Four basic models for characterizing indirect pharmacodynamic responses after drug administration have been developed and compared. The models are based on drug effects (inhibition or stimulation) on ...the factors controlling either the input or the dissipation of drug response. Pharmacokinetic parameters of methylprednisolone were used to generate plasma concentration and response-time profiles using computer simulations. It was found that the responses produced showed a slow onset and a slow return to baseline. The time of maximal response was dependent on the model and dose. In each case, hysteresis plots showed that drug concentrations preceded the response. When the responses were fitted with pharmacodynamic models based on distribution to a hypothetical effect compartment, the resulting parameters were dose-dependent and inferred biological implausibility. Indirect response models must be treated as distinct from conventional pharmacodynamic models which assume direct action of drugs. The assumptions, equations, and data patterns for the four basic indirect response models provide a starting point for evaluation of pharmacologic effects where the site of action precedes or follows the measured response variable.
This document corrects two errors in Eur. Phys. J. C77 (2017) no. 8, 56: the incorrect referencing of Fig. 1 labels in three paragraphs in the results section and a missing acknowledgements section.
A
bstract
The production of prompt D
s
+
mesons was measured for the first time in collisions of heavy nuclei with the ALICE detector at the LHC. The analysis was performed on a data sample of Pb-Pb ...collisions at a centre-of-mass energy per nucleon pair,
s
N
N
,
of 2.76 TeV in two different centrality classes, namely 0–10% and 20–50%. D
s
+
mesons and their antiparticles were reconstructed at mid-rapidity from their hadronic decay channel D
s
+
→
ϕπ
+
, with
ϕ
→ K
−
K
+
, in the transverse momentum intervals 4 <
p
T
< 12GeV/
c
and 6 <
p
T
< 12 GeV/
c
for the 0–10% and 20–50% centrality classes, respectively. The nuclear modification factor
R
AA
was computed by comparing the
p
T
-differential production yields in Pb-Pb collisions to those in proton-proton (pp) collisions at the same energy. This pp reference was obtained using the cross section measured at
s
=
7
TeV and scaled to
s
=
2.76
TeV. The
R
AA
of D
s
+
mesons was compared to that of non-strange D mesons in the 10% most central Pb-Pb collisions. At high
p
T
(8 <
p
T
< 12 GeV/
c
) a suppression of the D
s
+
-meson yield by a factor of about three, compatible within uncertainties with that of non-strange D mesons, is observed. At lower
p
T
(4 <
p
T
< 8 GeV/
c
) the values of the D
s
+
-meson
R
AA
are larger than those of non-strange D mesons, although compatible within uncertainties. The production ratios D
s
+
/D
0
and D
s
+
/D
+
were also measured in Pb-Pb collisions and compared to their values in proton-proton collisions.
A
bstract
Measurements of inclusive charged-particle jet production in pp and p-Pb collisions at center-of-mass energy per nucleon-nucleon collision
s
NN
= 5
.
02 TeV and the corresponding nuclear ...modification factor
R
pPb
ch
jet
are presented, using data collected with the ALICE detector at the LHC. Jets are reconstructed in the central rapidity region |
η
jet
|
<
0
.
5 from charged particles using the anti-
k
T
algorithm with resolution parameters
R
= 0
.
2, 0
.
3, and 0
.
4. The
p
T
-differential inclusive production cross section of charged-particle jets, as well as the corresponding cross section ratios, are reported for pp and p-Pb collisions in the transverse momentum range 10
<
p
T
,
jet
ch
<
140 GeV/
c
and 10
<
p
T
,
jet
ch
<
160 GeV/
c
, respectively, together with the nuclear modification factor
R
pPb
ch
jet
in the range 10
<
p
T
,
jet
ch
<
140 GeV/
c
. The analysis extends the
p
T
range of the previously-reported charged-particle jet measurements by the ALICE Collaboration. The nuclear modification factor is found to be consistent with one and independent of the jet resolution parameter with the improved precision of this study, indicating that the possible influence of cold nuclear matter effects on the production cross section of charged-particle jets in p-Pb collisions at
s
NN
= 5
.
