has become an important addition to the physician's armamentarium for the therapy of When a drug is administered, we need to have metrics for success. As for most antimicrobial chemotherapy, we contend that for therapy, these metrics should be a decline in the susceptible bacterial burden and the suppression of amplification of less-susceptible populations. To achieve optimal outcomes relative to these metrics, a dose and schedule of administration need to be chosen. For large populations of patients, there are true between-patient differences in important pharmacokinetic parameters. These distributions of parameter values may have an impact on these metrics, depending on what measure of drug exposure drives the metrics. To optimize dose and schedule choice of moxifloxacin, we performed a dose fractionation experiment in the hollow fiber infection model. We examined 12-, 24-, and 48-h dosing intervals with doses of 200, 400, and 800 mg for each interval, respectively. Within each interval, we had an arm where half-lives of 12, 8, and 4 h were simulated. We attempted to keep the average concentration () or area under the concentration-time curve (AUC) constant across arms. We found that susceptible bacterial load decline was linked to , as we had indicated previously. Resistance suppression, a nonmonotonic function, had minimum concentration () as the linked index. The 48-h interval with the 4-h half-life had the largest less-susceptible population. Balancing bacterial kill, resistance suppression, toxicity (linked to peak concentration []), and adherence, we conclude that the dose of 400 mg daily is optimal for moxifloxacin.
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http://dx.doi.org/10.1128/AAC.02533-20DOI Listing
March 2021

Physiologically-based pharmacokinetics modeling to investigate formulation factors influencing the generic substitution of dabigatran etexilate.

CPT Pharmacometrics Syst Pharmacol 2021 Mar 10;10(3):199-210. Epub 2021 Feb 10.

Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, Florida, USA.

The exposure-response relationship of direct acting oral anti-coagulants (DOACs) for bleeding risk is steep relative to ischemic stroke reduction. As a result, small changes in exposure may lead to bleeding events. The overall goal of this project was to determine the effect of critical formulation parameters on the pharmacokinetics (PKs) and thus safety and efficacy of generic DOACs. In this first installment of our overall finding, we developed and verified a physiologically-based PK (PBPK) model for dabigatran etexilate (DABE) and its metabolites. The model was developed following a middle out approach leveraging available in vitro and in vivo data. External validity of the model was confirmed by overlapping predicted and observed PK profiles for DABE as well as free and total dabigatran for a dataset not used during model development. The verified model was applied to interrogate the impact of modulating the microenvironment pH on DABE systemic exposure. The PBPK exploratory analyses highlighted the high sensitivity of DABE exposure to supersaturation ratio and precipitation kinetics.
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http://dx.doi.org/10.1002/psp4.12589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7965836PMC
March 2021

Lectin and Binding to Carbohydrate-Functionalized Oligo(ethylene glycol)-Based Microgels: Effect of Elastic Modulus, Crosslinker and Carbohydrate Density.

Molecules 2021 Jan 7;26(2). Epub 2021 Jan 7.

Institute for Organic and Macromolecular Chemistry, Heinrich-Heine-University, Universitätsstr 1, 40225 Düsseldorf, Germany.

The synthesis of carbohydrate-functionalized biocompatible poly(oligo(ethylene glycol) methacrylate microgels and the analysis of the specific binding to concanavalin A (ConA) and () is shown. By using different crosslinkers, the microgels' size, density and elastic modulus were varied. Given similar mannose (Man) functionalization degrees, the softer microgels show increased ConA uptake, possibly due to increased ConA diffusion in the less dense microgel network. Furthermore, although the microgels did not form clusters with in solution, surfaces coated with mannose-functionalized microgels are shown to bind the bacteria whereas galactose (Gal) and unfunctionalized microgels show no binding. While ConA binding depends on the overall microgels' density and Man functionalization degree, binding to microgels' surfaces appears to be largely unresponsive to changes of these parameters, indicating a rather promiscuous surface recognition and sufficiently strong anchoring to few surface-exposed Man units. Overall, these results indicate that carbohydrate-functionalized biocompatible oligo(ethylene glycol)-based microgels are able to immobilize carbohydrate binding pathogens specifically and that the binding of free lectins can be controlled by the network density.
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http://dx.doi.org/10.3390/molecules26020263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825725PMC
January 2021

Dual ionic liquid-based crosslinked chitosan for fine-tuning of antifouling, water throughput, and denitrification performance of polysulfone membrane.

Int J Biol Macromol 2021 Feb 29;170:572-582. Epub 2020 Dec 29.

Institut für Anorganische Chemie und Strukturchemie, Heinrich-Heine Universität Düsseldorf, 40204 Düsseldorf, Germany.

