scholarly journals Prolactin and fMRI response to SKF38393 in the baboon

2013 ◽  
Author(s):  
Brad D. Miller ◽  
Lauren A. Marks ◽  
Jonathan Koller ◽  
Blake J. Newman ◽  
G. Larry Bretthorst ◽  
...  
Keyword(s):  
Single Dose ◽  
Dopamine Agonist ◽  
Dose Response ◽  
Time Course ◽  
Plasma Prolactin ◽  
Response Curves ◽  
Prolactin Release ◽  
Drug Concentrations ◽  
Dose Response Curves ◽  
Prolactin Response

Background: This study’s goal was to provide dose-response data for a dopamine agonist in the baboon using standard methods (replicate measurements at each dose, across a range of doses), as a standard against which to subsequently validate a novel pharmacological MRI (phMRI) method. Dependent variables were functional MRI (fMRI) data from brain regions selected a priori, and systemic prolactin release. Necessary first steps included estimating the magnitude and time course of prolactin response to anesthesia alone and to various doses of agonist. These first steps (“time course studies”) were performed with three agonists, and the results were used to select promising agonists and to guide design details for the single-dose studies needed to generate dose-response curves. Methods: We studied 6 male baboons (Papio anubis) under low-dose isoflurane anesthesia after i.m. ketamine. Time course studies charted the changes in plasma prolactin levels over time after anesthesia alone or after an intravenous (i.v.) dose of the dopamine D1-like agonists SKF82958 and SKF38393 or the D2-like agonist pramipexole. In the single-dose dopamine agonist studies, one dose of SKF38393 (ranging from 0.0928 – 9.28 mg/kg, N=5 animals) or pramipexole (0.00928 – 0.2 mg/kg, N=1) was given i.v. during a 40-minute blood oxygen level dependent (BOLD) fMRI session, to determine BOLD and plasma prolactin responses to different drug concentrations. BOLD response was quantified as the area under the time-signal curve for the first 15 minutes after the start of the drug infusion, compared to the linearly predicted signal from the baseline data before drug. The ED50(estimated dose that produces 50% of the maximal possible response to drug) for SKF38393 was calculated for the serum prolactin response and for phMRI responses in hypothalamus, pituitary, striatum and midbrain. Results: Prolactin rose 2.4- to 12-fold with anesthesia alone, peaking around 50-90 minutes after ketamine administration and gradually tapering off but still remaining higher than baseline on isoflurane 3-5 hours after ketamine. Baseline prolactin level increased with age. SKF82958 0.1mg/kg i.v. produced no noticeable change in plasma prolactin concentration. SKF38393 produced a substantial increase in prolactin release that peaked at around 20-30 minutes and declined to pre-drug levels in about an hour. Pramipexole quickly reduced prolactin levels below baseline, reaching a nadir 2-3 hours after infusion. SKF38393 produced clear, dose-responsive BOLD signal changes, and across the four regions, ED50 was estimated at 1.6-7.7mg/kg. Conclusions: In the baboon, the dopamine D1receptor agonist SKF38393 produces clear plasma prolactin and phMRI dose-response curves. Variability in age and a modest sample size limit the precision of the conclusions.

scholarly journals Prolactin and fMRI response to SKF38393 in the baboon

2013 ◽  
Author(s):  
Brad D. Miller ◽  
Lauren A. Marks ◽  
Jonathan Koller ◽  
Blake J. Newman ◽  
G. Larry Bretthorst ◽  
...  
Keyword(s):  
Single Dose ◽  
Dopamine Agonist ◽  
Dose Response ◽  
Time Course ◽  
Plasma Prolactin ◽  
Response Curves ◽  
Prolactin Release ◽  
Drug Concentrations ◽  
Dose Response Curves ◽  
Prolactin Response

