scholarly journals Use of Drug Effect Interaction Modeling with Monte Carlo Simulation To Examine the Impact of Dosing Interval on the Projected Antiviral Activity of the Combination of Abacavir and Amprenavir

2000 ◽  
Vol 44 (6) ◽  
pp. 1655-1659 ◽  
Author(s):  
G. L. Drusano ◽  
D. Z. D'Argenio ◽  
S. L. Preston ◽  
C. Barone ◽  
W. Symonds ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Steady State ◽  
Protease Inhibitor ◽  
Antiviral Effect ◽  
In Vitro Assays ◽  
Maximal Effect ◽  
Dosing Interval ◽  
Average Percentage ◽  
The Impact

ABSTRACT The delineation of optimal regimens for combinations of agents is a difficult problem, in part because, to address it, one needs to (i) have effect relationships between the pathogen in question and the drugs in the combination, (ii) have knowledge of how the drugs interact (synergy, antagonism, and additivity), and (iii) address the issue of true between-patient variability in pharmacokinetics for the drugs in the population. We have developed an approach which employs a fully parametric assessment of drug interaction using the equation of W. R. Greco, G. Bravo, and J. C. Parsons (Pharmacol. Rev. 47:331–385, 1995) to generate an estimate of effects for the two drugs and have linked this approach to a population simulator, using Monte Carlo methods, which produce concentration-time profiles for the drugs in combination. This software automatically integrates the effect over a steady-state dosing interval and produces an estimate of the mean effect over a steady-state interval for each simulated subject. In this way, doses and schedules can be easily evaluated. This software allows for a rational choice of dose and schedule for evaluation in clinical trials. We evaluated different schedules of administration for the combination of the nucleoside analogue abacavir plus the human immunodeficiency virus type 1 protease inhibitor amprenavir. Amprenavir was simulated as either 800 mg every 8 h (q8h) or 1,200 mg q12h, each along with 300 mg q12h of abacavir. Both regimens produced excellent effects over the simulated population of 500 subjects, with average percentages of maximal effect (as determined from the in vitro assays) of 90.9% ± 11.4% and 80.9% ± 18.6%, respectively. This difference is statistically significant (P≪ 0.001). In addition, 68.8 and 46.0% of the population had an average percentage of maximal effect which was greater than or equal to 90% for the two regimens. We can conclude that the combination of abacavir plus amprenavir is a potent combination when it is given on either schedule. However, the more fractionated schedule for the protease inhibitor produced significantly better effects in combination. Clinicians need to explicitly balance the improvement in antiviral effect seen with the more fractionated regimen against the loss of compliance attendant to the use of such a regimen. This approach may be helpful in the preclinical evaluation of multidrug anti-infective regimens.

scholarly journals Modeling combinations of antiretroviral agents in vitro with integration of pharmacokinetics: guidance in regimen choice for clinical trial evaluation.

1996 ◽  
Vol 40 (5) ◽  
pp. 1143-1147 ◽  
Author(s):  
G L Drusano ◽  
M Prichard ◽  
P A Bilello ◽  
J A Bilello
Keyword(s):  
Drug Interaction ◽  
Steady State ◽  
Continuous Infusion ◽  
Three Dimensional ◽  
Pharmacokinetic Profile ◽  
Maximal Effect ◽  
Direct Evaluation ◽  
Average Percentage ◽  
The Mean

We propose a method for the selection of doses and dosing schedule for drugs to be used in combination. This approach uses the simulation of steady-state concentrations of the drugs in the combination and overlays these concentrations onto a three-dimensional effect surface. The MacSynergy II program is used to construct the three-dimensional drug interaction surface from the direct evaluation of drug combination effect in vitro. The study examined the combination of an inhibitor of the human immunodeficiency virus protease, A-77003, and the nucleoside analog zidovudine. Zidovudine concentrations from a steady-state interval were simulated on the basis of the administration of 100 mg every 12 h by mouth, while for A-77003 simulation profiles were for intravenous administration of 800 mg every 4 h as well as a continuous infusion of 200 mg/h. The average percentage of the maximal effect was taken as a measure of regimen effectiveness. Three different schedules of administration were examined. If both drugs were to be administered simultaneously, the model predicts a mean maximal effect of a steady-state interval (12 h) of 67%. If the drug doses were offset by 2 h, the mean maximal effect predicted was 71%. If A-77003 was to be given by continuous infusion, the mean maximal effect predicted was 90%. This method holds promise as a way of quickly evaluating potential combinations of agents that takes into account the drug interaction in a mathematically robust way and that allows the evaluation of the effect of each drug's pharmacokinetic profile.

