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1.
Molecules ; 26(2)2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33430287

RESUMO

The synthesis of carbohydrate-functionalized biocompatible poly(oligo(ethylene glycol) methacrylate microgels and the analysis of the specific binding to concanavalin A (ConA) and Escherichia coli (E. coli) 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 E. coli 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, E. coli 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.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33449439

RESUMO

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 (PK) and thus safety and efficacy of generic DOACs. In this first installment of our overall finding, we developed and verified a physiologically based pharmacokinetics (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.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33468465

RESUMO

The repurposed agent moxifloxacin has become an important addition to the physician's armamentarium for the therapy of Mycobacterium tuberculosis When a drug is administered, we need to have metrics for success. As for most antimicrobial chemotherapy, we contend that for Mycobacterium tuberculosis 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 hr dosing intervals with doses of 200 mg, 400 mg and 800 mg for each interval, respectively. Within each interval, we had an arm where half-lives of 12, 8 and 4 hr were simulated. We attempted to keep the CAvg (AUC) constant across arms. We found that susceptible bacterial load decline was linked to CAvg, as we had indicated previously. Resistance suppression, a non-monotonic function, had CMin as the linked index. The 48 hr interval with the 4 hr half-life had the largest less-susceptible population. Balancing bacterial kill, resistance suppression, toxicity (CPeak-linked) and adherence, we conclude that the 400 mg dose daily is optimal for moxifloxacin.

4.
J Clin Pharmacol ; 61(2): 234-243, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32895980

RESUMO

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 Emax 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.

5.
Contraception ; 2020 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-33345974

RESUMO

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.

6.
ACS Biomater Sci Eng ; 6(10): 5377-5398, 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33320564

RESUMO

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.

7.
J Clin Pharmacol ; 60 Suppl 2: S86-S102, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33274518

RESUMO

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.

8.
Artigo em Inglês | MEDLINE | ID: mdl-33217171

RESUMO

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/m2 ) 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.

9.
Clin Pharmacol Ther ; 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33236362

RESUMO

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.

10.
Epidemiology ; 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33196560

RESUMO

BACKGROUND: Accurate estimation of conception is critical in assessment of effects of drugs used during pregnancy or to prevent pregnancy. In a novel application, we studied the effectiveness of oral contraceptives (OC), 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 aged 12-48 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% 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.

11.
Artigo em Inglês | MEDLINE | ID: mdl-33199386

RESUMO

The Mycobacterium tuberculosis drug discovery effort has generated a substantial number of new/repurposed drugs for therapy of this pathogen. The arrival of these drugs is welcome, but another layer of difficulty has emerged. Having 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 6-8 new or repurposed agents, this translates into 15-28 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 NRP (Non-Replicative Persister)-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 Mycobacterium tuberculosis infection.

12.
Clin Pharmacol Ther ; 2020 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-33073366

RESUMO

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.

13.
Z Geburtshilfe Neonatol ; 224(6): 360-366, 2020 Dec.
Artigo em Alemão | MEDLINE | ID: mdl-33027822

RESUMO

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).

14.
J Periodontol ; 2020 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-33111988

RESUMO

BACKGROUND: Periimplantitis 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 periimplantitis. This study compared the safety and efficacy of Chlorhexidine gluconate 2.5 mg chip (CHX chips) as an adjunctive treatment to sub-gingival debridement in patients afflicted with periimplantitis. METHODS: A multicenter, randomized, single-blind, two-arm, parallel Phase-3 study was conducted. Periimplantitis patients with implant pocket depths (IPD) of 5-8 mm underwent sub-gingival implant surface debridement followed by repeated bi-weekly supra-gingival 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 periimplantitis that were treated with an intensive treatment protocol of bi-weekly supra-gingival 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. (Clinicaltrials.gov NCT02080403).

15.
CPT Pharmacometrics Syst Pharmacol ; 9(12): 678-685, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33067866

RESUMO

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.

16.
Front Neurol ; 11: 818, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32903376

RESUMO

Background: 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. Methods: 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. Results: 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; p = 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; p < 0.001), while bradycardia occurred more often in males (58.7% of all bradycardia events; p < 0.001). Furthermore, patients with a BMI below 25 had a higher incidence of second- or third-degree AV block. Conclusions: 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.

17.
Biomacromolecules ; 21(12): 4850-4856, 2020 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-32986404

RESUMO

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 (KD) of the PEGgylated compounds to ConA were larger. These results appear in line with Escherichia coli 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.

18.
Langmuir ; 36(42): 12555-12562, 2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-32975417

RESUMO

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 E. coli to monolayers composed of mannose-functionalized microgels with thermosensitive poly(N-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.

19.
Antimicrob Agents Chemother ; 64(11)2020 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-32900682

RESUMO

Multidrug therapy is often required. Examples include antiviral therapy, nosocomial infections, and, most commonly, anti-Mycobacterium tuberculosis 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 M. tuberculosis 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 (αs, αr-p, and αr-m) 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.

20.
Pharmacoeconomics ; 38(10): 1031-1042, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32734572

RESUMO

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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