Background: This study’s goal was to provide dose-response data for a dopamine agonist in the baboon using standard methods (replicate measurements at each dose, across a range of doses), as a standard against which to subsequently validate a novel pharmacological MRI (phMRI) method. Dependent variables were functional MRI (fMRI) data from brain regions selected a priori, and systemic prolactin release. Necessary first steps included estimating the magnitude and time course of prolactin response to anesthesia alone and to various doses of agonist. These first steps (“time course studies”) were performed with three agonists, and the results were used to select promising agonists and to guide design details for the single-dose studies needed to generate dose-response curves. Methods: We studied 6 male baboons (Papio anubis) under low-dose isoflurane anesthesia after i.m. ketamine. Time course studies charted the changes in plasma prolactin levels over time after anesthesia alone or after an intravenous (i.v.) dose of the dopamine D1-like agonists SKF82958 and SKF38393 or the D2-like agonist pramipexole. In the single-dose dopamine agonist studies, one dose of SKF38393 (ranging from 0.0928 – 9.28 mg/kg, N=5 animals) or pramipexole (0.00928 – 0.2 mg/kg, N=1) was given i.v. during a 40-minute blood oxygen level dependent (BOLD) fMRI session, to determine BOLD and plasma prolactin responses to different drug concentrations. BOLD response was quantified as the area under the time-signal curve for the first 15 minutes after the start of the drug infusion, compared to the linearly predicted signal from the baseline data before drug. The ED50(estimated dose that produces 50% of the maximal possible response to drug) for SKF38393 was calculated for the serum prolactin response and for phMRI responses in hypothalamus, pituitary, striatum and midbrain. Results: Prolactin rose 2.4- to 12-fold with anesthesia alone, peaking around 50-90 minutes after ketamine administration and gradually tapering off but still remaining higher than baseline on isoflurane 3-5 hours after ketamine. Baseline prolactin level increased with age. SKF82958 0.1mg/kg i.v. produced no noticeable change in plasma prolactin concentration. SKF38393 produced a substantial increase in prolactin release that peaked at around 20-30 minutes and declined to pre-drug levels in about an hour. Pramipexole quickly reduced prolactin levels below baseline, reaching a nadir 2-3 hours after infusion. SKF38393 produced clear, dose-responsive BOLD signal changes, and across the four regions, ED50 was estimated at 1.6-7.7mg/kg. Conclusions: In the baboon, the dopamine D1receptor agonist SKF38393 produces clear plasma prolactin and phMRI dose-response curves. Variability in age and a modest sample size limit the precision of the conclusions.

scholarly journals Prolactin and fMRI response to SKF38393 in the baboon

2013 ◽  
Author(s):  
Brad D. Miller ◽  
Lauren A. Marks ◽  
Jonathan Koller ◽  
Blake J. Newman ◽  
G. Larry Bretthorst ◽  
...  
Keyword(s):  
Single Dose ◽  
Dopamine Agonist ◽  
Dose Response ◽  
Time Course ◽  
Plasma Prolactin ◽  
Response Curves ◽  
Prolactin Release ◽  
Drug Concentrations ◽  
Dose Response Curves ◽  
Prolactin Response

Background: This study’s goal was to provide dose-response data for a dopamine agonist in the baboon using standard methods (replicate measurements at each dose, across a range of doses), as a standard against which to subsequently validate a novel pharmacological MRI (phMRI) method. Dependent variables were functional MRI (fMRI) data from brain regions selected a priori, and systemic prolactin release. Necessary first steps included estimating the magnitude and time course of prolactin response to anesthesia alone and to various doses of agonist. These first steps (“time course studies”) were performed with three agonists, and the results were used to select promising agonists and to guide design details for the single-dose studies needed to generate dose-response curves. Methods: We studied 6 male baboons (Papio anubis) under low-dose isoflurane anesthesia after i.m. ketamine. Time course studies charted the changes in plasma prolactin levels over time after anesthesia alone or after an intravenous (i.v.) dose of the dopamine D1-like agonists SKF82958 and SKF38393 or the D2-like agonist pramipexole. In the single-dose dopamine agonist studies, one dose of SKF38393 (ranging from 0.0928 – 9.28 mg/kg, N=5 animals) or pramipexole (0.00928 – 0.2 mg/kg, N=1) was given i.v. during a 40-minute blood oxygen level dependent (BOLD) fMRI session, to determine BOLD and plasma prolactin responses to different drug concentrations. BOLD response was quantified as the area under the time-signal curve for the first 15 minutes after the start of the drug infusion, compared to the linearly predicted signal from the baseline data before drug. The ED50(estimated dose that produces 50% of the maximal possible response to drug) for SKF38393 was calculated for the serum prolactin response and for phMRI responses in hypothalamus, pituitary, striatum and midbrain. Results: Prolactin rose 2.4- to 12-fold with anesthesia alone, peaking around 50-90 minutes after ketamine administration and gradually tapering off but still remaining higher than baseline on isoflurane 3-5 hours after ketamine. Baseline prolactin level increased with age. SKF82958 0.1mg/kg i.v. produced no noticeable change in plasma prolactin concentration. SKF38393 produced a substantial increase in prolactin release that peaked at around 20-30 minutes and declined to pre-drug levels in about an hour. Pramipexole quickly reduced prolactin levels below baseline, reaching a nadir 2-3 hours after infusion. SKF38393 produced clear, dose-responsive BOLD signal changes, and across the four regions, ED50 was estimated at 1.6-7.7mg/kg.Conclusions: In the baboon, the dopamine D1receptor agonist SKF38393 produces clear plasma prolactin and phMRI dose-response curves. Variability in age and a modest sample size limit the precision of the conclusions.