This study aimed to design a facile and efficient protocol for upgrading the performance indices of polysulfone (PS) membrane (porosity, hydrophilicity, pure water flux (PWF), surface charge, and fouling-resistance) by blending with newly synthesized poly(ionic) crosslinked chitosan Schiff bases (PICCSBs). The PS-PICCSBs mixed-matrix membranes (MMMs) have successfully fabricated and characterized based on spectral and microscopic analyses, porosity, zeta potential, water contact angle, and water uptake (wettability) measurements. The PWF, fouling-resistance against bovine serum albumin (BSA), as well as ion exchange capacity (IEC) against nitrate anion were studied. The wettability, hydrophilicity and overall porosity of new MMMs have greatly increased, in comparison to a pristine PS membrane (M). In addition, blending of PS with PICCSBs resulted in switching its surface from negatively- to positively-charged. The PWF of MMMs has increased to reach a maximum value of 238.6 L/m h for MMM (9.3-fold higher than M). Meanwhile, BSA rejection has declined from 96.62% for M to 41.9% for MMM. The fouling parameters results of MMMs indicated their low fouling propensity. The IEC of nitrate anions revealed that the nitrate uptake by MMM is higher than that for M and MMM by 34% and 14%, respectively.
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http://dx.doi.org/10.1016/j.ijbiomac.2020.12.186DOI Listing
February 2021

Comparison of contraceptive failures associated with CYP3A4-inducing drug-drug interactions by route of hormonal contraceptive in an adverse event reporting system.

Contraception 2021 Apr 17;103(4):222-224. Epub 2020 Dec 17.

Center for Drug Evaluation and Safety, Department of Pharmaceutical Outcomes and Policy, University of Florida College of Pharmacy, Gainesville, FL, United States. Electronic address:

Objective: To estimate associations between contraceptive failures and concomitant CYP3A4-inducing medications by route of administration.

Study Design: Comparison of unintended pregnancy outcomes within U.S. Food and Drug Administration's Adverse Event Reporting System by couse of CYP3A4-inducing drugs and route of administration for levonorgestrel and etonogestrel/desogestrel.

Results: Among 14,504 levonorgestrel case reports, the reporting odds ratio (ROR) was increased for oral (ROR = 4.2 [3.0-5.7]), implants (ROR = 8.0 [5.8-11.0]), but not intrauterine (ROR = 0.9 [0.6-1.3]) levonorgestrel products. For 9348 etonogestrel/desogestrel case reports, oral and vaginal products were not associated with contraceptive failure. Etonogestrel containing implants (ROR = 4.9 [4.1-5.9]) were associated with increased contraceptive failure.

Conclusion: Levonorgestrel containing combination oral products and implants containing levonorgestrel or etonogestrel were prone to CYP3A4-inducing drug-drug interactions that may increase contraceptive failures.

Implications: The progestin components of hormonal contraceptives are susceptible to drug-drug interactions, but this susceptibility is influenced by route of administration. This study provides evidence from an Adverse Event Reporting System that CYP3A4-inducing medications increase the risk of unintended pregnancy for oral and implant contraceptives but not intrauterine or vaginal devices.
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http://dx.doi.org/10.1016/j.contraception.2020.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7972989PMC
April 2021

Comparative Animal Mucomics: Inspiration for Functional Materials from Ubiquitous and Understudied Biopolymers.

ACS Biomater Sci Eng 2020 10 14;6(10):5377-5398. Epub 2020 Sep 14.

The PhD Program in Biochemistry, Graduate Center of the City University of New York, 365 Fifth Avenue, New York, New York 10016, United States.

The functions of secreted animal mucuses are remarkably diverse and include lubricants, wet adhesives, protective barriers, and mineralizing agents. Although present in all animals, many open questions related to the hierarchical architectures, material properties, and genetics of mucus remain. Here, we summarize what is known about secreted mucus structure, describe the work of research groups throughout the world who are investigating various animal mucuses, and relate how these studies are revealing new mucus properties and the relationships between mucus hierarchical structure and hydrogel function. Finally, we call for a more systematic approach to studying animal mucuses so that data sets can be compared, omics-style, to address unanswered questions in the emerging field of mucomics. One major result that we anticipate from these efforts is design rules for creating new materials that are inspired by the structures and functions of animal mucuses.
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http://dx.doi.org/10.1021/acsbiomaterials.0c00713DOI Listing
October 2020

Establishment of a Disease-Drug Trial Model for Postmenopausal Osteoporosis: A Zoledronic Acid Case Study.

J Clin Pharmacol 2020 12;60 Suppl 2:S86-S102

Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, Florida, USA.

Costly and lengthy clinical trials hinder the development of safe and effective treatments for postmenopausal osteoporosis. To reduce the expense associated with these trials, we established a mechanistic disease-drug trial model for postmenopausal osteoporosis that can predict phase 3 trial outcome based on short-term bone turnover marker data. To this end, we applied a previously developed model for tibolone to bisphosphonates using zoledronic acid as paradigm compound by (1) linking the mechanistic bone cell interaction model to bone turnover markers as well as bone mineral density in lumbar spine and total hip, (2) employing a mechanistic disease progression function, and (3) accounting for zoledronic acid's mechanism of action. Once developed, we fitted the model to clinical trial data of 581 postmenopausal women receiving (1) 5-mg zoledronic acid in year 1 and saline in year 2, (2) 5-mg zoledronic acid in year 1 and year 2, or (3) placebo (saline), calcium (500 mg), and vitamin D (400 IU). All biomarker data was fitted reasonably well, with no apparent bias or model misspecification. Age, years since menopause, and body mass index at baseline were identified as significant covariates. In the future, the model can be modified to explore the link between short-term biomarkers and fracture risk.
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http://dx.doi.org/10.1002/jcph.1748DOI Listing
December 2020

Public Workshop Summary Report on Fiscal Year 2021 Generic Drug Regulatory Science Initiatives: Data Analysis and Model-Based Bioequivalence.

