Fluorocarbons and Fluorosurfactants for In Vivo Oxygen Transport (Blood Substitutes), Imaging, and Drug Delivery

MRS Bulletin ◽  
1999 ◽  
Vol 24 (5) ◽  
pp. 42-48 ◽  
Author(s):  
Jean G. Riess ◽  
Marie Pierre Krafft
Keyword(s):  
Drug Delivery ◽  
Lipid Membranes ◽  
Research Collaboration ◽  
The United States ◽  
Blood Substitutes ◽  
Oxygen Carriers ◽  
Colloidal Systems ◽  
Preclinical Development ◽  
The Impact

The development of biomaterials to treat, repair, or reconstruct the human body is an increasingly important component of materials research. Collaboration between materials researchers and their industrial and clinical partners is essential for the development of this complex field. To demonstrate the importance of these interactions, two articles in this issue focus on advances in biomaterials relating to the use of colloidal systems for transport, drug delivery, and other medical applications. These articles were coordinated by Dominique Muster (Université Louis Pasteur, Strasbourg) and Franz Burny (Hôpital Erasme, Brussels). The following is the first of these two articles.A large variety of colloidal Systems involving highly fluorinated components have been prepared and investigated in recent years. These fluorinated Systems comprise diverse ty pes of emulsions (e.g., direct, reverse, and multiple emulsions; microemulsions; gel emulsions; waterless emulsions) with a fluorocarbon phase (and often a fluorinated Surfactant), and a ränge of self-assemblies (vesicles, tubules, helices, ribbons, etc.) made from fluorinated amphiphiles. Fluorinated Langmuir films and fluorinated black lipid membranes (BLMs) also have been investigated.Research in this area was driven by the potential applications of such materials in medicine and biology. Fluorocarbon-based products are being developed as injectable oxygen carriers (“blood Substitutes”), media for liquid Ventilation, drug delivery Systems, and contrast agents for ultrasound imaging. One such agent has recently been approved for use in Europe and the United States. Several more products are in an advanced stage of clinical evaluation, and others are in various stages of preclinical development. From a more fundamental Standpoint, these materials are being investigated for assessing and understanding the impact that fluorinated components have on the formation, stability, structure, and properties of colloida l Systems in comparison with their hydrocarbon counterparts. The attention given to fluorinated colloids prompted the synthesis of numerous new families of fluorinated amphiphiles, which were to become components of such colloids.

scholarly journals In VitroSusceptibility of Canine Influenza A (H3N8) Virus to Nitazoxanide and Tizoxanide

2010 ◽  
Vol 2010 ◽  
pp. 1-5 ◽  
Author(s):  
Laura V. Ashton ◽  
Robert L. Callan ◽  
Sangeeta Rao ◽  
Gabriele A. Landolt
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
The United States ◽  
Canine Influenza Virus ◽  
Valuable Adjunct ◽  
Canine Influenza ◽  
The Impact ◽  
H3n8 Virus

Infection of dogs with canine influenza virus (CIV) is considered widespread throughout the United States following the first isolation of CIV in 2004. While vaccination against influenza A infection is a common and important practice for disease control, antiviral therapy can serve as a valuable adjunct in controlling the impact of the disease. In this study, we examined the antiviral activity of nitazoxanide (NTZ) and tizoxanide (TIZ) against three CIV isolatesin vitro. NTZ and TIZ inhibited virus replication of all CIVs with 50% and 90% inhibitory concentrations ranging from 0.17 to 0.21 μMand from 0.60 to 0.76 μM, respectively. These results suggest that NTZ and TIZ are effective against CIV and may be useful for treatment of canine influenza in dogs but further investigation of thein vivoefficacy against CIV as well as the drug's potential for toxicity in dogs is needed.

scholarly journals Genetic signatures of human cytomegalovirus variants acquired by seronegative glycoprotein B vaccinees

2018 ◽  
Author(s):  
Cody S. Nelson ◽  
Diana Vera Cruz ◽  
Melody Su ◽  
Guanhua Xie ◽  
Nathan Vandergrift ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Rational Design ◽  
Hcmv Infection ◽  
Vaccine Trial ◽  
The United States ◽  
Glycoprotein B ◽  
Viral Population ◽  
The Impact ◽  
Placebo Recipients