scholarly journals In Vitro Antiviral Activity of the Novel, Tyrosyl-Based Human Immunodeficiency Virus (HIV) Type 1 Protease Inhibitor Brecanavir (GW640385) in Combination with Other Antiretrovirals and against a Panel of Protease Inhibitor-Resistant HIV

2007 ◽  
Vol 51 (9) ◽  
pp. 3147-3154 ◽  
Author(s):  
Richard Hazen ◽  
Robert Harvey ◽  
Robert Ferris ◽  
Charles Craig ◽  
Phillip Yates ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiviral Activity ◽  
Protease Inhibitor ◽  
Reverse Transcriptase ◽  
In Vitro Assays ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT Brecanavir, a novel tyrosyl-based arylsulfonamide, high-affinity, human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI), has been evaluated for anti-HIV activity in several in vitro assays. Preclinical assessment of brecanavir indicated that this compound potently inhibited HIV-1 in cell culture assays with 50% effective concentrations (EC50s) of 0.2 to 0.53 nM and was equally active against HIV strains utilizing either the CXCR4 or CCR5 coreceptor, as was found with other PIs. The presence of up to 40% human serum decreased the anti-HIV-1 activity of brecanavir by 5.2-fold, but under these conditions the compound retained single-digit nanomolar EC50s. When brecanavir was tested in combination with nucleoside reverse transcriptase inhibitors, the antiviral activity of brecanavir was synergistic with the effects of stavudine and additive to the effects of zidovudine, tenofovir, dideoxycytidine, didanosine, adefovir, abacavir, lamivudine, and emtricitabine. Brecanavir was synergistic with the nonnucleoside reverse transcriptase inhibitor nevirapine or delavirdine and was additive to the effects of efavirenz. In combination with other PIs, brecanavir was additive to the activities of indinavir, lopinavir, nelfinavir, ritonavir, amprenavir, saquinavir, and atazanavir. Clinical HIV isolates from PI-experienced patients were evaluated for sensitivity to brecanavir and other PIs in a recombinant virus assay. Brecanavir had a <5-fold increase in EC50s against 80% of patient isolates tested and had a greater mean in vitro potency than amprenavir, indinavir, lopinavir, atazanavir, tipranavir, and darunavir. Brecanavir is by a substantial margin the most potent and broadly active antiviral agent among the PIs tested in vitro.

Soaps and Detergents: Alternatives to Animal Eye Irritation Tests

1996 ◽  
Vol 15 (1) ◽  
pp. 1-44 ◽  
Author(s):  
Mildred S. Christian ◽  
Robert M. Diener
Keyword(s):  
False Negative ◽  
Screening Tools ◽  
Current Status ◽  
In Vitro Assays ◽  
Computer Search ◽  
Eye Irritation ◽  
Vitro Assay ◽  
Predictive Values ◽  
The Impact

An extensive computer search was conducted, and a comprehensive overview of the current status of alternatives to animal eye irritation tests was obtained. A search of Medline and Toxline databases (1988 to present) was supplemented with references from sources regarding in vitro eye irritation. Particular attention was paid to soap and detergent products and related ingredients. Eighty-five references are included in the review; the in vitro assays are categorized, and their predictive values for assessing acute ocular irritation are evaluated and compared with the Draize rabbit eye irritation assay and with each other. The present review shows that the increased activity of scientists from academia, industry, and regulatory agencies has resulted in substantial progress in developing alternative in vitro procedures and that a number of large, interlaboratory evaluations and international workshops have assisted in the selection process. However, none of these methodologies has obtained acceptance for regulatory classification purposes. Conclusions drawn from this review include that (a) no single in vitro assay is considered capable of replacing the Draize eye irritation test; (b) the chorioallantoic membrane vascular assay (CAMVA) or the hen egg test-chorio-allantoic membrane test (HET-CAM), the chicken or bovine enucleated eye test, the neutral red and plasminogen activation assays for cytotoxicity, and the silicon microphysiometer appear to have the greatest potential as screening tools for eye irritation; and (c) choosing a specific assay or series of assays will depend on the type of agent tested and the impact of false-negative or false-positive results. New assays will continue to be developed and should be included in future evaluations, when sufficient data are available.