Clin Pharmacol Ther 2020 Nov 24. Epub 2020 Nov 24.

Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.

On May 4, 2020, the US Food and Drug Administration (FDA) hosted an online public workshop titled "FY 2020 Generic Drug Regulatory Science Initiatives Public Workshop" to provide an overview of the status of the science and research priorities and to solicit input on the development of Generic Drug User Fee Amendments fiscal year 2021 priorities. This report summarizes the podium presentations and the outcome of discussions along with innovative ways to overcome challenges and significant opportunities related to model-based approaches in bioequivalence assessment for breakout session 4 titled, "Data analysis and model-based bioequivalence (BE)." This session focused on the application of model-based approaches in the generic drug development, with a vision of accelerating regulatory decision making for abbreviated new drug application assessments. The session included both podium presentations and panel discussions with three topics of interest: (i) in vitro study evaluation methods and their clinical relevance, (ii) challenges in model-based BE, (iii) emerging expertise and tools in implementing new BE approaches.
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http://dx.doi.org/10.1002/cpt.2120DOI Listing
November 2020

Quantitative Assessment of Levonorgestrel Binding Partner Interplay and Drug-Drug Interactions Using Physiologically Based Pharmacokinetic Modeling.

CPT Pharmacometrics Syst Pharmacol 2021 Jan 13;10(1):48-58. Epub 2020 Dec 13.

Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, Florida, USA.

Levonorgestrel (LNG) is the active moiety in many hormonal contraceptive formulations. It is typically coformulated with ethinyl estradiol (EE) to decrease intermenstrual bleeding. Due to its widespread use and CYP3A4-mediated metabolism, there is concern regarding drug-drug interactions (DDIs), particularly a suboptimal LNG exposure when co-administered with CYP3A4 inducers, potentially leading to unintended pregnancies. The goal of this analysis was to determine the impact of DDIs on the systemic exposure of LNG. To this end, we developed and verified a physiologically-based pharmacokinetic (PBPK) model for LNG in PK-Sim (version 8.0) accounting for the impact of EE and body mass index (BMI) on LNG's binding to sex-hormone binding globulin. Model parameters were optimized following intravenous and oral administration of 0.09 mg LNG. The combined LNG-EE PBPK model was verified regarding CYP3A4-mediated interaction by comparing to published clinical DDI study data with carbamazepine, rifampicin, and efavirenz (CYP3A4 inducers). Once verified, the model was applied to predict systemic LNG exposure in normal BMI and obese women (BMI ≥ 30 kg/m ) with and without co-administration of itraconazole (competitive CYP3A4 inhibitor) and clarithromycin (mechanism-based CYP3A4 inhibitor). Total and free LNG exposures, when co-administered with EE, decreased 2-fold in the presence of rifampin, whereas they increased 1.5-fold in the presence of itraconazole. Although changes in total and unbound exposure were decreased in obese women compared with normal BMI women, the relative impact of DDIs on LNG exposure was similar between both groups.
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http://dx.doi.org/10.1002/psp4.12572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825189PMC
January 2021

The Funnel: a Screening Technique for Identifying Optimal Two-Drug Combination Chemotherapy Regimens.

Antimicrob Agents Chemother 2021 01 20;65(2). Epub 2021 Jan 20.

Institute for Therapeutic Innovation, College of Medicine, University of Florida, Orlando, Florida, USA.

The drug discovery effort has generated a substantial number of new/repurposed drugs for therapy for this pathogen. The arrival of these drugs is welcome, but another layer of difficulty has emerged. Single agent therapy is insufficient for patients with late-stage tuberculosis because of resistance emergence. To achieve our therapeutic ends, it is requisite to identify optimal combination regimens. These regimens go through a lengthy and expensive evaluative process. If we have a modest group of 6 to 8 new or repurposed agents, this translates into 15 to 28 possible 2-drug combinations. There is neither time nor resources to give an extensive evaluation for all combinations. We sought a screening procedure that would identify combinations that had a high likelihood of achieving good bacterial burden decline. We examined pretomanid, moxifloxacin, linezolid, and bedaquiline in log-phase growth, acid-phase growth, and nonreplicative persister (NRP) phase in the Greco interaction model. We employed the interaction term α and the calculated bacterial burden decline as metrics to rank different regimens in different metabolic states. No relationship was found between α and bacterial kill. We chose bacterial kill as the prime metric. The combination of pretomanid plus moxifloxacin emerged as the clear frontrunner, as the largest bacterial declines were seen in log phase and acid phase with this regimen and it was second best in NRP phase. Bedaquiline also produced good kill. This screening process may identify optimal combinations that can be further evaluated in both the hollow-fiber infection model and in animal models of infection.
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http://dx.doi.org/10.1128/AAC.02172-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848982PMC
January 2021

A Pharmacoepidemiologic Approach to Evaluate Real-world Effectiveness of Hormonal Contraceptives in the Presence of Drug-drug Interactions.