AbstractHuman cytomegalovirus (HCMV) is the most common congenital infection worldwide, and a frequent cause of hearing loss or debilitating neurologic disease in newborn infants. Thus, a vaccine to prevent HCMV-associated congenital disease is a public health priority. One potential strategy is vaccination of women of child-bearing age to prevent maternal HCMV acquisition during pregnancy. The glycoprotein B (gB) + MF59 adjuvant subunit vaccine is the most efficacious tested clinically to date, demonstrating approximately 50% protection against HCMV infection of seronegative women in multiple phase 2 trials. Yet, the impact of gB/MF59-elicited immune responses on the population of viruses acquired by trial participants has not been assessed. In this analysis, we employed quantitative PCR as well as multiple sequencing methodologies to interrogate the magnitude and genetic composition of HCMV populations infecting gB/MF59 vaccinees and placebo recipients. We identified several differences between the viral dynamics of acutely-infected vaccinees and placebo recipients. First, there was reduced magnitude viral shedding in the saliva of gB vaccinees. Additionally, employing a panel of tests for genetic compartmentalization, we noted tissue-specific gB haplotypes in the majority of vaccinees though only in a single placebo recipient. Finally, we observed reduced acquisition of genetically-related gB1, gB2, and gB4 genotype “supergroup” HCMV variants among vaccine recipients, suggesting that the gB1 genotype vaccine construct may have elicited partial protection against HCMV viruses with antigenically-similar gB sequences. These findings indicate that gB immunization may have had a measurable impact on viral intrahost population dynamics and support future analysis of a larger cohort.Author SummaryThough not a household name like Zika virus, human cytomegalovirus (HCMV) causes permanent neurologic disability in one newborn child every hour in the United States - more than Down syndrome, fetal alcohol syndrome, and neural tube defects combined. There are currently no established effective preventative measures to inhibit congenital HCMV transmission following acute or chronic HCMV infection of a pregnant mother. However, the glycoprotein B (gB) vaccine is the most effective HCMV vaccine tried clinically to date. Here, we utilized high-throughput, next-generation sequencing of viral DNA isolated from patients enrolled in a gB vaccine trial, and identified several impacts that this vaccine had on the size, distribution, and composition of thein vivoviral population. These results have increased our understanding of why the gB/MF59 vaccine was partially efficacious and will inform future rational design of a vaccine to prevent congenital HCMV.

scholarly journals 1591. Updated Fluoroquinolone MIC Breakpoints: Impact on Susceptibility Rates in the United States

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S580-S581
Author(s):  
Robert K Flamm ◽  
Michael A Pfaller ◽  
Paul G Ambrose ◽  
David Andes ◽  
John S Bradley ◽  
...  
Keyword(s):  
United States ◽  
Pseudomonas Aeruginosa ◽  
Ad Hoc ◽  
The United States ◽  
Broth Microdilution ◽  
Successful Model ◽  
Consultative Process ◽  
The Impact ◽  
Comparison Data

Abstract Background In 2015 USCAST, the National Advisory Committee for the United States (US) to EUCAST, produced a report (Version 1.0) on their website (www.uscast.org) re-evaluating fluoroquinolone (FQ) breakpoint interpretive criteria (IC) based on analysis of current microbiology and pharmacokinetic/pharmacodynamic (PK/PD) data. EUCAST initiated a consultative process using USCAST analyses in an effort to update FQ IC, released in 2017. CLSI formed an ad-hoc working group in late 2015 to review the USCAST FQ document and formulate questions about content. In 2018, USCAST released V1.3 of the FQ document and CLSI subsequently published updated FQ MIC IC in the M100-S29 (2019) document. This study evaluated the impact on susceptibility (S) rates for US surveillance data that these IC changes created. Methods Clinical isolates (reference broth microdilution MIC) from 2016–2018 US SENTRY Program were analyzed for S based on current and previous IC. FQ results for ciprofloxacin (CIP), levofloxacin (LEV), and moxifloxacin (MOX) were evaluated. Benchmark S comparison data for meropenem, cefepime, piperacillin–tazobactam and delafloxacin (new FQ) were also included. Results S rates for Enterobacteriaceae (ENT;Figure) were reduced by 3.8/3.7% for CIP/LEV (CLSI) and 2.3/2.5% (EUCAST). MOX-S rate vs. ENT declined 5.7% (EUCAST). Although reductions in S occurred for most organism groups, K. pneumoniae (6.0/5.5% for CIP/LEV [CLSI] and 4.0/4.2% [EUCAST]) and S. marcescens (7.4/4.1% for CIP/LEV [CLSI] and 4.1/5.0% [EUCAST]) reductions were among the largest changes. For Pseudomonas aeruginosa (PSA), CIP-S decreased 6.8% and LEV-S 10.1% (CLSI); but potential for false-S results remain using CLSI IC (5 pathogens). Conclusion USCAST’s comprehensive analyses of FQ IC in 2015 led to revised breakpoints for most organism/drug combinations among ENT and PSA compared with those being used before. USCAST analysis was most influenced by PK/PD in vivo data as current clinical outcomes data by MIC was limited. Awareness and interactions (both formal and informal) among breakpoint setting organizations has modified FQ ICs which are lower than previously recommended, and although not perfectly harmonized in time and detail, this represents a successful model. Disclosures All authors: No reported disclosures.

