scholarly journals Mathematical model indicates nonlinearity of noradrenaline effect on rat renal artery

2008 ◽  
pp. 785-788
Author(s):  
M Ďurišová ◽  
L Dedík ◽  
V Kristová ◽  
R Vojtko
Keyword(s):  
Mathematical Model ◽  
Renal Artery ◽  
Computational Procedure ◽  
Maximal Effect ◽  
Evaluation Procedures ◽  
Sensitivity Parameter ◽  
Vascular Responsiveness ◽  
Na Effect ◽  
Effect Time

The aim of this work is to present the efficacy of a previously introduced computational procedure, developed for evaluation of vascular responsiveness. On this reason, as an example a common study of noradrenaline (NA) effect on a rat renal artery under in vitro conditions was arbitrarily selected. The response of the arterial segment to NA doses (0.1-10 μg) was digitally recorded on a PC and employed to develop mathematical model of NA effect. Using the model, the following NA effect variables were determined: the vessel sensitivity parameter, mean effect time and rate constant, respectively, characterizing the effect intensity, duration, and regression and also classic response variables: the maximal effect and time of the maximal effect. The two-way analysis of variance followed by Bonferroni’s test revealed a significant influence of the increasing NA dose on the vessel sensitivity parameter and mean effect time. These findings indicated nonlinearity of processes underlying NA effect on the rat renal artery over the given range of NA doses. The procedure exemplified has the potential for use as an effective adjunct to routine studies of vascular responsiveness as it enables the extraction of meaningful information which cannot by obtained by common manual evaluation procedures.

Usefulness of collaboration between mathematical models and cell engineering for elucidating complex disease mechanisms and discover effective drugs

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
H Kohjitani ◽  
A Kashiwa ◽  
T Makiyama ◽  
F Toyoda ◽  
Y Yamamoto ◽  
...  
Keyword(s):  
Mathematical Model ◽  
In Silico ◽  
Complex Disease ◽  
Ion Selectivity ◽  
Public Institution ◽  
Cell Engineering ◽  
Funding Source ◽  
Patch Clamp Technique ◽  
In Silico Model

Abstract Background A missense mutation, CACNA1C-E1115K, located in the cardiac L-type calcium channel (LTCC), was recently reported to be associated with diverse arrhythmias. Several studies reported in-vivo and in-vitro modeling of this mutation, but actual mechanism and target drug of this disease has not been clarified due to its complex ion-mechanisms. Objective To reveal the mechanism of this diverse arrhythmogenic phenotype using combination of in-vitro and in-silico model. Methods and results Cell-Engineering Phase: We generated human induced pluripotent stem cell (hiPSC) from a patient carrying heterozygous CACNA1C-E1115K and differentiated into cardiomyocytes. Spontaneous APs were recorded from spontaneously beating single cardiomyocytes by using the perforated patch-clamp technique. Mathematical-Modeling Phase: We newly developed ICaL-mutation mathematical model, fitted into experimental data, including its impaired ion selectivity. Furthermore, we installed this mathematical model into hiPSC-CM simulation model. Collaboration Phase: Mutant in-silico model showed APD prolongation and frequent early afterdepolarization (EAD), which are same as in-vitro model. In-silico model revealed this EAD was mostly related to robust late-mode of sodium current occurred by Na+ overload and suggested that mexiletine is capable of reducing arrhythmia. Afterward, we applicated mexiletine onto hiPSC-CMs mutant model and found mexiletine suppress EADs. Conclusions Precise in-silico disease model can elucidate complicated ion currents and contribute predicting result of drug-testing. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Japan Society for the Promotion of Science, Grant-in-Aid for Young Scientists

scholarly journals Predicting the in vivo developmental toxicity of benzo[a]pyrene (BaP) in rats by an in vitro–in silico approach

2021 ◽  
Author(s):  
Danlei Wang ◽  
Maartje H. Rietdijk ◽  
Lenny Kamelia ◽  
Peter J. Boogaard ◽  
Ivonne M. C. M. Rietjens
Keyword(s):  
Dose Response ◽  
In Silico ◽  
Response Curve ◽  
Developmental Toxicity ◽  
Toxicity Testing ◽  
Maximal Effect ◽  
Blood Concentrations ◽  
Reverse Dosimetry