Epidemiology 2021 Mar;32(2):268-276

From the Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, FL.

Background: Accurate estimation of conception is critical in the assessment of the effects of drugs used during pregnancy or to prevent pregnancy. In a novel application, we studied the effectiveness of oral contraceptives (OCs), where misclassification of conception relative to OC exposure may obscure effect estimates.

Methods: We studied OC failure, in a large claims database, among women who used antiepileptic drugs with metabolizing enzyme-inducing properties (carbamazepine or oxcarbazepine), which reduce OC's effectiveness or enzyme-neutral properties (lamotrigine or levetiracetam), with no expected impact on OC effectiveness. We compared conception rates in women 12-48 years of age concomitantly using OCs and enzyme-inducing drugs with rates in concomitant users of OCs and enzyme-neutral drugs. We measured conception with a validated algorithm that estimates gestational age based on pregnancy endpoints. We estimated relative and attributable risk using generalized estimating equation models after standardized mortality ratio weighting.

Results: We identified 89,777 concomitant use episodes with adjusted contraceptive failure rates of 1.6 (95% confidence interval (CI) = 1.4, 1.8) per 100 person-years among users of enzyme-neutral drugs and 18,964 episodes with a rate of 2.3 (1.9, 2.8) among users of enzyme-inducing drugs. The relative risk of conception for enzyme-inducing group was 1.4 (1.1, 1.8), and the rate difference was 0.7 (0.2, 1.2).

Conclusions: OCs in combination with antiepileptic drugs that interact with metabolic enzymes were associated with increased contraceptive failure rates. Measurement of conception in claims data had adequate accuracy to uncover a strong drug-drug interaction, offering promise for broader application in comparative effectiveness studies on hormonal contraceptives to inform clinical and regulatory decisionmaking.
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http://dx.doi.org/10.1097/EDE.0000000000001302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850590PMC
March 2021

Repeated delivery of chlorhexidine chips for the treatment of peri-implantitis: A multicenter, randomized, comparative clinical trial.

J Periodontol 2021 Jan 11;92(1):11-20. Epub 2020 Nov 11.

Division of Periodontology, Department of Oral Medicine Infection and Immunity, Harvard School of Dental Medicine, Harvard University, Boston, Massachusetts, USA.

Background: Peri-implantitis is a challenging condition to manage and is frequently treated using non-surgical debridement. The local delivery of antimicrobial agents has demonstrated benefit in mild to moderate cases of peri-implantitis. This study compared the safety and efficacy of chlorhexidine gluconate 2.5 mg chip (CHX chips) as an adjunctive treatment to subgingival debridement in patients afflicted with peri-implantitis.

Methods: A multicenter, randomized, single-blind, two-arm, parallel Phase-3 study was conducted. Peri-implantitis patients with implant pocket depths (IPD) of 5-8 mm underwent subgingival implant surface debridement followed by repeated bi-weekly supragingival plaque removal and chlorhexidine chips application (ChxC group) for 12 weeks, or similar therapy but without application of ChxC (control group). All patients were followed for 24 weeks. Plaque and gingival indices were measured at every visit whereas IPD, recession, and bleeding on probing were assessed at 8, 12, 16, 24 week.

Results: A total of 290 patients were included: 146 in the ChxC group and 144 in the control. At 24 weeks, a significant reduction in IPD (P = 0.01) was measured in the ChxC group (1.76 ± 1.13 mm) compared with the control group (1.54 ± 1.13 mm). IPD reduction of ≥2 mm was found in 59% and 47.2% of the implants in the ChxC and control groups, respectively (P = 0.03). Changes in gingival recession (0.29 ± 0.68 mm versus 0.15 ± 0.55 mm, P = 0.015) and relative attachment gain (1.47 ± 1.32 mm and 1.39 ± 1.27 mm, P = 0.0017) were significantly larger in the ChxC group. Patients in the ChxC group that were < 65 years exhibited significantly better responses (P < 0.02); likewise, non-smokers had similarly better response (P < 0.02). Both protocols were well tolerated, and no severe treatment-related adverse events were recorded throughout the study.

Conclusions: Patients with peri-implantitis that were treated with an intensive treatment protocol of bi-weekly supragingival plaque removal and local application of chlorhexidine chips had greater mean IPD reduction and greater percentile of sites with IPD reduction of ≥2 mm as compared with bi-weekly supra-gingival plaque removal.
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http://dx.doi.org/10.1002/JPER.20-0353DOI Listing
January 2021

Quantitative Benefit-Risk Assessment of P-gp-Mediated Drug-Drug Interactions of Dabigatran Coadministered With Pharmacokinetic Enhancers in Patients With Renal Impairment.

Clin Pharmacol Ther 2021 Jan 10;109(1):193-200. Epub 2020 Dec 10.

Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, Florida, USA.