scholarly journals Intratumoral injection reduces toxicity and antibody-mediated neutralization of immunocytokine in a mouse melanoma model

2020 ◽  
Vol 8 (2) ◽  
pp. e001262
Author(s):  
Claire C Baniel ◽  
Elizabeth G Sumiec ◽  
Jacqueline A Hank ◽  
Amber M Bates ◽  
Amy K Erbe ◽  
...  
Keyword(s):  
Tumor Regression ◽  
Interleukin 2 ◽  
Intratumoral Injection ◽  
In Vitro Assays ◽  
Human Antibody ◽  
Severe Toxicity ◽  
Tumor Bearing ◽  
The Impact

BackgroundSome patients with cancer treated with anticancer monoclonal antibodies (mAbs) develop antidrug antibodies (ADAs) that recognize and bind the therapeutic antibody. This response may neutralize the therapeutic mAb, interfere with mAb effector function or cause toxicities. We investigated the potential influence of ADA to modify the tumor-binding capability of a tumor-reactive ‘immunocytokine’ (IC), namely, a fusion protein (hu14.18-IL2) consisting of a humanized, tumor-reactive, anti-GD2 mAb genetically linked to interleukin 2. We characterize the role of treatment delivery of IC (intravenous vs intratumoral) on the impact of ADA on therapeutic outcome following IC treatments in an established antimelanoma (MEL) regimen involving radiotherapy (RT) +IC.MethodsC57BL/6 mice were injected with human IgG or the hu14.18-IL2 IC to develop a mouse anti-human antibody (MAHA) response (MAHA+). In vitro assays were performed to assess ADA binding to IC using sera from MAHA+ and MAHA− mice. In vivo experiments assessed the levels of IC bound to tumor in MAHA+ and MAHA− mice, and the influence of IC route of delivery on its ability to bind to B78 (GD2+) MEL tumors.ResultsMAHA is inducible in C57BL/6 mice. In vitro assays show that MAHA is capable of inhibiting the binding of IC to GD2 antigen on B78 cells, resulting in impaired ADCC mediated by IC. When B78-bearing mice are injected intravenously with IC, less IC binds to B78-MEL tumors in MAHA+ mice than in MAHA− mice. In contrast, when IC is injected intratumorally in tumor-bearing mice, the presence of MAHA does not detectibly impact IC binding to the tumor. Combination therapy with RT+IT-IC showed improved tumor regression compared with RT alone in MAHA+ mice. If given intratumorally, IC could be safely readministered in tumor-bearing MAHA+ mice, while intravenous injections of IC in MAHA+ mice caused severe toxicity. Histamine levels were elevated in MAHA+ mice compared with MAHA− mice after reintroduction of IC.ConclusionsIntratumoral injection may be a means of overcoming ADA neutralization of therapeutic activity of tumor-reactive mAbs or ICs and may reduce systemic toxicity, which could have significant translational relevance.

How changes in the crystal temperature and the doping concentration impact upon bulk wurtzite zinc oxide’s electron transport response

MRS Advances ◽  
2019 ◽  
Vol 4 (50) ◽  
pp. 2673-2678
Author(s):  
Poppy Siddiqua ◽  
Walid A. Hadi ◽  
Michael S. Shur ◽  
Stephen K. O’Leary
Keyword(s):  
Monte Carlo ◽  
Steady State ◽  
Electron Transport ◽  
Drift Velocity ◽  
Doping Concentration ◽  
Electron Drift ◽  
Crystal Temperature ◽  
Transient Transport ◽  
Transport Response ◽  
The Impact

ABSTRACTThe role that changes in the crystal temperature and the doping concentration play in shaping the character of the steady-state and transient transport response of electrons within bulk wurtzite zinc oxide will be examined. Monte Carlo electron transport simulations are drawn upon for the purposes of this analysis. We find that both the crystal temperature and the doping concentration greatly influence the character of the steady-state and transient electron transport response. In particular, for the case of steady-state electron transport, the peak drift velocity decreases by 30% as the crystal temperature is increased from 100 to 700 K, this decrease in velocity being only 20% as the doping concentration is increased from 1015 to 1019 cm-3. The impact on the transient electron drift velocity is not as acute.