AbstractDevelopmental toxicity testing is an animal-intensive endpoints in toxicity testing and calls for animal-free alternatives. Previous studies showed the applicability of an in vitro–in silico approach for predicting developmental toxicity of a range of compounds, based on data from the mouse embryonic stem cell test (EST) combined with physiologically based kinetic (PBK) modelling facilitated reverse dosimetry. In the current study, the use of this approach for predicting developmental toxicity of polycyclic aromatic hydrocarbons (PAHs) was evaluated, using benzo[a]pyrene (BaP) as a model compound. A rat PBK model of BaP was developed to simulate the kinetics of its main metabolite 3-hydroxybenzo[a]pyrene (3-OHBaP), shown previously to be responsible for the developmental toxicity of BaP. Comparison to in vivo kinetic data showed that the model adequately predicted BaP and 3-OHBaP blood concentrations in the rat. Using this PBK model and reverse dosimetry, a concentration–response curve for 3-OHBaP obtained in the EST was translated into an in vivo dose–response curve for developmental toxicity of BaP in rats upon single or repeated dose exposure. The predicted half maximal effect doses (ED50) amounted to 67 and 45 mg/kg bw being comparable to the ED50 derived from the in vivo dose–response data reported for BaP in the literature, of 29 mg/kg bw. The present study provides a proof of principle of applying this in vitro–in silico approach for evaluating developmental toxicity of BaP and may provide a promising strategy for predicting the developmental toxicity of related PAHs, without the need for extensive animal testing.

scholarly journals Modelling Degradation and Replication Kinetics of the Zika Virus In Vitro Infection

Viruses ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 547
Author(s):  
Veronika Bernhauerová ◽  
Veronica V. Rezelj ◽  
Marco Vignuzzi
Keyword(s):  
Mathematical Model ◽  
Viral Infection ◽  
Host Cell ◽  
Decay Time ◽  
Zika Virus ◽  
Infectious Virus ◽  
Numerical Characterization ◽  
The Mathematical Model

Mathematical models of in vitro viral kinetics help us understand and quantify the main determinants underlying the virus–host cell interactions. We aimed to provide a numerical characterization of the Zika virus (ZIKV) in vitro infection kinetics, an arthropod-borne emerging virus that has gained public recognition due to its association with microcephaly in newborns. The mathematical model of in vitro viral infection typically assumes that degradation of extracellular infectious virus proceeds in an exponential manner, that is, each viral particle has the same probability of losing infectivity at any given time. We incubated ZIKV stock in the cell culture media and sampled with high frequency for quantification over the course of 96 h. The data showed a delay in the virus degradation in the first 24 h followed by a decline, which could not be captured by the model with exponentially distributed decay time of infectious virus. Thus, we proposed a model, in which inactivation of infectious ZIKV is gamma distributed and fit the model to the temporal measurements of infectious virus remaining in the media. The model was able to reproduce the data well and yielded the decay time of infectious ZIKV to be 40 h. We studied the in vitro ZIKV infection kinetics by conducting cell infection at two distinct multiplicity of infection and measuring viral loads over time. We fit the mathematical model of in vitro viral infection with gamma distributed degradation time of infectious virus to the viral growth data and identified the timespans and rates involved within the ZIKV-host cell interplay. Our mathematical analysis combined with the data provides a well-described example of non-exponential viral decay dynamics and presents numerical characterization of in vitro infection with ZIKV.