Drug-drug interactions (DDIs) between dabigatran and ritonavir/cobicistat are of major concern in people living with HIV, particularly in those with impaired renal function, because they can result in increased dabigatran exposure and thus an increased risk of major bleeding events. However, the extent of this interaction and subsequent need for dose adjustment in subjects with varying degrees of renal function is currently not yet fully understood. To close this knowledge gap, we conducted an integrated population physiologically-based pharmacokinetic/pharmacodynamic analysis linking changes in dabigatran exposure due to DDIs and varying degrees of renal function to the probability of experiencing an ischemic stroke or major bleeding event within 1 year. The results of our analysis suggest that coadministration of dabigatran etexilate (dabigatran prodrug) and ritonavir/cobicistat should be avoided in subjects with severe renal impairment. A 2-hour dose separation or dabigatran etexilate dose reduction to 110 mg b.i.d. (twice daily) should be considered in subjects with moderate renal impairment when coadministered with ritonavir, while the dabigatran etexilate dose should be further reduced to 75 mg b.i.d. when coadministered with cobicistat. No dabigatran etexilate dose adjustment is needed in subjects with normal renal function receiving ritonavir, but dabigatran etexilate dose reduction to 110 mg b.i.d. should be considered when coadministered with cobicistat.
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http://dx.doi.org/10.1002/cpt.2087DOI Listing
January 2021

Examination of Metoprolol Pharmacokinetics and Pharmacodynamics Across CYP2D6 Genotype-Derived Activity Scores.

CPT Pharmacometrics Syst Pharmacol 2020 Dec 3;9(12):678-685. Epub 2020 Nov 3.

Department of Pharmacotherapy and Translation Research, Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, Florida, USA.

Recent CYP2D6 phenotype standardization efforts by CYP2D6 activity score (AS) are based on limited pharmacokinetic (PK) and pharmacodynamic (PD) data. Using data from two independent clinical trials of metoprolol, we compared metoprolol PK and PD across CYP2D6 AS with the goal of determining whether the PK and PD data support the new phenotype classification. S-metoprolol apparent oral clearance (CLo), adjusted for clinical factors, was correlated with CYP2D6 AS (P < 0.001). The natural log of CLo was lower with an AS of 1 (7.6 ± 0.4 mL/minute) vs. 2-2.25 (8.3 ± 0.6 mL/minute; P = 0.012), similar between an AS of 1 and 1.25-1.5 (7.8 ± 0.5 mL/minute; P = 0.702), and lower with an AS of 1.25-1.5 vs. 2-2.25 (P = 0.03). There was also a greater reduction in heart rate with metoprolol among study participants with AS of 1 (-10.8 ± 5.5) vs. 2-2.25 (-7.1 ± 5.6; P < 0.001) and no significant difference between those with an AS of 1 and 1.25-1.5 (-9.2 ± 4.7; P = 0.095). These data highlight linear trends among CYP2D6 AS and metoprolol PK and PD, but inconsistencies with the phenotypes assigned by AS based on the current standards. Overall, this case study with metoprolol suggests that utilizing CYP2D6 AS, instead of collapsing AS into phenotype categories, may be the most precise approach for utilizing CYP2D6 pharmacogenomics in clinical practice.
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http://dx.doi.org/10.1002/psp4.12563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762806PMC
December 2020

[Critical Outcome and Hypoxic Ischemic Encephalopathy - A quality Assurance Issue].

Z Geburtshilfe Neonatol 2020 Dec 7;224(6):360-366. Epub 2020 Oct 7.

Klinik für Kinder- und Jugendmedizin, Klinikum Frankfurt Höchst GmbH, Frankfurt am Main.

The study evaluates the predictive value of the critical status of a newborn as to the risk of developing hypoxic ischemic encephalopathy (HIE).

Methods: On the basis of the data set from the perinatal survey in Hesse, Germany, in the year 2016, including 52,122 live births (singleton, 37+0 GA), cases of critical newborns were identified. A conjoined analysis with the data set of the neonatal survey from the identical period provided the basis to evaluate the relationship to cases compromised by HIE.

Results: The incidence of cases with a critical outcome (n=11) and those with HIE (n=29) was low. The sensitivity of the status of the newborn for detecting a risk of HIE was 10.34%. The specificity was 99.98%. The positive predictive value was 27.35%. The negative predictive value was 99.95%. The detailed, confidential single-case analysis indicated the ability to avoid negative outcomes in about one third of cases with a critical status of the newborn (4/11) and HIE (9/29).

Discussion And Conclusion: The likelihood of developing encephalopathy (HIE) increases after a critical outcome after birth. Intensified monitoring of these newborns is justified. A single-case analysis identifies the potential ways to improve perinatal outcomes. Measures of external quality assurance should integrate the analysis of both perinatal and neonatal surveys as a basis for quality management (QM).
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http://dx.doi.org/10.1055/a-1258-4639DOI Listing
December 2020

Effect of PEGylation on Receptor Anchoring and Steric Shielding at Interfaces: An Adhesion and Surface Plasmon Resonance Study with Precision Polymers.

Biomacromolecules 2020 12 13;21(12):4850-4856. Epub 2020 Oct 13.

Institute of Organic and Macromolecular Chemistry, Heinrich-Heine-University Düsseldorf, Universitätsstraße 1, 40225 Dusseldorf, Germany.

