Dose-response curves after in vivo experimental chemotherapy: Influence of rouze of administration on biological outcomes

1985 ◽  
Vol 15 (2) ◽  
Author(s):  
JamesV. Moore
Keyword(s):  
Dose Response ◽  
Response Curves ◽  
Experimental Chemotherapy ◽  
Dose Response Curves ◽  
Biological Outcomes

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.

Histamine H2-receptor of human and rabbit parietal cells

1987 ◽  
Vol 253 (4) ◽  
pp. G497-G501 ◽  
Author(s):  
R. Leth ◽  
B. Elander ◽  
U. Haglund ◽  
L. Olbe ◽  
E. Fellenius
Keyword(s):  
Dose Response ◽  
In Vivo Model ◽  
Response Curves ◽  
Gastric Glands ◽  
Histamine H2 Receptor ◽  
Receptor Affinity ◽  
H2 Receptor ◽  
Dose Response Curves

The histamine H2-receptor on the human parietal cell has been characterized by using dose-response curves and the negative logarithm of the molar concentration of an antagonist (pA2) analyses of cimetidine antagonism of betazole, histamine, and impromidine stimulation in isolated human and rabbit gastric glands. To evaluate the in vitro results, betazole-stimulated gastric acid secretion with and without cimetidine was also studied in healthy subjects. In the in vivo model, individual dose-response curves were shifted to the right with increasing cimetidine concentrations, but this was counteracted by increasing betazole doses, indicating competitive, reversible antagonism. The pA2 values ranged from 6.1 to 6.3. In isolated human gastric glands, impromidine was shown to be eight times more potent than histamine, indicating higher receptor affinity, but the maximally stimulated aminopyrine accumulation was the same as for histamine, and the pA2 values for cimetidine antagonism did not differ significantly, i.e., 5.7 (histamine) and 6.1 (impromidine). In isolated rabbit gastric glands, cimetidine inhibited the histamine- and impromidine-stimulated response with pA2 values of 6.0 and 7.3, respectively. Impromidine was shown to be approximately 100 times more potent than in human gastric glands, whereas histamine had the same potency. This confirms the role of the histamine H2-receptor and suggests a difference between the species concerning receptor affinity.

scholarly journals Pharmacological curve fitting to analyze cutaneous adrenergic responses

2011 ◽  
Vol 111 (6) ◽  
pp. 1703-1709 ◽  
Author(s):  
Megan M. Wenner ◽  
Thad E. Wilson ◽  
Scott L. Davis ◽  
Nina S. Stachenfeld
Keyword(s):  
Dose Response ◽  
Curve Fitting ◽  
Repeated Measures ◽  
Nonlinear Modeling ◽  
Response Curves ◽  
Data Set ◽  
Sigmoidal Model ◽  
Dose Response Curves ◽  
Cutaneous Vasoconstriction

Although dose-response curves are commonly used to describe in vivo cutaneous α-adrenergic responses, modeling parameters and analyses methods are not consistent across studies. The goal of the present investigation was to compare three analysis methods for in vivo cutaneous vasoconstriction studies using one reference data set. Eight women (22 ± 1 yr, 24 ± 1 kg/m2) were instrumented with three cutaneous microdialysis probes for progressive norepinephrine (NE) infusions (1 × 10−8, 1 × 10−6, 1 × 10−5, 1 × 10−4, and 1 × 10−3 logM). NE was infused alone, co-infused with NG-monomethyl-l-arginine (l-NMMA, 10 mM) or Ketorolac tromethamine (KETO, 10 mM). For each probe, dose-response curves were generated using three commonly reported analyses methods: 1) nonlinear modeling without data manipulation, 2) nonlinear modeling with data normalization and constraints, and 3) percent change from baseline without modeling. Not all data conformed to sigmoidal dose-response curves using analysis 1, whereas all subjects' curves were modeled using analysis 2. When analyzing only curves that fit the sigmoidal model, NE + KETO induced a leftward shift in ED50 compared with NE alone with analyses 1 and 2 ( F test, P < 0.05) but only tended to shift the response leftward with analysis 3 (repeated-measures ANOVA, P = 0.08). Neither maximal vasoconstrictor capacity (Emax) in analysis 1 nor %change CVC change from baseline in analysis 3 were altered by blocking agents. In conclusion, although the overall detection of curve shifts and interpretation was similar between the two modeling methods of curve fitting, analysis 2 produced more sigmoidal curves.