Light-dependent hydration of the space surrounding photoreceptors in the cat retina

1994 ◽  
Vol 11 (4) ◽  
pp. 743-752 ◽  
Author(s):  
Jian-Dong Li ◽  
Victor I. Govardovskii ◽  
Roy H. Steinberg
Keyword(s):  
Mathematical Model ◽  
Time Course ◽  
Distal Portion ◽  
Subretinal Space ◽  
Volume Increase ◽  
Physiological Event ◽  
Cat Retina ◽  
Interphotoreceptor Matrix ◽  
Space Marker

AbstractWe have studied the effect of retinal illumination on the concentration of the extracellular space marker tetramethylammonium (TMA+) in the dark-adapted cat retina using double-barreled ion-selective microelectrodes. The retina was loaded with TMA+ by a single intravitreal injection. Retinal illumination produced a slow decrease in , which was maximal in amplitude in the most distal portion of the space surrounding photoreceptors, the subretinal space. The light-evoked decrease in was considerably slower and of a different overall time course than the light-evoked decrease in , also recorded in the subretinal space. decreased to a peak at 38 s after the onset of illumination, then slowly recovered towards the baseline, and transiently increased following the offset of illumination. It resembled the light-evoked decreases previously recorded in the in vitro preparations of frog (Huang & Karwoski, 1990, 1992) and chick (Li et al., 1992, 1994) but was considerably larger in amplitude, 22% compared with 7%. As in frog, where it was first recorded, the light-evoked decrease is considered to originate from a light-evoked increase in the volume of the subretinal space (or subretinal hydration). A mathematical model accounting for diffusion predicted that the volume increase underlying the response was 63% on average and could be as large as 95% and last for minutes. The estimated volume increase was then used to examine its effect on K+ concentration in the subretinal space. We conclude that a light-dependent hydration of the subretinal space represents a significant physiological event in the intact cat eye, which should affect the organization of the interphotoreceptor matrix, and the concentrations of all ions and metabolites located in the subretinal space.

scholarly journals In Vitro Pharmacodynamics of the New Ketolides HMR 3004 and HMR 3647 (Telithromycin) against Chlamydia pneumoniae

2000 ◽  
Vol 44 (7) ◽  
pp. 1846-1849 ◽  
Author(s):  
I. Gustafsson ◽  
E. Hjelm ◽  
O. Cars
Keyword(s):  
Kinetic Model ◽  
Chlamydia Pneumoniae ◽  
Time Dependent ◽  
Intracellular Pathogen ◽  
Maximal Effect ◽  
Subinhibitory Concentration ◽  
Killing Effect ◽  
New Class ◽  
Unit Reduction

ABSTRACT The ketolides HMR 3004 and HMR 3647 (telithromycin) are a new class of macrolides that have a potential clinical efficacy against intracellular pathogens. The objectives of this study were to investigate the MIC, minimum bactericidal concentration, and time-dependent killing of two Chlamydia pneumoniaestrains of the two ketolides. The killing effect was also studied with a newly developed intracellular in vitro kinetic model. Furthermore, HMR 3647 was studied for the effect of a subinhibitory concentration of 0.5 times the MIC after a preexposure of 10 times the MIC during 12 h. The MICs for both strains were 0.0039 and 0.0156 mg/liter for HMR 3004 and HMR 3647, respectively. Killing with 10 times the MIC was time dependent, increasing from a 1-log-unit decrease in the number of inclusions per well at 48 h to a maximal effect of 2.8-log-unit decrease after 96 h. A preexposure of 10 times the MIC of HMR 3647 for 12 h followed by a subinhibitory concentration of 0.5 times the MIC increased the killing effect to a 1.2-log-unit reduction in inclusions per well. An exposure for 12 h gave poor reduction of inclusions, while a static dose of 10 times the MIC for 72 h showed a 2.2-log-unit reduction in inclusions per well. In the kinetic model, a small number of inclusions were detected after 72 h by one exposure of 10 times the MIC. Regrowth could not be detected after 120 h. The ketolides HMR 3004 and HMR 3647 have bactericidal activity and show a significant sub-MIC effect on the intracellular pathogenC. pneumoniae.

scholarly journals THE RATE OF BACTERICIDAL ACTION OF PENICILLIN IN VITRO AS A FUNCTION OF ITS CONCENTRATION, AND ITS PARADOXICALLY REDUCED ACTIVITY AT HIGH CONCENTRATIONS AGAINST CERTAIN ORGANISMS