This study aims at quantifying the steric shielding effect of multivalent glycoconjugates targeting pathogens by blocking their carbohydrate binding sites. Specifically, PEGylated and non-PEGylated glycoconjugates are studied as inhibitors of lectins and bacterial adhesins evaluating the steric repulsion effect of the nonbinding PEG chains. We use the soft colloidal probe (SCP) adhesion assay to monitor the change in the adhesion energy of mannose (Man)-decorated hydrogel particles on a layer of concanavalin A (ConA) in the presence of sequence-defined multivalent glycoconjugate inhibitors over time. The results show that PEGylated glycoconjugates achieve a stronger adhesion inhibition when compared to non-PEGylated glycoconjugates although the dissociation constants () of the PEGgylated compounds to ConA were larger. These results appear in line with adhesion inhibition assays showing a small increase of bacteria detachment by PEGgylated glycoconjugates compared to non-PEGylated compounds. This suggests that an increase of sterical shielding via PEGylation may help reduce the invasiveness of pathogens even after they have adhered. Adhesion studies based on electrostatic interactions using amine-linked PEG of varying molecular weight confirm that such sterical shielding effect is not limited to carbohydrate-mediated adhesion.
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http://dx.doi.org/10.1021/acs.biomac.0c01060DOI Listing
December 2020

Switchable Adhesion of to Thermosensitive Carbohydrate-Presenting Microgel Layers: A Single-Cell Force Spectroscopy Study.

Langmuir 2020 10 14;36(42):12555-12562. Epub 2020 Oct 14.

Institute for Organic and Macromolecular Chemistry, Heinrich-Heine-University, Universitätsstr. 1, 40225 Düsseldorf, Germany.

Adhesion processes at the cellular scale are dominated by carbohydrate interactions, including the attachment and invasion of pathogens. Carbohydrate-presenting responsive polymers can bind pathogens and inhibit pathogen invasion by remote stimuli for the development of new antibiotic strategies. In this work, the adhesion forces of to monolayers composed of mannose-functionalized microgels with thermosensitive poly(-isopropylacrylamide) (PNIPAM) and poly(oligo(ethylene glycol)) (PEG) networks are quantified using single-cell force spectroscopy (SCFS). When exceeding the microgels' lower critical solution temperature (LCST), the adhesion increases up to 2.5-fold depending on the polymer backbone and the mannose density. For similar mannose densities, the softer PNIPAM microgels show a significantly stronger adhesion increase when crossing the LCST as compared to the stiffer PEG microgels. This is explained by a stronger shift in swelling, mannose density, and surface roughness of the softer gels when crossing the LCST. When using nonbinding galactose instead of mannose, or when inhibiting bacterial receptors, a certain level of adhesion remains, indicating that also polymer-fimbria entanglements contribute to adhesion. The presented quantitative analysis provides insights into carbohydrate-mediated bacterial adhesion and the relation to material properties and shows the prospects and limitations of interactive polymer materials to control the attachment of bacteria.
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http://dx.doi.org/10.1021/acs.langmuir.0c02040DOI Listing
October 2020

A Comprehensive Monitoring Study on Electrocardiographic Assessments and Cardiac Events After Fingolimod First Dose-Possible Predictors of Cardiac Outcomes.

Front Neurol 2020 12;11:818. Epub 2020 Aug 12.

Division for Metabolism and Cardiology, Department of Cardiology, Charité Universitaetsmedizin Berlin, Berlin, Germany.

First dose observation for cardiac effects is required for fingolimod. Previous results in patients with relapsing remitting multiple sclerosis (RRMS) suggest that transient bradycardia and conduction abnormalities during the observation phase are rare, benign and reversible. Prior analyses corroborate these findings. The present large scale dataset allows subgroup analyses for differences in the incidence of cardiac findings depending on patient characteristics. START was an open-label, multi-center study that enrolled 6,998 RRMS patients. Primary endpoints were incidence of bradycardia (heart rate < 45 bpm) and second-/third-degree atrioventricular (AV) block during treatment initiation. Subgroup analyses were performed according to age, gender, body mass index (BMI), baseline expanded disability status scale (EDSS), and concomitant medication to determine the impact of these variables on cardiac outcomes parameters. 63 patients (0.9%) developed bradycardia (<45 bpm), 120 patients (1.7%) had a second-degree Mobitz I (Wenkebach) block and/or 2:1 AV block. One case of an asymptomatic third-degree AV block occurred. No Mobitz II AV block was observed. After 1 week, no second-/third-degree AV block was observed. The incidence of second- or third-degree AV blocks was significantly higher in older patients (≥50 years; = 0.014 vs. patients 35-49 years). Second- or third-degree AV blocks were more frequent in females (87.5% of all patients with a second- or third-degree AV block; < 0.001), while bradycardia occurred more often in males (58.7% of all bradycardia events; < 0.001). Furthermore, patients with a BMI below 25 had a higher incidence of second- or third-degree AV block. In summary, transient bradycardia and AV conduction abnormalities after the first dose of fingolimod were rare and asymptomatic. When compared to females, male patients might have a higher risk for bradycardia during treatment initiation, presumably due to a lower resting heart rate. Furthermore, a low heart rate before treatment initiation, low body weight, or low BMI possibly increases the risk for bradycardia. Second- or third-degree AV blocks were more frequent in females, older patients and patients with a low BMI. Nevertheless, these cardiac events remained rare and benign, confirming the favorable cardiac safety profile of fingolimod upon treatment initiation in MS patients without cardiovascular comorbidities.
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http://dx.doi.org/10.3389/fneur.2020.00818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434833PMC
August 2020

Building Optimal Three-Drug Combination Chemotherapy Regimens.