In vivo evaluation of the effectiveness of bronchial thermoplasty with computed tomography

2005 ◽  
Vol 98 (5) ◽  
pp. 1603-1606 ◽  
Author(s):  
Robert H. Brown ◽  
William Wizeman ◽  
Christopher Danek ◽  
Wayne Mitzner
Keyword(s):  
Computed Tomography ◽  
Smooth Muscle ◽  
Dose Response ◽  
Response Curves ◽  
High Resolution Computed Tomography ◽  
In Vivo Evaluation ◽  
Airway Narrowing ◽  
Bronchial Thermoplasty ◽  
Dose Response Curves

A recent study has reported that the application of thermal energy delivered through a bronchoscope (bronchial thermoplasty) impairs the ability of airway smooth muscle to shorten in response to methacholine (MCh)(Danek CJ, Lombard CM, Dungworth DL, Cox PG, Miller JD, Biggs MJ, Keast TM, Loomas BE, Wizeman WJ, Hogg JC, and Leff AR. J Appl Physiol 97: 1946–1953, 2004). If such a technique is successful, it has the potential to serve as a therapy to attenuate airway narrowing in asthmatic subjects regardless of the initiating cause that stimulates the smooth muscle. In the present study, we have applied high-resolution computed tomography to accurately quantify the changes in airway area before and after a standard MCh aerosol challenge in airways treated with bronchial thermoplasty. We studied a total of 193 airways ranging from 2 to 15 mm in six dogs. These were divided into treated and control populations. The MCh dose-response curves in untreated airways and soon-to-be-treated airways were superimposable. In contrast, the dose-response curves in treated airways were shifted upward at all points, showing a significantly decreased sensitivity to MCh at both 2 and 4 wk posttreatment. These results thus show that treated airways have significantly increased luminal area at any dose of inhaled MCh compared with untreated airways. The work in this study thus supports the underlying concept that impairing the smooth muscle may be an effective treatment for asthma.

scholarly journals A Model Mechanism Based Explanation of an In Vitro-In Vivo Disconnect for Improving Extrapolation and Translation

2017 ◽  
Author(s):  
Andrew K. Smith ◽  
Yanli Xu ◽  
Glen E.P. Ropella ◽  
C. Anthony Hunt
Keyword(s):  
Dose Response ◽  
Mitochondrial Damage ◽  
System Level ◽  
Central Vein ◽  
Response Curves ◽  
Causal Explanations ◽  
Dose Response Curves ◽  
Virtual Culture

AbstractAn improved understanding of in vivo-to-in vitro hepatocyte changes is crucial to interpreting in vitro data correctly and further improving hepatocyte-based in vitro-to-in vivo extrapolations to human targets. We demonstrate using virtual experiments as a means to help untangle plausible causes of inaccurate extrapolations. We start with virtual mice that have biomimetic software livers. Earlier, using those mice, we discovered model mechanisms that enabled achieving quantitative validation targets while also providing plausible causal explanations for temporal characteristics of acetaminophen hepatotoxicity. We isolated virtual hepatocytes, created a virtual culture, and then conducted dose-response experiments in both culture and mice. We expected the two dose-response curves to be displaced. We were surprised that they crossed because it evidenced that simulated acetaminophen metabolism and toxicity are different for virtual culture and mouse contexts even though individual hepatocyte mechanisms were unchanged. Crossing dose-response curves is a virtual example of an in vivo-to-in vitro disconnect. We use detailed results of experiments to explain the disconnect. Individual hepatocytes contribute differently to system level phenomena. In liver, hepatocytes are exposed to acetaminophen sequentially. Relative production of the reactive acetaminophen metabolite is largest (smallest) in pericentral (periportal) hepatocytes. Because that sequential exposure is absent in culture, hepatocytes from different lobular locations do not respond the same. A virtual Culture-to-Mouse translation can stand as a scientifically challengeable theory explaining an in vitro-in vivo disconnect. It provides a framework to develop more reliable interpretations of in vitro observations, which then may be used to improve extrapolations.AbbreviationsaHPCanalog hepatocyteAPAPacetaminophenCVCentral VeinSSsinusoidal segmentNAPQIN-acetyl-p-benzoquinone iminemitoDmitochondrial damage productsnonMDnon-mitochondrial damage products

