The guinea pig tracheobronchial spiral strip: responses to selected agonists

1978 ◽  
Vol 56 (5) ◽  
pp. 823-827 ◽  
Author(s):  
C. J. Hanna ◽  
S. H. Roth
Keyword(s):  
Regression Analysis ◽  
Guinea Pig ◽  
Dose Response ◽  
Effective Concentration ◽  
Relative Order ◽  
Response Curves ◽  
Response Data ◽  
Significant Difference ◽  
Dose Dependent

The guinea pig tracheal spiral strip is a useful preparation for studying bronchoconstrictor and bronchodilator compounds. Employing a simple and rapid modification of this technique, experiments were performed in vitro to quantitate the effects of selected bronchospastic agents on guinea pig tracheobronchial smooth muscle. Three sections of the main airways were prepared from each animal: an upper tracheal, a lower tracheal, and a bronchial segment. The dose-dependent contractile responses of the three tissue segments were determined for carbachol, acetylcholine, histamine, 5-hydroxytryptamine, and bradykinin, Differences were observed amongst the agonists in magnitudes of contraction, effective concentration ranges, and slopes of dose–response curves. ED25, ED50, and ED75, values were calculated from regression analysis of dose–response data. The relative order for these agents to produce maximum contractions was found to be carbachol [Formula: see text] acetylcholine > histamine > 5-hydroxytryptamine > bradykinin. Furthermore, it was found that there was no significant difference between the three tissue segments in their responses to the various agonists.

scholarly journals Prediction of dose-dependent in vivo acetylcholinesterase inhibition by profenofos in rats and humans using physiologically based kinetic (PBK) modeling-facilitated reverse dosimetry

2021 ◽  
Vol 95 (4) ◽  
pp. 1287-1301
Author(s):  
Isaac Omwenga ◽  
Shensheng Zhao ◽  
Laetitia Kanja ◽  
Hans Mol ◽  
Ivonne M. C. M. Rietjens ◽  
...  
Keyword(s):  
Dose Response ◽  
In Silico ◽  
Acetylcholinesterase Inhibition ◽  
Ache Inhibition ◽  
Response Data ◽  
Physiologically Based ◽  
Parameter Values ◽  
Dose Dependent

AbstractOrganophosphate pesticides (OPs) are known to inhibit acetylcholine esterase (AChE), a critical effect used to establish health-based guidance values. This study developed a combined in vitro–in silico approach to predict AChE inhibition by the OP profenofos in rats and humans. A physiologically based kinetic (PBK) model was developed for both species. Parameter values for profenofos conversion to 4-bromo-2-chlorophenol (BCP) were derived from in vitro incubations with liver microsomes, liver cytosol, and plasma from rats (catalytic efficiencies of 1.1, 2.8, and 0.19 ml/min/mg protein, respectively) and humans (catalytic efficiencies of 0.17, 0.79, and 0.063 ml/min/mg protein, respectively), whereas other chemical-related parameter values were derived using in silico calculations. The rat PBK model was evaluated against literature data on urinary excretion of conjugated BCP. Concentration-dependent inhibition of rat and human AChE was determined in vitro and these data were translated with the PBK models to predicted dose-dependent AChE inhibition in rats and humans in vivo. Comparing predicted dose-dependent AChE inhibition in rats to literature data on profenofos-induced AChE inhibition revealed an accurate prediction of in vivo effect levels. Comparison of rat predictions (BMDL10 of predicted dose–response data of 0.45 mg/kg bw) and human predictions (BMDL10 of predicted dose–response data of 0.01 mg/kg bw) suggests that humans are more sensitive than rats, being mainly due to differences in kinetics. Altogether, the results demonstrate that in vivo AChE inhibition upon acute exposure to profenofos was closely predicted in rats, indicating the potential of this novel approach method in chemical hazard assessment.

Methacholine dose-response curves in normal and asthmatic man: Effect of starting conductance and pharmacological antagonism

1984 ◽  
Vol 66 (6) ◽  
pp. 665-673 ◽  
Author(s):  
K. F. Chung ◽  
P. D. Snashall
Keyword(s):  
Dose Response ◽  
Normal Subjects ◽  
Small Degree ◽  
Response Curves ◽  
Significant Difference ◽  
Positive Linear Correlation ◽  
Dose Response Curves ◽  
Dose Dependent Increase ◽  
Dose Dependent ◽  
Different Doses