Antimicrob Agents Chemother 2020 10 20;64(11). Epub 2020 Oct 20.

Institute for Therapeutic Innovation, College of Medicine, University of Florida, Orlando, Florida, USA.

Multidrug therapy is often required. Examples include antiviral therapy, nosocomial infections, and, most commonly, anti- therapy. Our laboratory previously identified a mathematical approach to identify 2-drug regimens with a synergistic or additive interaction using a full factorial study design. Our objective here was to generate a method to identify an optimal 3-drug therapy. We studied isolate H37Rv in log-phase growth in flasks. Pretomanid and moxifloxacin were chosen as the base 2-drug regimen. Bedaquiline (plus M2 metabolite) was chosen as the third drug for evaluation. Total bacterial burden and bacterial burden less-susceptible to study drugs were enumerated. A large mathematical model was fit to all the data. This allowed extension to evaluation of the 3-drug regimen by employing a Monte Carlo simulation. Pretomanid plus moxifloxacin demonstrated excellent bacterial kill and suppressed amplification of less-susceptible pathogens. Total bacterial burden was driven to extinction in 3 weeks in 6 of 9 combination therapy evaluations. Only the lowest pretomanid/moxifloxacin exposures in combination did not extinguish the bacterial burden. No combination regimen allowed resistance amplification. Generation of 95% credible intervals about estimates of the interaction parameters α (α, α, and α) by bootstrapping showed the interaction was near synergistic. The addition of bedaquiline/M2 metabolite was evaluated by forming a 95% confidence interval regarding the decline in bacterial burden. The addition of bedaquiline/M2 metabolite shortened the time to eradication by 1 week and was significantly different. A model-based system approach to evaluating combinations of 3 agents shows promise to rapidly identify the most promising combinations that can then be trialed.
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http://dx.doi.org/10.1128/AAC.01610-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577121PMC
October 2020

Development and Verification of a Body Weight-Directed Disease Trial Model for Glucose Homeostasis.

J Clin Pharmacol 2021 Feb 7;61(2):234-243. Epub 2020 Sep 7.

Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, Florida, USA.

Weight loss has been associated with improvement in insulin sensitivity. It is consequently a cornerstone in the management of type 2 diabetes mellitus (T2DM). However, the strictly quantitative relationship between weight loss, insulin sensitivity, and clinically relevant glucose homeostasis biomarkers as well as changes therein as T2DM progresses is not yet fully understood. Therefore, the objective of our research was to establish a body weight-directed disease trial model for glucose homeostasis. To that end, we conducted a model-based meta-analysis using time course data of body weight loss (following lifestyle change or surgical procedure) and corresponding improvement of insulin sensitivity expressed as the Matsuda index. Changes in body weight were best described by a sigmoidal E model, whereas changes in the Matsuda index were best described by a linear model with a slope of 3.49. Once developed and verified, the model-based meta-analysis was linked to a disease-drug trial model for T2DM previously developed by our group to characterize and predict the impact of weight loss on clinically relevant glucose homeostasis biomarkers. The joint model was then used to conduct clinical trial simulations, which showed that weight loss can greatly improve clinically relevant glucose homeostasis biomarkers in T2DM patients.
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http://dx.doi.org/10.1002/jcph.1728DOI Listing
February 2021

Quantifying Thermoswitchable Carbohydrate-Mediated Interactions via Soft Colloidal Probe Adhesion Studies.

Macromol Biosci 2020 10 5;20(10):e2000186. Epub 2020 Aug 5.

Institute of Organic and Macromolecular Chemistry, Heinrich-Heine-University Düsseldorf, Universitatsstraße 1, Dusseldorf, 40225, Germany.

Thermosensitive polymers enable externally controllable biomolecular interactions but hysteresis effects hamper the reversibility and repeated use of these materials. To quantify the temperature-dependent interactions and hysteresis effects, an optical adhesion assay based on poly(ethylene glycol) microgels (soft colloidal probes, SCPs) with mannose binding concanavalin A surfaces is used. A series of thermoresponsive glycopolymers is synthesized varying the carbohydrate type, their density, and linker type, and then grafted to the SCPs. The carbohydrate-mediated adhesion is influenced by the density of sugar ligands and increased above the lower critical solution temperature (LCST) of the glycopolymer. Importantly, a strong hysteresis is observed, i.e., cooling back below the LCST does not reduce the adhesion back to the initial value before heating. The hysteresis is stronger for hydrophobic linkers and for low carbohydrate functionalization degrees suggesting insufficient reswelling of the polymers due to hydrophobic interactions. The results are confirmed by studying the adhesion of Escherichia coli to the SCPs, where an enhanced capture of the bacteria is observed above the LCST while the detachment upon cooling is not possible. Overall, the quantitative data on the switchable adhesion of specifically binding polymers may provide potential avenues for the design of the next-generation interactive biomaterials.
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http://dx.doi.org/10.1002/mabi.202000186DOI Listing
October 2020

Incorporating Pharmacometrics into Pharmacoeconomic Models: Applications from Drug Development.