1948 ◽  
Vol 88 (1) ◽  
pp. 99-131 ◽  
Author(s):  
Harry Eagle ◽  
A. D. Musselman
Keyword(s):  
Bacterial Species ◽  
Fold Increase ◽  
Bactericidal Effect ◽  
Penicillin G ◽  
Bacterial Suspension ◽  
Maximal Effect ◽  
Maximal Rate ◽  
Effective Level ◽  
High Concentrations

1. The concentrations of penicillin G which (a) reduced the net rate of multiplication, (b) exerted a net bactericidal effect, and (c) killed the organisms at a maximal rate, have been defined for a total of 41 strains of α- and ß-hemolytic streptococci, Staphylococcus aureus and Staphylococcus albus, Diplococcus pneumoniae, and the Reiter treponoma. 2. The concentration which killed the organisms at a maximal rate was 2 to 20 times the minimal effective level ("sensitivity" as ordinarily defined). With some organisms, even a 32,000-fold increase beyond this maximally effective level did not further increase the rate of its bactericidal effect. However, with approximately half the strains here studied (all 4 strains of group B ß-hemolytic streptococci, 4 of 5 group C strains, 5 of 7 strains of Streptococcus fecalis, 2 of 4 other α-hemolytic streptococci, and 4 of 9 strains of staphylococci), when the concentration of penicillin was increased beyond that optimal level, the rate at which the organisms died was paradoxically reduced rather than increased, so that the maximal effect was obtained only within a relatively narrow optimal zone. 3. There were marked differences between bacterial species, and occasionally between different strains of the same species, not only with respect to the effective concentrations of penicillin, but also with respect to the maximal rate at which they could be killed by the drug in any concentration. Although there was a rough correlation between these two factors, there were many exceptions; individual strains affected only by high concentrations of penicillin might nevertheless be killed rapidly, while strains sensitive to minute concentrations might be killed only slowly. 4. Within the same bacterial suspension, individual organisms varied only to a minor degree with respect to the effective concentrations of penicillin. They varied strikingly, however, in their resistance to penicillin as measured by the times required to kill varying proportions of the cells.

AN ENHANCEMENT OF SOLUBILITY OF PIOGLITAZONE HYDROCHLORIDE USING LIQUISOLID TECHNIQUE

INDIAN DRUGS ◽  
2013 ◽  
Vol 50 (06) ◽  
pp. 36-39
Author(s):  
S Deshmane ◽  
◽  
K Gandhi ◽  
S. Nagpure ◽  
A. Sawant ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Drug Release ◽  
Dissolution Rate ◽  
In Vivo Study ◽  
Dimethyl Acetamide ◽  
Volatile Liquid ◽  
Ft Ir ◽  
Ir Study

The new mathematical model was developed by studying angle of slide using N, N-dimethyl acetamide, non-volatile liquid vehicle and prepared liquisolid tablets, in which the different concentrations of non-volatile liquid adsorbed over carrier and coating material separately. Both DSC and FT-IR study showed better compatibility and stability. The optimized formulation showed higher drug release during in-vitro and in-vivo study against conventional and marketed preparation. The present work concludes that N, N-dimethyl acetamide enhanced the solubility of pioglitazone HCl with higher dissolution rate through liquisolid technique.

Stereoselective Loss of Righting Reflex in Rats by Isoflurane

2000 ◽  
Vol 93 (3) ◽  
pp. 837-843 ◽  
Author(s):  
Robert Dickinson ◽  
Ian White ◽  
William R. Lieb ◽  
Nicholas P. Franks
Keyword(s):  
Molecular Targets ◽  
Maximal Effect ◽  
General Anesthetics ◽  
General Anesthetic ◽  
Response Curves ◽  
Loss Of Righting Reflex ◽  
Large Numbers ◽  
Righting Reflex ◽  
Volatile Agents

