During imbibition, initially connected oil is displaced until it is trapped as immobile clusters. While initial and final states have been well described before, here we image the dynamic transient ...process in a sandstone rock using fast synchrotron‐based X‐ray computed microtomography. Wetting film swelling and subsequent snap off, at unusually high saturation, decreases nonwetting phase connectivity, which leads to nonwetting phase fragmentation into mobile ganglia, i.e., ganglion dynamics regime. We find that in addition to pressure‐driven connected pathway flow, mass transfer in the oil phase also occurs by a sequence of correlated breakup and coalescence processes. For example, meniscus oscillations caused by snap‐off events trigger coalescence of adjacent clusters. The ganglion dynamics occurs at the length scale of oil clusters and thus represents an intermediate flow regime between pore and Darcy scale that is so far dismissed in most upscaling attempts.
Key Points
Ganglion dynamics contributes to nonwetting phase transport
Coalescence of nonwetting phase clusters is triggered by snap off
Ganglion dynamics occurs from 75% nonwetting phase saturation on
Darcy‐scale multiphase flow in geological formations is significantly influenced by the wettability of the fluid‐solid system. So far it has not been understood how wettability impacts the pore‐scale ...flow regimes within rocks, which were in most cases regarded as an alteration from the base case of strongly water‐wet conditions by adjustment of contact angles. In this study, we directly image the pore‐scale flow regime in a carbonate altered to a mixed‐wet condition by aging with crude oil to represent the natural configuration in an oil reservoir with fast synchrotron‐based X‐ray computed tomography. We find that the pore‐scale flow regime is dominated by ganglion dynamics in which the pore space is intermittently filled with oil and brine. The frequency and size of these fluctuations are greater than in water‐wet rock such that their impact on the overall flow and relative permeability cannot be neglected in modeling approaches.
Plain Language Summary
In geological systems, in particular in oil reservoirs, the wetting condition of rock, the preference of a fluid to be in contact with a surface in the presence of another fluid, has a significant impact on multiphase flow. Often a simplified picture based on static, wettability‐dependent fluid configurations is used as a basis for modeling where the fluids are assumed to flow through the porous rock within definite connected pathways. Our research, which is based on a time series of 3‐D images obtained during multiphase flow showing the pore‐scale fluid configurations of the brine and oil, demonstrates that this picture is too simplistic. In reality the flow paths change. In systems in which one phase is strongly wetting those changes are fast, small, and rare. However, oil reservoirs are mostly mixed‐wet as surface active components contained in crude oil alter the rock surface. In such mixed‐wet situations, we observe that the movement is slower (minutes instead of seconds), is more frequent, and involves larger fluid volumes. This indicates a different flow regime that cannot be estimated from an extrapolation from strongly wetting rock. This has consequences for the way how multiphase flow in mixed‐wet rock is described in models.
Key Points
Ganglion dynamics in mixed‐wet systems is observed
Oil‐filling events are more frequent and of larger size in mixed‐wet systems and depend on the aging state/wettability of the rock surface
This behavior may impact the overall relative permeability and must be considered in pore‐scale flow simulations
Flash pyrolysis and sequential chemical degradation were combined to study the molecular composition of an immature Type II-S kerogen from the Miocene Monterey Formation. Firstly, base hydrolysis was ...performed in order to hydrolyse ester bonds, in the second step aliphatic ethers were cleaved and in the third step sulfur–sulfur and sulfur–carbon bonds in the kerogen were broken. Linear and isoprenoid alkanes and alkenes were partially released upon cleavage of ether-bonds and are probably derived from
n-alkyl and isoprenoid algaenans, respectively, biosynthesized by marine algae. The precursor moieties of the alkylthiophenes generated upon pyrolysis were released upon cleavage of sulfide-bonds indicating that their precursors, probably sugars, were sulfur-bound to the kerogen. Upon ether- as well as sulfur-bond cleavage, alkylpyrroles were released indicating that their precursors, probably tetrapyrrole pigments, occur as ether- as well as sulfur-bound in the kerogen. Furthermore, prist-1-ene as well as tocopherols were removed from the flash pyrolysate after ether-bond cleavage, indicating that ether-bound tocopherols are probably a major source of prist-1-ene in kerogen pyrolysates. Furthermore, our degradation approach resulted in the recognition of specific ester-, ether- and sulfur-bound low-molecular-weight biomarkers attached to the kerogen. However, the release of these biomarkers into the extract has hardly any impact on the residue pyrolysate and thus most of the compounds identified in the extracts are probably less important constituents of the kerogen.
Aprocitentan is a novel, potent, dual endothelin receptor antagonist that recently demonstrated efficacy in the treatment of difficult-to-treat (resistant) hypertension. The aim of this study was to ...develop a population pharmacokinetic (PK) model describing aprocitentan plasma concentration over time, to investigate relationships between subject-specific factors (covariates) and model parameters, and to quantify the influence of the identified covariates on the exposure to aprocitentan via model-based simulations, enabling judgment about the clinical relevance of the covariates.
PK data from 902 subjects in ten Phase 1, one Phase 2, and one Phase 3 study were pooled to develop a joint population PK model. The concentration-time course of aprocitentan was described by a two-compartment model with absorption lag time, first-order absorption and elimination, and reduced relative bioavailability following very high doses of 300 and 600 mg.