Pharmacoeconomics 2020 10;38(10):1031-1042

College of Pharmacy, Howard University, Washington, DC, USA.

Pharmacometrics is the science of quantifying the relationship between the pharmacokinetics and pharmacodynamics of drugs in combination with disease models and trial information to aid in drug development and dosing optimization for clinical practice. Considering the variability in the dose-concentration-effect relationship of drugs, an opportunity exists in linking pharmacokinetic and pharmacodynamic model-based estimates with pharmacoeconomic models. This link may provide early estimates of the cost effectiveness of drug therapies, thus informing late-stage drug development, pricing, and reimbursement decisions. Published case studies have demonstrated how integrated pharmacokinetic-pharmacodynamic-pharmacoeconomic models can complement traditional pharmacoeconomic analyses by identifying the impact of specific patient sub-groups, dose, dosing schedules, and adherence on the cost effectiveness of drugs, thus providing a mechanistic basis to predict the economic value of new drugs. Greater collaboration between the pharmacoeconomics and pharmacometrics community can enable methodological improvements in pharmacokinetic-pharmacodynamic-pharmacoeconomic models to support drug development.
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http://dx.doi.org/10.1007/s40273-020-00944-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578131PMC
October 2020

Physiologically Based Pharmacokinetic Modeling of Monoclonal Antibodies in Pediatric Populations Using PK-Sim.

Front Pharmacol 2020 11;11:868. Epub 2020 Jun 11.

Clinical Pharmacometrics, Bayer AG, Leverkusen, Germany.

Physiologically based pharmacokinetic (PBPK) models are increasingly used to support pediatric dose selection for small molecule drugs. In contrast, only a few pediatric PBPK models for therapeutic antibodies have been published recently, and the knowledge on the maturation of the processes relevant for antibody pharmacokinetics (PK) is limited compared to small molecules. The aim of this study was, thus, to evaluate predictions from antibody PBPK models for children which were scaled from PBPK models for adults in order to identify respective knowledge gaps. For this, we used the generic PBPK model implemented in PK-Sim without further modifications. Focusing on general clearance and distribution mechanisms, we selected palivizumab and bevacizumab as examples for this evaluation since they show simple, linear PK which is not governed by drug-specific target mediated disposition at usual therapeutic dosages, and their PK has been studied in pediatric populations after intravenous application. The evaluation showed that the PK of palivizumab was overall reasonably well predicted, while the clearance for bevacizumab seems to be underestimated. Without implementing additional ontogeny for antibody PK-specific processes into the PBPK model, bodyweight normalized clearance increases only moderately in young children compared to adults. If growth during aging at the time of the simulation was considered, the apparent clearance is approximately 20% higher compared to simulations for which growth was not considered for newborns due to the long half-life of antibodies. To fully understand the differences and similarities in the PK of antibodies between adults and children, further research is needed. By integrating available information and data, PBPK modeling can contribute to reveal the relevance of involved processes as well as to generate and test hypothesis.
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http://dx.doi.org/10.3389/fphar.2020.00868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300301PMC
June 2020

Janus-faced course of COVID-19 infection in patients with hematological malignancies.

Eur J Haematol 2020 Oct 2;105(4):502-504. Epub 2020 Jul 2.

Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria.

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http://dx.doi.org/10.1111/ejh.13470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323382PMC
October 2020

Temperature-Switchable Glycopolymers and Their Conformation-Dependent Binding to Receptor Targets.

Biomacromolecules 2020 07 25;21(7):2913-2921. Epub 2020 Jun 25.

Institute of Organic and Macromolecular Chemistry, Heinrich-Heine-University Düsseldorf, Universitätsstraße 1, Dusseldorf 40225, Germany.

The temperature-dependent binding of copolymers from poly(-isopropylacrylamide) (PNIPAM) and mannose ligands to and concanavalin A (ConA) is determined. Through polymer analogous reactions using poly(-acryloxysuccinimide) and amine-linked mannose residues with different linkers, glycopolymers are prepared with the variation of the mannose density. Quantitative adhesion inhibition assays show the inhibitory potential of the glycopolymers as a function of the mannose/NIPAM ratio and linker type above and below their lower critical solution temperature (LCST). Intriguingly, opposite temperature effects on the binding to and ConA are observed. While the inhibition is stronger above the LCST, the ConA inhibition is, in overall, weaker at elevated temperatures. When going beyond the LCST, the polymers undergo a coil-to-globule transition, forming microphases with surface-enriched hydrophilic sugar moieties exhibiting increased inhibition through steric shielding. However, the formation of such microphases above the LCST renders a fraction of carbohydrate ligands inaccessible,and the polymers remaining in the solution phase then have coil sizes below the minimum binding site spacing of the ConA receptor, explaining reduced ConA inhibition. Overall, these results suggest that the coil-to-globule transition of glycopolymers may induce lower or higher inhibitory potentials due to the adverse effects of steric shielding and carbohydrate ligand accessibility.
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http://dx.doi.org/10.1021/acs.biomac.0c00676DOI Listing
July 2020