Abstracts

2008 ◽  
Vol 27 (6) ◽  
pp. 405-405
Author(s):  
David J. Dix
Keyword(s):  
Risk Assessment ◽  
High Throughput ◽  
Environmental Protection Agency ◽  
High Throughput Screening ◽  
Human Health Risk ◽  
Environmental Chemicals ◽  
In Vitro Assays ◽  
The Impact ◽  
Toxicity Pathways

The U.S. Environmental Protection Agency (EPA), National Toxicology Program (NTP), and National Institutes of Health (NIH) Chemical Genomics Center (NCGC) have complementary research programs designed to improve chemical toxicity evaluations by developing high throughput screening (HTS) methods that evaluate the impact of environmental chemicals on key toxicity pathways. These federal partners are coordinating an extension of the EPA’s ToxCast program, the NTP’s HTS initiative, and the NCGC’s Molecular Libraries Initiative into a collaborative research program focused on identifying toxicity pathways and developing in vitro assays to characterize the ability of chemicals to perturb those pathways. The goal is to develop new paradigm for high throughput toxicity testing that collects mechanistic and quantitative data from in vitro assays measuring chemical modulation of biological processes involved in the progression to toxicity. As toxicity pathways are identified, the in vitro assays can be optimized for comparison to in vivo animal studies, and for predicting effects in humans. Subsequent computational modeling of toxicity pathway responses and appropriate chemical dosimetry will need to be developed to make these predictions relevant for human health risk assessment. This work was reviewed by EPA and approved for publication but does not necessarily reflect official Agency policy. Index Terms: Toxicogenomics, High Throughput Screening/Testing, EPA ToxCast, Chemical Risk Assessment

scholarly journals Effects of Processing on Polyphenolic and Volatile Composition and Fruit Quality of Clery Strawberries

Antioxidants ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 632
Author(s):  
Stefania Garzoli ◽  
Francesco Cairone ◽  
Simone Carradori ◽  
Andrei Mocan ◽  
Luigi Menghini ◽  
...  
Keyword(s):  
Antioxidant Activity ◽  
Central Italy ◽  
In Vitro Assays ◽  
Bioactive Metabolites ◽  
Total Phenolic ◽  
Color Analysis ◽  
Food Ingredient ◽  
Red Color ◽  
The Impact

Strawberries belonging to cultivar Clery (Fragaria x ananassa (Duchesne ex Weston)), cultivated in central Italy were subjected to a multi-methodological experimental study. Fresh and defrosted strawberries were exposed to different processing methods, such as homogenization, thermal and microwave treatments. The homogenate samples were submitted to CIEL*a*b* color analysis and Head-Space GC/MS analysis to determine the impact of these procedures on phytochemical composition. Furthermore, the corresponding strawberry hydroalcoholic extracts were further analyzed by HPLC-DAD for secondary metabolites quantification and by means of spectrophotometric in vitro assays to evaluate their total phenolic and total flavonoid contents and antioxidant activity. These chemical investigations confirmed the richness in bioactive metabolites supporting the extraordinary healthy potential of this fruit as a food ingredient, as well as functional food, highlighting the strong influence of the processing steps which could negatively impact on the polyphenol composition. Despite a more brilliant red color and aroma preservation, non-pasteurized samples were characterized by a lower content of polyphenols and antioxidant activity with respect to pasteurized samples, as also suggested by the PCA analysis of the collected data.

scholarly journals The Enterovirus Protease Inhibitor Rupintrivir Exerts Cross-Genotypic Anti-Norovirus Activity and Clears Cells from the Norovirus Replicon

2014 ◽  
Vol 58 (8) ◽  
pp. 4675-4681 ◽  
Author(s):  
J. Rocha-Pereira ◽  
M. S. J. Nascimento ◽  
Q. Ma ◽  
R. Hilgenfeld ◽  
J. Neyts ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Antiviral Effect ◽  
Inhibitory Effect ◽  
Murine Norovirus ◽  
Norwalk Virus ◽  
Rna Dependent Rna Polymerase ◽  
Human Norovirus ◽  
Polymerase Inhibitors ◽  
Murine Noroviruses