Application of Drug Receptor Theories to the Analysis of the Myotropic Effects of Bradykinin

1975 ◽  
Vol 53 (3) ◽  
pp. 345-353 ◽  
Author(s):  
J. Barabé ◽  
W. K. Park ◽  
D. Regoli
Keyword(s):  
Dose Response ◽  
Terminal Ileum ◽  
Maximal Response ◽  
Rat Stomach ◽  
Response Curves ◽  
Rat Uterus ◽  
Drug Concentrations ◽  
General Pharmacology ◽  
Dose Response Curves ◽  
Drug Receptor

Cat jejunum and terminal ileum, and rat stomach strip and rat uterus contract to bradykinin, while rat duodenum relaxes. Dose–response curves of classical hyperbolic shape are obtained in the first three preparations, but not in the others.The negative logs of the drug concentrations which give 50% of the maximal response. (pD2) values were, respectively, 7.68 and 7.77 in the cat jejunum and terminal ileum, 6.78 in the rat stomach strip and 8.64 in the rat uterus in estrus.Theoretical dose–response curves, constructed by using experimental pD2 values in the equation of Clark, (General pharmacology. Verlag Van J. Springer, Berlin, 1937), are superimposed to experimental curves, obtained in the cat jejunum and terminal ileum, but not in the rat stomach strip. This comparison was not made in the rat uterus and duodenum.The myotropic effect of bradykinin appears to be a direct one in the cat jejunum, the terminal ileum and the rat stomach strip, because it is not affected by anticholinergics, antiadrenergics, antihistaminics and indomethacin. pD2 values and the slope of the dose–response curves of the rat uterus were reduced by indomethacin.The results indicate that cat jejunum and terminal ileum are sensitive and specific for bradykinin and appear to be the most reliable preparations for studies on the structure–activity relationships of this peptide.

Role of adenosine in postocclusion coronary vasodilation

1980 ◽  
Vol 238 (2) ◽  
pp. H214-H219
Author(s):  
K. Kroll ◽  
J. J. Schipperheyn ◽  
F. F. Hendriks ◽  
J. D. Laird
Keyword(s):  
Dose Response ◽  
Time Course ◽  
Accumulation Rate ◽  
Receptor Interaction ◽  
Coronary Vasodilation ◽  
Response Curves ◽  
Flow Perfusion ◽  
Anesthetized Dogs ◽  
Dose Response Curves ◽  
The Hill

Coronary vasodilation after brief (less than 15 s) occlusions was studied in closed-chest, anesthetized dogs, using constant-flow perfusion of a large coronary artery. We assumed occlusion duration to be a measure of the concentration of endogeneous adenosine and determined adenosine dose-response curves by varying occlusion duration and measuring the resulting drop in vascular resistance. The curves were compared to dose-response curves measured by continuously infusing adenosine. Both dose-response relations were found to follow the Hill equation for ligand receptor interaction; the slopes of the two curves were not significantly different, and the estimated adenosine accumulation rate in the myocardium was found to be in close agreement with data in the literature, measured by direct tissue assay. The time course of recovery of vascular tone after short occlusions was not very sensitive to flow, at least not for normal flow levels or higher. The results confirm that adenosine accumulation plays an important role in causing postocclusion vasodilation. However, autoregulation of coronary flow based on an adenosine washout mechanism additionally requires tissue clearance to be highly flow dependent for flow levels below normal, but approaches a constant value when flow increases above normal.