1. The bronchial response of 11 normal and ten stable asthmatic subjects to increasing concentrations of methacholine aerosol was assessed by serial measurements of specific airways conductance (scaw) in a body plethysmograph. 2. Cumulative log dose-response curves were constructed. The threshold provocative dose of methacholine needed to cause a 35% fall in starting sCaw (pD35) and the steepest slope of the response were measured from each curve. 3. On separate days subjects were premedicated with 0.9% NaCl solution (control) in duplicate, chlorpheniramine, salbutamol and atropine, the last-named at two different doses, one twice the other. 4. Asthmatic subjects had a lower mean PD35 and a lower mean slope than normal subjects. 5. Pretreatment with salbutamol resulted in a greater increase in sGaw than after atropine but caused a smaller increase in PD35 in both groups. There was a dose-dependent increase in PD3s after the two doses of atropine, but no significant difference in bronchodilatation between doses. Mean steepest slope approximately doubled in these three sets of challenges. 6. Chlorpheniramine caused a small degree of bronchodilatation and there was a non-significant increase in mean PD3s and in mean steepest slope in both normal and asthmatic groups. 7. There was a positive linear correlation between starting sGaw and steepest slope in each group of premedicated challenges, such that when

OVARIAN ASCORBIC ACID DEPLETION TEST FOR LUTEINIZING HORMONE

1967 ◽  
Vol 56 (4) ◽  
pp. 619-625 ◽  
Author(s):  
Hans Jacob Koed ◽  
Christian Hamburger
Keyword(s):  
Ascorbic Acid ◽  
Luteinizing Hormone ◽  
Dose Response ◽  
Response Curve ◽  
Dose Response Curve ◽  
Human Origin ◽  
Response Curves ◽  
Significant Difference ◽  
The Mean ◽  
Different Levels

ABSTRACT Comparison of the dose-response curves for LH of ovine origin (NIH-LH-S8) and of human origin (IRP-HMG-2) using the OAAD test showed a small, though statistically significant difference, the dose-response curve for LH of human origin being a little flatter. Two standard curves for ovine LH obtained with 14 months' interval, were parallel but at different levels of ovarian ascorbic acid. When the mean ascorbic acid depletions were calculated as percentages of the control levels, the two curves for NIH-LH-S8 were identical. The use of standards of human origin in the OAAD test for LH activity of human preparations is recommended.

scholarly journals Dose–Response Effects of 3-Nitrooxypropanol Combined with Low- and High-Concentrate Feed Proportions in the Dairy Cow Ration on Fermentation Parameters in a Rumen Simulation Technique

Animals ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 1784
Author(s):  
Matthias Schilde ◽  
Dirk von Soosten ◽  
Liane Hüther ◽  
Susanne Kersten ◽  
Ulrich Meyer ◽  
...  
Keyword(s):  
Dose Response ◽  
Gas Production ◽  
Hydrogen Gas ◽  
Simulation Technique ◽  
Mitigation Strategies ◽  
Feed Additive ◽  
Future Research ◽  
Dependent Manner ◽  
Dose Dependent

Methane (CH4) from ruminal feed degradation is a major pollutant from ruminant livestock, which calls for mitigation strategies. The purpose of the present 4 × 2 factorial arrangement was to investigate the dose–response relationships between four doses of the CH4 inhibitor 3-nitrooxypropanol (3-NOP) and potential synergistic effects with low (LC) or high (HC) concentrate feed proportions (CFP) on CH4 reduction as both mitigation approaches differ in their mode of action (direct 3-NOP vs. indirect CFP effects). Diet substrates and 3-NOP were incubated in a rumen simulation technique to measure the concentration and production of volatile fatty acids (VFA), fermentation gases as well as substrate disappearance. Negative side effects on fermentation regarding total VFA and gas production as well as nutrient degradability were observed for neither CFP nor 3-NOP. CH4 production decreased from 10% up to 97% in a dose-dependent manner with increasing 3-NOP inclusion rate (dose: p < 0.001) but irrespective of CFP (CFP × dose: p = 0.094). Hydrogen gas accumulated correspondingly with increased 3-NOP dose (dose: p < 0.001). In vitro pH (p = 0.019) and redox potential (p = 0.066) varied by CFP, whereas the latter fluctuated with 3-NOP dose (p = 0.01). Acetate and iso-butyrate (mol %) decreased with 3-NOP dose, whereas iso-valerate increased (dose: p < 0.001). Propionate and valerate varied inconsistently due to 3-NOP supplementation. The feed additive 3-NOP was proven to be a dose-dependent yet effective CH4 inhibitor under conditions in vitro. The observed lack of additivity of increased CFP on the CH4 inhibition potential of 3-NOP needs to be verified in future research testing further diet types both in vitro and in vivo.