ABSTRACTPotent and safe inhibitors of norovirus replication are needed for the treatment and prophylaxis of norovirus infections. We here report that thein vitroanti-norovirus activity of the protease inhibitor rupintrivir is extended to murine noroviruses and that rupintrivir clears human cells from their Norwalk replicon after only two passages of antiviral pressure. In addition, we demonstrate that rupintrivir inhibits the human norovirus (genogroup II [GII]) protease and further explain the inhibitory effect of the molecule by means of molecular modeling on the basis of the crystal structure of the Norwalk virus protease. The combination of rupintrivir with the RNA-dependent RNA polymerase inhibitors 2′-C-methylcytidine and favipiravir (T-705) resulted in a merely additive antiviral effect. The fact that rupintrivir is active against noroviruses belonging to genogroup I (Norwalk virus), genogroup V (murine norovirus), and the recombinant 3C-like protease of a GII norovirus suggests that the drug exerts cross-genotypic anti-norovirus activity and will thus most likely be effective against the clinically relevant human norovirus strains. The design of antiviral molecules targeting the norovirus protease could be a valuable approach for the treatment and/or prophylaxis of norovirus infections.

scholarly journals Human Bone Marrow Mesenchymal Stem/Stromal Cells Preserve Their Immunomodulatory and Chemotactic Properties When Expanded in a Human Plasma Derived Xeno-Free Medium

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
A. Blázquez-Prunera ◽  
C. R. Almeida ◽  
M. A. Barbosa
Keyword(s):  
Bone Marrow ◽  
Human Plasma ◽  
Medium Composition ◽  
In Vitro Assays ◽  
Migration And Invasion ◽  
Potential Candidate ◽  
Free Medium ◽  
Cell Therapies ◽  
The Impact

Due to their immunomodulatory and chemotactic properties, hMSC are being explored to treat immune-related diseases. For their use in human therapies, it is necessary to culture hMSC in xeno-free conditions. In this study, the impact that a xeno-free medium based on a human plasma derivate has on these properties was analysed. Bone marrow-derived hMSC preserved their immunosuppressive and immunostimulatory properties, as observed with in vitro assays with hMSC cocultured with mixed leukocyte reactions or with mitogen-stimulated leukocytes. Moreover, hMSC expanded in xeno-free medium were recruited by macrophages in both migration and invasion assays, which indicates that the cells maintained their chemotactic properties. These data suggest that xeno-free expanded hMSC preserved their immunomodulatory and chemotactic properties, indicating that the described xeno-free medium composition is a potential candidate to culture and expand hMSC for human cell therapies.

scholarly journals The continuing evolution of the Langendorff and ejecting murine heart: new advances in cardiac phenotyping

2012 ◽  
Vol 303 (2) ◽  
pp. H156-H167 ◽  
Author(s):  
Ronglih Liao ◽  
Bruno K. Podesser ◽  
Chee Chew Lim
Keyword(s):  
Vascular Reactivity ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Isolated Heart ◽  
Ischemia Reperfusion ◽  
In Vitro Assays ◽  
Mouse Heart ◽  
Heart Preparation ◽  
The Impact

The isolated retrograde-perfused Langendorff heart and the isolated ejecting heart have, over many decades, resulted in fundamental discoveries that form the underpinnings of our current understanding of the biology and physiology of the heart. These two experimental methodologies have proven invaluable in studying pharmacological effects on myocardial function, metabolism, and vascular reactivity and in the investigation of clinically relevant disease states such as ischemia-reperfusion injury, diabetes, obesity, and heart failure. With the advent of the genomics era, the isolated mouse heart preparation has gained prominence as an ex vivo research tool for investigators studying the impact of gene modification in the intact heart. This review summarizes the historical development of the isolated heart and provides a practical guide for the establishment of the Langendorff and ejecting heart preparations with a particular emphasis on the murine heart. In addition, current applications and novel methods of recording cardiovascular parameters in the isolated heart preparation will be discussed. With continued advances in methodological recordings, the isolated mouse heart preparation will remain physiologically relevant for the foreseeable future, serving as an integral bridge between in vitro assays and in vivo approaches.

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