scholarly journals 734. Modeling the Pharmacokinetics and Pharmacodynamics of Intravenous and Oral Omadacycline with and without a Loading Dose

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S329-S329
Author(s):  
Lawrence Friedrich ◽  
Marla Curran ◽  
Surya Chitra ◽  
Amy Manley ◽  
Stephen Bai ◽  
...  
Keyword(s):  
Steady State ◽  
Bacterial Pneumonia ◽  
Phase 1 ◽  
The United States ◽  
Clinical Impact ◽  
Loading Dose ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Dosing Regimens ◽  
The Impact

Abstract Background Omadacycline (OMC) is an intravenous (IV) and oral aminomethylcycline antibiotic in the tetracycline class approved in the United States to treat acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP) in adults. The approved dosing regimens of OMC include a loading dose designed to achieve steady-state exposures early in the course of therapy. We assessed the impact on OMC exposure and subsequent pharmacodynamics (PD) on Day 2 and at steady state (Day 5) in the situation where a loading dose may not be given. Methods Phase 1 pharmacokinetic (PK) data were used to determine OMC exposure on Day 2 and at steady state (Day 5) for the following: IV regimens 100 mg IV q12h on Day 1 then 100 mg IV QD (load), 100 mg IV QD (no load); and oral regimens 450 mg oral QD on Days 1 and 2 then 300 mg QD (load) and 300 mg oral QD (no load). AUCs on Day 2 and Day 5 for no-load regimens were compared with the regimens with loading doses. Additionally, AUC:MIC ratios were calculated using OMC MIC90 for two main pathogens of interest in ABSSSI and CABP, respectively, Staphylococcus aureus (0.25 mg/L) and Streptococcus pneumoniae (0.12 mg/L). In vivo AUC:MIC targets for stasis and 1-log kill used were 21.9 and 57.7 (S. aureus) and 31.2 and 65.8 (S. pneumoniae). Results Day 2 and 5 AUCs are shown in the Figure. AUCs on Day 2 were lower for the two regimens without loading doses and were 72% (IV) and 73% (oral) of those with a loading dose. However, at steady state on Day 5, no-load regimen AUCs were essentially the same at 98% for both the IV and oral regimens. Despite lower AUCs on Day 2 for the no-load regimens, the AUC:MIC ratio would still be expected to exceed the stasis threshold for both pathogens and the 1-log kill threshold for S. pneumoniae (figure). This same pattern was also noted on Day 5. Conclusion Exposure as assessed using AUC was lower early on in therapy on Day 2 for both IV and oral regimens. However, exposures were not different on Day 5 at steady state. Despite lower exposure on Day 2, OMC would still be expected to meet or exceed PK/PD thresholds associated with stasis for S. aureus and S. pneumoniae. The 1-log kill threshold was exceeded for S. pneumoniae. Further studies are needed to confirm any clinical impact of the omission of OMC loading doses. Disclosures All authors: No reported disclosures.

scholarly journals Pharmacodynamic Evaluation of the Activities of Six Parenteral Vancomycin Products Available in the United States

2014 ◽  
Vol 59 (1) ◽  
pp. 622-632 ◽  
Author(s):  
Arnold Louie ◽  
Michael T. Boyne ◽  
Vikram Patel ◽  
Clayton Huntley ◽  
Weiguo Liu ◽  
...  
Keyword(s):  
United States ◽  
Drug Exposure ◽  
The United States ◽  
Mouse Serum ◽  
Infection Model ◽  
Population Pharmacokinetic ◽  
Bacterial Killing ◽  
The Impact