02 TeV is smaller than the current precision. The obtained results are in agreement with other minimum bias jet measurements available for RHIC and LHC energies, and are well reproduced by the NLO perturbative QCD P
owheg
calculations with parton shower provided by P
ythia
8 as well as by J
etscape
simulations.
The ALICE Collaboration has measured the energy dependence of exclusive photoproduction of Formula omitted vector mesons off proton targets in ultra-peripheral p-Pb collisions at a centre-of-mass ...energy per nucleon pair Formula omitted TeV. The e Formula omittede Formula omitted and Formula omitted decay channels are used to measure the cross section as a function of the rapidity of the Formula omitted in the range Formula omitted, corresponding to an energy in the Formula omittedp centre-of-mass in the interval Formula omitted GeV. The measurements, which are consistent with a power law dependence of the exclusive Formula omitted photoproduction cross section, are compared to previous results from HERA and the LHC and to several theoretical models. They are found to be compatible with previous measurements.
The measurements of the production of prompt Formula omitted, Formula omitted, Formula omitted, and Formula omitted mesons in proton-proton (pp) collisions at Formula omitted with the ALICE detector ...at the Large Hadron Collider (LHC) are reported. D mesons were reconstructed at mid-rapidity ( Formula omitted) via their hadronic decay channels Formula omitted, Formula omitted, Formula omitted, Formula omitted, and their charge conjugates. The production cross sections were measured in the transverse momentum interval Formula omitted for Formula omitted, Formula omitted for Formula omitted and Formula omitted, and in Formula omitted for Formula omitted mesons. Thanks to the higher integrated luminosity, an analysis in finer Formula omitted bins with respect to the previous measurements at Formula omitted was performed, allowing for a more detailed description of the cross-section Formula omitted shape. The measured Formula omitted-differential production cross sections are compared to the results at Formula omitted TeV and to four different perturbative QCD calculations. Its rapidity dependence is also tested combining the ALICE and LHCb measurements in pp collisions at Formula omitted. This measurement will allow for a more accurate determination of the nuclear modification factor in p-Pb and Pb-Pb collisions performed at the same nucleon-nucleon centre-of-mass energy.
GLP-1 is an insulinotropic hormone that synergistically with glucose gives rise to an increased insulin response. Its secretion is increased following a meal and it is thus of interest to describe ...the secretion of this hormone following an oral glucose tolerance test (OGTT). The aim of this study was to build a mechanism-based population model that describes the time course of total GLP-1 and provides indices for capability of secretion in each subject. The goal was thus to model the secretion of GLP-1, and not its effect on insulin production. Single 75 g doses of glucose were administered orally to a mixed group of subjects ranging from healthy volunteers to patients with type 2 diabetes (T2D). Glucose, insulin, and total GLP-1 concentrations were measured. Prior population data analysis on measurements of glucose and insulin were performed in order to estimate the glucose absorption rate. The individual estimates of absorption rate constants were used in the model for GLP-1 secretion. Estimation of parameters was performed using the FOCE method with interaction implemented in NONMEM VI. The final transit/indirect-response model obtained for GLP-1 production following an OGTT included two stimulation components (fast, slow) for the zero-order production rate. The fast stimulation was estimated to be faster than the glucose absorption rate, supporting the presence of a proximal–distal loop for fast secretion from
l
-cells. The fast component (
st
3
= 8.64·10
−5
mg
−1
) was estimated to peak around 25 min after glucose ingestion, whereas the slower component (
st
4
= 26.2·10
−5
mg
−1
) was estimated to peak around 100 min. Elimination of total GLP-1 was characterised by a first-order loss. The individual values of the early phase GLP-1 secretion parameter (
st
3
) were correlated (
r
= 0.52) with the AUC(0–60 min.) for GLP-1. A mechanistic population model was successfully developed to describe total GLP-1 concentrations over time observed after an OGTT. The model provides indices related to different mechanisms of subject abilities to secrete GLP-1. The model provides a good basis to study influence of different demographic factors on these components, presented mainly by indices of the fast- and slow phases of GLP-1 response.
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