Single Dose Response Curves of Normal CellsIn Situ

Radiology ◽  
1977 ◽  
Vol 122 (1) ◽  
pp. 233-237 ◽  
Author(s):  
Kouji Masuda ◽  
H. Rodney Withers
Keyword(s):  
Single Dose ◽  
Dose Response ◽  
Response Curves ◽  
Dose Response Curves

Contributions to mathematical pharmacology: new receptor theory with dimeric receptor models

2021 ◽  
Author(s):  
◽  
Carla White
Keyword(s):  
Ligand Binding ◽  
Dose Response ◽  
Time Course ◽  
Receptor Activation ◽  
Receptor Interaction ◽  
Published Data ◽  
Response Curves ◽  
Receptor Theory ◽  
Binding Models ◽  
Dose Response Curves

Classical receptor theory is largely built on assumptions of monomeric receptors. In this thesis, we contribute to receptor theory by considering the now widely accepted cases of dimeric receptors. The implications of dimerisation for drug discovery and therapeutics remain unclear. Therefore, a theoretical consideration of ligand binding and signalling via receptor dimers is warranted. Here, we develop mathematical models for ligand bind-ing at dimerised and dimerising receptors. A key factor in developing these theoretical models is cooperativity across the dimer, whereby binding of a ligand to one protomer affects the binding of a ligand to the other protomer. The effects of cooperativity on binding dynamics are a primary point of interest.The first models we present focus on G protein-coupled receptors, where we assume that all receptors are pre-dimerised. Ligand binding models give linear systems of differ-ential equations which we use to analyse time course behaviours. At equilibrium, these models may exhibit multi-phasic log dose response curves, critically depending on co-operativity factors. When considering receptor activation, we see dose response curves that are indicative of non-standard ligand-receptor interactions, giving a quantitative and qualitative platform for analysing and interpreting data when dimers are suspected. A ligand induced model for vascular endothelial growth factor receptors is developed, whereby receptors exist constitutively as monomers and dimerise in response to ligand binding. The resulting nonlinear system of differential equations is investigated using numerical computations and perturbation methods. We see an excellent fit to published data, validating the model.The utility of our models in parameter estimation is explored theoretically using structural identifiability analysis. This determines which parameters can be theoretically estimated from fitting. This analysis is valuable but often overlooked when fitting to ligand-receptor interaction models. We explore the identifiability of some canonical lig-and binding models, and our dimer binding models, providing a tutorial and results to contribute to the receptor theory toolbox.

Single-Dose-Response Curves of Murine Gastrointestinal Crypt Stem Cells

1977 ◽  
Vol 69 (1) ◽  
pp. 65 ◽  
Author(s):  
Kouji Masuda ◽  
H. Rodney Withers ◽  
Kathryn A. Mason ◽  
Kuang Y. Chen
Keyword(s):  
Stem Cells ◽  
Single Dose ◽  
Dose Response ◽  
Response Curves ◽  
Dose Response Curves

Dose-response Curves in the Fibrin Plate Assay Fibrinolytic Activity of Proteases

1974 ◽  
Vol 32 (02/03) ◽  
pp. 356-365 ◽  
Author(s):  
F Haverkate ◽  
D. W Traas
Keyword(s):  
Dose Response ◽  
Fibrinolytic Activity ◽  
Enzyme Concentration ◽  
Response Curves ◽  
Agar Gel ◽  
Porcine Tissue ◽  
Plate Assay ◽  
Fibrin Plate ◽  
Different Types ◽  
Dose Response Curves

SummaryIn the fibrin plate assay different types of relationships between the dose of applied proteolytic enzyme and the response have been previously reported. This study was undertaken to determine whether a generally valid relationship might exist.Trypsin, chymotrypsin, papain, the plasminogen activator urokinase and all of the microbial proteases investigated, including brinase gave a linear relationship between the logarithm of the enzyme concentration and the diameter of the circular lysed zone. A similar linearity of dose-response curves has frequently been found by investigators who used enzyme plate assays with substrates different from fibrin incorporated in an agar gel. Consequently, it seems that this linearity of dose-response curves is generally valid for the fibrin plate assay as well as for other enzyme plate bioassays.Both human plasmin and porcine tissue activator of plasminogen showed deviations from linearity of semi-logarithmic dose-response curves in the fibrin plate assay.

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