A Methodological Investigation On The One-Stage Factor VIII Assay

1981 ◽  
Author(s):  
J Over ◽  
J A van Mourik ◽  
P van den Brink-Zantingh ◽  
R Smit-Jansen
Keyword(s):  
Factor Viii ◽  
Dose Response ◽  
Red Cross ◽  
Response Curves ◽  
One Stage ◽  
Factor Viii Concentrates ◽  
Dose Response Curves ◽  
The One ◽  
Protein Rich

Assay of Factor VIII coagulant activity (VIII: C) in Factor VIII concentrates has since long met difficulties, such as l) non-paralleility of dose-response curves of plasma standard and Factor VIII concentrate, 2) spuriously low values of VIII: C in concentrates as revealed by abnormally high in vivo recoveries after transfusion, and 3) large interlaboratory variation in assay results. In an attempt to analyze the cause of these problems several parameters of the one-stage assay system were varied systematically and their effect on the parallellity of dose-response curves and on the final VIII: C value was analyzed. Nonparallel1ity was partially corrected with a protein-rich dilution medium, and almost always completely with undiluted instead of 1:1 diluted hemophilic substrate plasma. In both conditions apparently higher VIII:C values were found.A number of assay systems used by different producers of Factor VIII concentrates were compared. The standard and, in some cases, the phospholipid reagent seemed to contribute for the largest past to the inter1aboratory variation, but also other, as yet unidentified, factors exerted some influence. These findings initiated a cooperative study by five Red Cross Blood Transfusion Services in Europe on standardization of the one-stage assay for VIII:C. This resulted in a better correspondence between these institutes (CV 13%) compared to the previous situation (CV 23%).It is concluded that 1) substrate plasma should not be diluted, especially when Factor VIII concentrate is to be tested against a plasma standard, 2) the standard should be of the same type as the testmaterial, and 3) this standard should be properly calibrated against the International Standard for Factor VIII.

scholarly journals Aged platelets have an impaired response to thrombin as quantitated by P-selectin expression

Blood ◽  
1994 ◽  
Vol 83 (1) ◽  
pp. 161-166 ◽  
Author(s):  
J Peng ◽  
P Friese ◽  
E Heilmann ◽  
JN George ◽  
SA Burstein ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Cell Surface ◽  
Dose Response ◽  
Intravenous Infusion ◽  
Total Population ◽  
Response Curves ◽  
Dose Response Curves

Abstract After the intravenous infusion of N-hydroxysuccinimido biotin into dogs, 80.6% +/- 9.7% (n = 5) of platelets were covalently labeled with biotin. The in vivo survival of the biotinylated platelets was monitored by flow cytometry and was normal as compared with previous reports for dog platelets. The ability of the biotinylated platelets to be activated was analyzed by measuring the expression of cell-surface P- selectin after incubation with graded concentrations of thrombin. When P-selectin expression was examined 3 hours after labeling, biotinylated platelets were indistinguishable from the nonlabeled population of platelets, indicating that biotinylation did not adversely affect the cells. On consecutive days after biotinylation, the thrombin dose- response curves for biotinylated and nonbiotinylated platelets were repeated, and as the biotinylated-platelets aged, they became less responsive to thrombin. On days 3, 4, and 5, the thrombin EC50 for the aged, biotinylated platelets as compared with the total population of platelets was 136%, 150%, and 178%, respectively. Increasing age clearly impairs the reactivity of platelets towards thrombin as quantitated by the expression of cell-surface P-selectin.