ABSTRACTA recent report found that generic parenteral vancomycin products may not havein vivoefficacies equivalent to those of the innovator in a neutropenic murine thigh infection model despite having similarin vitromicrobiological activities and murine serum pharmacokinetics. We compared thein vitroandin vivoactivities of six of the parenteral vancomycin products available in the United States. Thein vitroassessments for the potencies of the vancomycin products included MIC/minimal bactericidal concentration (MBC) determinations, quantifying the impact of human and murine serum on the MIC values, and time-kill studies. Also, the potencies of the vancomycin products were quantified with a biological assay, and the human and mouse serum protein binding rates for the vancomycin products were measured. Thein vivostudies included dose-ranging experiments with the 6 vancomycin products for three isolates ofStaphylococcus aureusin a neutropenic mouse thigh infection model. The pharmacokinetics of the vancomycin products were assessed in infected mice by population pharmacokinetic modeling. No differences were seen across the vancomycin products with regard to anyin vitroevaluation. Inhibitory sigmoid maximal bacterial kill (Emax) modeling of the relationship between vancomycin dosage and the killing of the bacteria in micein vivoyielded similarEmaxand EC50(drug exposure driving one-halfEmax) values for bacterial killing. Further, there were no differences in the pharmacokinetic clearances of the 6 vancomycin products from infected mice. There were no important pharmacodynamic differences in thein vitroorin vivoactivities among the six vancomycin products evaluated.

scholarly journals The Impact of Head Model Choice on the In Vitro Evaluation of Aerosol Drug Delivery

Pharmaceutics ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 24
Author(s):  
Lauren Gallagher ◽  
Mary Joyce ◽  
Barry Murphy ◽  
Marc Mac Giolla Eain ◽  
Ronan MacLoughlin
Keyword(s):  
Drug Delivery ◽  
Head Model ◽  
Model Choice ◽  
Aerosol Delivery ◽  
Test Conditions ◽  
Volume Measurements ◽  
Internal Volume ◽  
The Impact

There are variations in the values reported for aerosol drug delivery across in vitro experiments throughout the published literature, and often with the same devices or similar experimental setups. Factors contributing to this variability include, but are not limited to device type, equipment settings, drug type and quantification methods. This study assessed the impact of head model choice on aerosol drug delivery using six different adults and three different paediatric head models in combination with a facemask, mouthpiece, and high-flow nasal cannula. Under controlled test conditions, the quantity of drug collected varied depending on the choice of head model. Head models vary depending on a combination of structural design differences, facial features (size and structure), internal volume measurements and airway geometries and these variations result in the differences in aerosol delivery. Of the widely available head models used in this study, only three were seen to closely predict in vivo aerosol delivery performance in adults compared with published scintigraphy data. Further, this testing identified the limited utility of some head models under certain test conditions, for example, the range reported across head models was aerosol drug delivery of 2.62 ± 2.86% to 37.79 ± 1.55% when used with a facemask. For the first time, this study highlights the impact of head model choice on reported aerosol drug delivery within a laboratory setting and contributes to explaining the differences in values reported within the literature.

Liposomes as colloidal nanovehicles: on the road to success in intravenous drug delivery

2018 ◽  
Vol 34 (3) ◽  
pp. 365-383 ◽  
Author(s):  
Sumaira Naeem ◽  
Geetha Viswanathan ◽  
Misni Bin Misran
Keyword(s):  
Drug Delivery ◽  
Drug Loading ◽  
Delivery Systems ◽  
Stimuli Responsive ◽  
Colloidal Systems ◽  
Triggered Release ◽  
The Road ◽  
On The Road

AbstractThe advancement of research in colloidal systems has led to the increased application of this technology in more effective and targeted drug delivery. Nanotechnology enables control over functionality parameters and allows innovations in biodegradable, biocompatible, and stimuli-responsive delivery systems. The first closed bilayer phospholipid system, the liposome system, has been making steady progress over five decades of extensive research and has been efficient in achieving many desirable parameters such as remote drug loading, size-controlling measures, longer circulation half-lives, and triggered release. Liposome-mediated drug delivery has been successful in overcoming obstacles to cellular and tissue uptake of drugs with improved biodistributionin vitroandin vivo. These colloidal nanovehicles have moved on from a mere concept to clinical applications in various drug delivery systems for antifungal, antibiotic, and anticancer drugs.

scholarly journals A thermodynamic scaling law for electrically perturbed lipid membranes: validation with the steepest-entropy-ascent framework

2020 ◽  
Author(s):  
I. Goswami ◽  
R. Bielitz ◽  
S.S. Verbridge ◽  
M.R. von Spakovsky
Keyword(s):  
Electric Fields ◽  
Lipid Membranes ◽  
Lipid Membrane ◽  
Scaling Law ◽  
Cancer Therapeutics ◽  
Successful Implementation ◽  
Outer Cell ◽  
Scaling Model ◽  
The Impact