Background Although it is accepted widely that optically active intravenous general anesthetics produce stereoselective effects in animals, the situation regarding volatile agents is confused. Conventional studies with scarce isoflurane enantiomers have been limited to small numbers of animals and produced conflicting results. By injecting these volatile enantiomers intravenously, however, it is possible to study large numbers of animals and obtain reliable results that can help to identify the molecular targets for isoflurane. Methods Pure isoflurane enantiomers were administered intravenously to rats after solubilization in a lipid emulsion. The ability of each enantiomer to produce a loss of righting reflex was determined as a function of dose, and quantal dose-response curves were constructed. In addition, sleep times were recorded with each enantiomer. Chiral gas chromatography was used to measure relative enantiomer concentrations in the brains of rats injected with racemic isoflurane. Results The S(+)-enantiomer was 40 +/- 8% more potent than the R(-)-enantiomer at producing a loss of righting reflex. The S(+)-enantiomer induced longer sleep times (by about 50%) than did the R(-)-enantiomer. Rats anesthetized by a dose of racemic isoflurane sufficient to achieve a half-maximal effect had essentially identical brain concentrations of the two enantiomers. Conclusions The S(+)-enantiomer of the general anesthetic isoflurane is significantly (P < 0.001) more potent than the R(-)-enantiomer at causing a loss of righting reflex in rats. This confirms the view that isoflurane acts by binding to chiral sites. The observed degree of stereoselectivity provides a useful guide for ascertaining from in vitro experiments which molecular targets are most likely to play major roles in the loss of righting reflex caused by isoflurane.

scholarly journals Modelling the population-level protection conferred by COVID-19 vaccination

2021 ◽  
Author(s):  
Pranesh Padmanabhan ◽  
Rajat Desikan ◽  
Narendra M Dixit
Keyword(s):  
Mathematical Model ◽  
Severe Acute Respiratory Syndrome ◽  
Dose Response ◽  
Neutralizing Antibodies ◽  
Population Level ◽  
Response Curves ◽  
Post Vaccination ◽  
Dose Response Curves ◽  
Vaccine Availability

Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines work predominantly by eliciting neutralizing antibodies (NAbs), how the protection they confer depends on the NAb response to vaccination is unclear. Here, we collated and analysed in vitro dose-response curves of >70 NAbs and constructed a landscape defining the spectrum of neutralization efficiencies of NAbs elicited. We mimicked responses of individuals by sampling NAb subsets of known sizes from the landscape and found that they recapitulated responses of convalescent patients. Combining individual responses with a mathematical model of within-host SARS-CoV-2 infection post-vaccination, we predicted how the population-level protection conferred would increase with the NAb response to vaccination. Our predictions captured the outcomes of vaccination trials. Our formalism may help optimize vaccination protocols, given limited vaccine availability.

scholarly journals Assessment of a mathematical model considering the effect of flow rate on in-vitro drug-release from PLGA films

2021 ◽  
Vol 321 ◽  
pp. 04011
Author(s):  
Navideh Abbasnezhad ◽  
Farid Bakir ◽  
Stéphane Champmartin ◽  
Mohammadali Shirinbayan
Keyword(s):  
Mathematical Model ◽  
Drug Release ◽  
Flow Rate ◽  
Drug Carrier ◽  
Diclofenac Sodium ◽  
Drug Eluting Stents ◽  
In Vitro Drug Release ◽  
Drug Eluting ◽  
Release Profiles

Drug-eluting stents implanted in blood vessels are subject to various dynamics of blood flow. In this study, we present the evaluation of a mathematical model considering the effect of flow rate, to simulate the kinetic profiles of drug release (Diclofenac Sodium (DS)) from in-vitro from PLGA films. This model solves a set of non-linear equation for modeling simultaneously the burst, diffusion, swelling and erosion involved in the mechanisms of liberation. The release parameters depending on the flow rate are determined using the corresponding mathematical equations. For the evaluation of the proposed model, test data obtained in our laboratory are used. To quantify DS release from drug-carrier PLGA films, we used the flow-through cell apparatus in a closed-loop. Four flow rate values are applied. For each value, the model-substance liberation kinetics showed an increase in drug released with the flow rate. The simulated release profiles show good agreement with the experimental results. Therefore, the use of this model could provide a practical tool to assess in-vitro drug release profiles from polymer matrices under continuous flow rate constraint, and could help improve the design of drug eluting stents.

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