Immunomodulatory activities of whey fractions in efferent prefemoral lymph of sheep

1996 ◽  
Vol 63 (2) ◽  
pp. 257-267 ◽  
Author(s):  
Chun W. Wong ◽  
Geoffrey O. Regester ◽  
Geoffrey L. Francis ◽  
Dennis L. Watson
Keyword(s):  
Immune Responses ◽  
Bovine Milk ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Milk Whey ◽  
Significant Difference ◽  
Lymphocyte Phenotypes ◽  
Dose Dependent

SummaryStudies on the immunomodulatory activities of ruminant milk and colostral whey fractions were undertaken. By comparing with boiled colostral whey in a preliminary experiment, a putative heat-labile immunostimulatory factor for antibody responses was found to be present in ovine colostral whey. Studies were then undertaken in sheep in which the efferent prefemoral lymphatic ducts were cannulated bilaterally, and immune responses in the node were measured following subcutaneous injection in the flank fold of whey protein preparations of various purities. A significant sustained decline of efferent lymphocyte output was observed following injection with autologous crude milk whey or colostral whey preparations, but no changes were observed in interferon-gamma levels in lymph plasma. Two bovine milk whey fractions (lactoperoxidase and lactoferrin) of high purity were compared in bilaterally cannulated sheep. A transient decline over the first 6 h was seen in the efferent lymphocyte output and lymph flow rate after injection of both fractions. A significant difference was seen between the two fractions in interferongamma levels in lymph at 6 h after injection. However, no significant changes in the proportion of the various efferent lymphocyte phenotypes were seen following either treatment. Whereas both fractions showed a significant inhibitory effect in a dose-dependent manner on the proliferative response of T lymphocytes, but not B lymphocytes, to mitogenic stimulation in vitro, no similar changes were seen following in vivo stimulation with these two fractions.

scholarly journals Physiologically based kinetic modelling based prediction of in vivo rat and human acetylcholinesterase (AChE) inhibition upon exposure to diazinon

2021 ◽  
Author(s):  
Shensheng Zhao ◽  
Sebastiaan Wesseling ◽  
Bert Spenkelink ◽  
Ivonne M. C. M. Rietjens
Keyword(s):  
Dose Response ◽  
Kinetic Modelling ◽  
Ache Inhibition ◽  
Response Curves ◽  
Alternative Testing ◽  
Dose Response Curves ◽  
Physiologically Based Kinetic Modelling ◽  
Point Of Departure

AbstractThe present study predicts in vivo human and rat red blood cell (RBC) acetylcholinesterase (AChE) inhibition upon diazinon (DZN) exposure using physiological based kinetic (PBK) modelling-facilitated reverse dosimetry. Due to the fact that both DZN and its oxon metabolite diazoxon (DZO) can inhibit AChE, a toxic equivalency factor (TEF) was included in the PBK model to combine the effect of DZN and DZO when predicting in vivo AChE inhibition. The PBK models were defined based on kinetic constants derived from in vitro incubations with liver fractions or plasma of rat and human, and were used to translate in vitro concentration–response curves for AChE inhibition obtained in the current study to predicted in vivo dose–response curves. The predicted dose–response curves for rat matched available in vivo data on AChE inhibition, and the benchmark dose lower confidence limits for 10% inhibition (BMDL10 values) were in line with the reported BMDL10 values. Humans were predicted to be 6-fold more sensitive than rats in terms of AChE inhibition, mainly because of inter-species differences in toxicokinetics. It is concluded that the TEF-coded DZN PBK model combined with quantitative in vitro to in vivo extrapolation (QIVIVE) provides an adequate approach to predict RBC AChE inhibition upon acute oral DZN exposure, and can provide an alternative testing strategy for derivation of a point of departure (POD) in risk assessment.

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 Impact of L-carnitine supplementation on the in vitro developmental competence and cryotolerance of buffalo embryos

2021 ◽  
pp. 3164-3169
Author(s):  
Mohamed M. M. El-Sokary ◽  
Al-Shimaa Al-H. H. El-Naby ◽  
Amal R. Abd El Hameed ◽  
Karima Gh. M. Mahmoud ◽  
T. H. Scholkamy
Keyword(s):  
Embryo Culture ◽  
In Vitro Maturation ◽  
Culture Media ◽  
Effective Concentration ◽  
Developmental Competence ◽  
Carnitine Supplementation ◽  
Oocyte Developmental Competence ◽  
High Lipid ◽  
Significant Difference