Effect of angiotensin II and norepinephrine on isolated rat afferent and efferent arterioles

1990 ◽  
Vol 258 (3) ◽  
pp. F741-F750 ◽  
Author(s):  
B. H. Yuan ◽  
J. B. Robinette ◽  
J. D. Conger
Keyword(s):  
Angiotensin Ii ◽  
Dose Response ◽  
Rat Kidney ◽  
Differential Sensitivity ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Response Curves ◽  
Dose Response Curves ◽  
Isolated Rat

Differential sensitivity of the pre- and postglomerular arterial vessels to vasoconstrictor activity of angiotensin II (ANG II) and norepinephrine (NE) is controversial. To avoid the complex extravascular neurohumoral variables that may have accounted for different results in the intact rat kidney, an isolated arteriole technique was used to examine the dose responses of ANG II and NE on afferent (AA) and efferent arterioles (EA) from Sprague-Dawley rats. EA were more sensitive than AA to ANG II (EC50 = 3.2 +/- 1.8 x 10(-11) and 1.0 +/- 1.6 x 10(-9) M, respectively, P less than 0.001), whereas EC50 of both AA and EA to NE were similar (3.4 +/- 2.3 x 10(-8) and 1.4 +/- 2.6 x 10(-8) M, respectively). The dose-response curves of AA to ANG II were not different when perfused at different luminal pressures (90 and 30 mmHg). In contrast, EA were more sensitive to ANG II at 30 than at 90 mmHg (3.0 +/- 1.2 x 10(-11) and 5.0 +/- 1.8 x 10(-10) M, respectively, P less than 0.005). The EC50 of EA to NE was unaffected by similar changes in luminal pressures. The mean dose-response curves of AA to ANG II were the same with and without the addition of 10(-5) M indomethacin; however, in arterioles displaying a focal constriction pattern to ANG II the response became uniform. It is concluded that, in the isolated rat glomerular arterioles, EA are more sensitive to ANG II than AA, but both vessels respond similarly to NE. The decreased ANG II sensitivity in AA is not related to the higher in vivo pressure, and the attenuated response in AA does not appear to be mediated primarily through ANG II-stimulated vasodilator prostanoid activity. EA sensitivity to ANG II appears to be inversely related to lumen pressure.

scholarly journals Aged platelets have an impaired response to thrombin as quantitated by P-selectin expression

Blood ◽  
1994 ◽  
Vol 83 (1) ◽  
pp. 161-166
Author(s):  
J Peng ◽  
P Friese ◽  
E Heilmann ◽  
JN George ◽  
SA Burstein ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Cell Surface ◽  
Dose Response ◽  
Intravenous Infusion ◽  
Total Population ◽  
Response Curves ◽  
Dose Response Curves

After the intravenous infusion of N-hydroxysuccinimido biotin into dogs, 80.6% +/- 9.7% (n = 5) of platelets were covalently labeled with biotin. The in vivo survival of the biotinylated platelets was monitored by flow cytometry and was normal as compared with previous reports for dog platelets. The ability of the biotinylated platelets to be activated was analyzed by measuring the expression of cell-surface P- selectin after incubation with graded concentrations of thrombin. When P-selectin expression was examined 3 hours after labeling, biotinylated platelets were indistinguishable from the nonlabeled population of platelets, indicating that biotinylation did not adversely affect the cells. On consecutive days after biotinylation, the thrombin dose- response curves for biotinylated and nonbiotinylated platelets were repeated, and as the biotinylated-platelets aged, they became less responsive to thrombin. On days 3, 4, and 5, the thrombin EC50 for the aged, biotinylated platelets as compared with the total population of platelets was 136%, 150%, and 178%, respectively. Increasing age clearly impairs the reactivity of platelets towards thrombin as quantitated by the expression of cell-surface P-selectin.

Positive control dose response curves in the in vivo comet assay

2015 ◽  
Vol 238 (2) ◽  
pp. S99
Author(s):  
C. Beevers ◽  
G. Pearce ◽  
L. Foster ◽  
R. Mortimer
Keyword(s):  
Comet Assay ◽  
Dose Response ◽  
Positive Control ◽  
Response Curves ◽  
Dose Response Curves
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