AbstractExperimental evidence has demonstrated the potential of transient pulses of electric fields to alter mammalian cell phenotypes. Strategies with these pulsed electric fields (PEFs) have been developed for clinical applications in cancer therapeutics, in-vivo decellularization, and tissue regeneration. Successful implementation of these strategies involves understanding how PEFs impact the cellular structures and, hence, cell behavior. The caveat, however, is that the PEF parameter space comprised of different pulse widths, amplitudes, and the number of pulses is very large, and design of experiments to explore all possible combinations of PEF parameters is prohibitive from a cost and time standpoint. In this study, a scaling law based on the Ising model is introduced to understand the impact of PEFs on the outer cell lipid membrane so that an understanding developed in one PEF pulse regime may be extended to another. Experimental study is used to argue for the scaling model. Next, the validity of this scaling model to predict the behavior of both thermally quenched and electrically perturbed lipid membranes is demonstrated via computational predictions made by the steepest-entropy-ascent quantum thermodynamic (SEAQT) framework. Based on the simulation results, a form of scaled PEF parameters is thus proposed for lipid membrane.

scholarly journals NLRP3 inflammasome activation in aged macrophages is diminished during Streptococcus pneumoniae infection

2018 ◽  
Vol 314 (3) ◽  
pp. L372-L387 ◽  
Author(s):  
Soo Jung Cho ◽  
Kristen Rooney ◽  
Augustine M. K. Choi ◽  
Heather W. Stout-Delgado
Keyword(s):  
Streptococcus Pneumoniae ◽  
Nlrp3 Inflammasome ◽  
The United States ◽  
Biological Aging ◽  
Inflammasome Activation ◽  
Pneumococcal Infections ◽  
Nlrp3 Inflammasome Activation ◽  
The Impact

Pneumococcal infections are the eigth leading cause of death in the United States, and it is estimated that older patients (≥65 yr of age) account for the most serious cases. The goal of our current study is to understand the impact of biological aging on innate immune responses to Streptococcus pneumoniae, a causative agent of bacterial pneumonia. With the use of in vitro and in vivo aged murine models, our findings demonstrate that age-enhanced unfolded protein responses (UPRs) contribute to diminished inflammasome assembly and activation during S. pneumoniae infection. Pretreatment of aged mice with endoplasmic reticulum chaperone and the stress-reducing agent tauroursodeoxycholic acid (TUDCA) decreased mortality in aged hosts that was associated with increased NLRP3 inflammasome activation, improved pathogen clearance, and decreased pneumonitis during infection. Taken together, our data provide new evidence as to why older persons are more susceptible to S. pneumoniae and provide a possible therapeutic target to decrease morbidity and mortality in this population.

scholarly journals Phage Therapy of Pneumonia Is Not Associated with an Overstimulation of the Inflammatory Response Compared to Antibiotic Treatment in Mice

2019 ◽  
Vol 63 (8) ◽  
Author(s):  
Nicolas Dufour ◽  
Raphaëlle Delattre ◽  
Anne Chevallereau ◽  
Jean-Damien Ricard ◽  
Laurent Debarbieux
Keyword(s):  
Inflammatory Response ◽  
Antibiotic Treatment ◽  
Bacterial Infections ◽  
Phage Therapy ◽  
Bacterial Load ◽  
The United States ◽  
Experimental Models ◽  
Interleukin 12 ◽  
The Impact

ABSTRACT Supported by years of clinical use in some countries and more recently by literature on experimental models, as well as its compassionate use in Europe and in the United States, bacteriophage (phage) therapy is providing a solution for difficult-to-treat bacterial infections. However, studies of the impact of such treatments on the host remain scarce. Murine acute pneumonia initiated by intranasal instillation of two pathogenic strains of Escherichia coli (536 and LM33) was treated by two specific bacteriophages (536_P1 and LM33_P1; intranasal) or antibiotics (ceftriaxone, cefoxitin, or imipenem-cilastatin; intraperitoneal). Healthy mice also received phages alone. The severity of pulmonary edema, acute inflammatory cytokine concentration (blood and lung homogenates), complete blood counts, and bacterial and bacteriophage counts were determined at early (≤12 h) and late (≥20 h) time points. The efficacy of bacteriophage to decrease bacterial load was faster than with antibiotics, but the two displayed similar endpoints. Bacteriophage treatment was not associated with overinflammation but in contrast tended to lower inflammation and provided a faster correction of blood cell count abnormalities than did antibiotics. In the absence of bacterial infection, bacteriophage 536_P1 promoted a weak increase in the production of antiviral cytokines (gamma interferon [IFN-γ] and interleukin-12 [IL-12]) and chemokines in the lungs but not in the blood. However, such variations were no longer observed when bacteriophage 536_P1 was administered to treat infected animals. The rapid lysis of bacteria by bacteriophages in vivo does not increase the innate inflammatory response compared to that with antibiotic treatment.

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