Background and Aim: Despite many trials, buffalo embryos have poor cryosurvivability because of their high lipid content. L-carnitine was found to be a lipid-reducing agent when added to oocyte and embryo culture media. The study aimed to determine the most effective concentration of L-carnitine to improve the oocyte developmental competence and cryotolerance of buffalo embryos. Materials and Methods: In vitro maturation and embryo culture media were supplemented with four concentrations of L-carnitine: 0 (control), 0.25, 0.5, and 1 mM. Good-quality embryos on 7 days were vitrified using mixtures of dimethyl sulfoxide and ethylene glycol at two concentrations (3.5 and 7 M). Results: The result showed that the cleavage and morula rates were significantly (p<0.05) higher in the 0.5 mM group. Blastocyst rates were significantly (p<0.05) higher at both 0.5 and 1 mM. The rates of viable embryos directly after thawing were significantly (p<0.05) increased in the 0.5 mM group. No significant difference was found in embryos cultured for 24 h after warming among all the groups. Conclusion: The addition of L-carnitine at a concentration of 0.5 mM to the culture media improves the oocyte developmental competence and cryotolerance of buffalo embryos directly after warming but not after 24 h of culture. Nevertheless, further studies must identify how L-carnitine exerts its beneficial micromechanisms.

scholarly journals Fungicide Sensitivity of U.S. Genotypes of Phytophthora infestans to Six Oomycete-Targeted Compounds

Plant Disease ◽  
2015 ◽  
Vol 99 (5) ◽  
pp. 659-666 ◽  
Author(s):  
Amanda Saville ◽  
Kim Graham ◽  
Niklaus J. Grünwald ◽  
Kevin Myers ◽  
William E. Fry ◽  
...  
Keyword(s):  
United States ◽  
Phytophthora Infestans ◽  
The United States ◽  
Effective Concentration ◽  
Response Curves ◽  
Baseline Sensitivity ◽  
Fungicide Sensitivity ◽  
The Past ◽  
The Us

Phytophthora infestans causes potato late blight, an important and costly disease of potato and tomato crops. Seven clonal lineages of P. infestans identified recently in the United States were tested for baseline sensitivity to six oomycete-targeted fungicides. A subset of the dominant lineages (n = 45) collected between 2004 and 2012 was tested in vitro on media amended with a range of concentrations of either azoxystrobin, cyazofamid, cymoxanil, fluopicolide, mandipropamid, or mefenoxam. Dose-response curves and values for the effective concentration at which 50% of growth was suppressed were calculated for each isolate. The US-8 and US-11 clonal lineages were insensitive to mefenoxam while the US-20, US-21, US-22, US-23, and US-24 clonal lineages were sensitive to mefenoxam. Insensitivity to azoxystrobin, cyazofamid, cymoxanil, fluopicolide, or mandipropamid was not detected within any lineage. Thus, current U.S. populations of P. infestans remained sensitive to mefenoxam during the displacement of the US-22 lineage by US-23 over the past 5 years.

scholarly journals Advancing risk assessment: mechanistic dose–response modelling of Listeria monocytogenes infection in human populations

2018 ◽  
Vol 5 (8) ◽  
pp. 180343 ◽  
Author(s):  
Ashrafur Rahman ◽  
Daniel Munther ◽  
Aamir Fazil ◽  
Ben Smith ◽  
Jianhong Wu
Keyword(s):  
Listeria Monocytogenes ◽  
Dose Response ◽  
Geometric Interpretation ◽  
Human Populations ◽  
Response Curves ◽  
Future Experimentation ◽  
Limited Power ◽  
Mechanistic Basis ◽  
Response Modelling

The utility of characterizing the effects of strain variation and individual/subgroup susceptibility on dose–response outcomes has motivated the search for new approaches beyond the popular use of the exponential dose–response model for listeriosis. While descriptive models can account for such variation, they have limited power to extrapolate beyond the details of particular outbreaks. By contrast, this study exhibits dose–response relationships from a mechanistic basis, quantifying key biological factors involved in pathogen–host dynamics. An efficient computational algorithm and geometric interpretation of the infection pathway are developed to connect dose–response relationships with the underlying bistable dynamics of the model. Relying on in vitro experiments as well as outbreak data, we estimate plausible parameters for the human context. Despite the presence of uncertainty in such parameters, sensitivity analysis reveals that the host response is most influenced by the pathogen–immune system interaction. In particular, we show how variation in this interaction across a subgroup of the population dictates the shape of dose–response curves. Finally, in terms of future experimentation, our model results provide guidelines and highlight vital aspects of the interplay between immune cells and particular strains of Listeria monocytogenes that should be examined.

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