The population PK model described the observed data well. Volume and clearance parameters were associated with body weight. Renal function as reflected by estimated glomerular filtration rate (eGFR), hepatic impairment, and sex were identified as relevant covariates on clearance.
The subject-specific characteristics of body weight, eGFR, hepatic impairment, and sex were shown to influence exposure parameters area under the concentration-time curve and maximum concentration in steady state to a limited extent, i.e., not more than 25% different from a reference subject, and therefore do not warrant dose adjustments.
Antagonism of the chemokine receptor CXCR7 has shown promising effects in diverse disease areas through modulation of its ligands, CXCL11 and CXCL12. Preclinical data of the first-in-class CXCR7 ...antagonist, ACT-1004-1239, showed efficacy in animal models of multiple sclerosis and acute lung injury. In healthy humans, single-dose administration of ACT-1004-1239 revealed a favorable clinical profile. Here, we report the target engagement of ACT-1004-1239 in healthy mice and humans after multiple doses using CXCL11 and CXCL12 as biomarkers. In addition, safety/tolerability, concentration-QTc relationship, and pharmacokinetics (PK) were assessed in a randomized, double-blind, placebo-controlled Phase 1 clinical study. Multiple-dose ACT-1004-1239 dose-dependently increased CXCL12 plasma concentration across the investigated dose range in mice and humans (mice: 1–100 mg/kg b.i.d.; humans: 30–200 mg o.d.) when compared to vehicle/placebo demonstrating target engagement. Mouse and human PK/PD models predicted that CXCL12 concentration approached a plateau within these dose ranges. In humans, ACT-1004-1239 was rapidly absorbed (tmax: 1.75–3.01 h) and the terminal t1/2 was approximately 19 h. Steady-state conditions were reached by Day 3 with an accumulation index of 1.2. Female subjects had overall higher exposure compared to males. Multiple-dose ACT-1004-1239 was well tolerated up to 200 mg once daily in humans. There was no evidence of ACT-1004-1239-mediated QTc interval prolongation. Overall, multiple oral doses of ACT-1004-1239 showed target engagement with CXCR7 in healthy mice and humans, therefore, assessment of CXCL12 as translational tool for further investigations in patients is warranted. Favorable safety/tolerability and PK profiles allow for further clinical development.
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•ACT-1004-1239 is the first-in-class CXCR7 antagonist studied in humans.•Target engagement of ACT-1004-1239 was shown using plasma CXCL12 as biomarker.•CXCL12 plasma concentration approached a plateau based on a PK/PD model.•ACT-1004-1239 showed a favorable safety profile.•A once-daily dosing regimen of ACT-1004-1239 in humans is proposed.
Various in vitro, animal, and limited human adult studies suggest a profound inhibitory effect of inflammation and disease on cytochrome P-450 3A (CYP3A)-mediated drug metabolism. Studies showing ...this relationship in critically ill patients are lacking, whereas clearance of many CYP3A drug substrates may be decreased, potentially leading to toxicity.
To prospectively study the relationship between inflammation, organ failure, and midazolam clearance as a validated marker of CYP3A-mediated drug metabolism in critically ill children.
From 83 critically ill children (median age, 5.1 mo range, 0.02-202 mo), midazolam plasma (n = 532), cytokine (e.g., IL-6, tumor necrosis factor-α), and C-reactive protein (CRP) levels; organ dysfunction scores (Pediatric Risk of Mortality II, Pediatric Index of Mortality 2, Pediatric Logistic Organ Dysfunction); and number of failing organs were prospectively collected. A population pharmacokinetic model to study the impact of inflammation and organ failure on midazolam pharmacokinetics was developed using NONMEM 7.3.
In a two-compartmental pharmacokinetic model, body weight was the most significant covariate for clearance and volume of distribution. CRP and organ failure were significantly associated with clearance (P < 0.01), explaining both interindividual and interoccasional variability. In simulations, a CRP of 300 mg/L was associated with a 65% lower clearance compared with 10 mg/L, and three failing organs were associated with a 35% lower clearance compared with one failing organ.
Inflammation and organ failure strongly reduce midazolam clearance, a surrogate marker of CYP3A-mediated drug metabolism, in critically ill children. Hence, critically ill patients receiving CYP3A substrate drugs may be at risk of increased drug levels and associated toxicity.
Using a combined pharmacological and gene-deletion approach, we have delineated a novel mechanism of neurokinin-1 (NK-1) receptor-dependent hyperalgesia induced by proteinase-activated receptor-2 ...(PAR2), a G-protein-coupled receptor expressed on nociceptive primary afferent neurons. Injections into the paw of sub-inflammatory doses of PAR2 agonists in rats and mice induced a prolonged thermal and mechanical hyperalgesia and elevated spinal Fos protein expression. This hyperalgesia was markedly diminished or absent in mice lacking the NK-1 receptor, preprotachykinin-A or PAR2 genes, or in rats treated with a centrally acting cyclooxygenase inhibitor or treated by spinal cord injection of NK-1 antagonists. Here we identify a previously unrecognized nociceptive pathway with important therapeutic implications, and our results point to a direct role for proteinases and their receptors in pain transmission.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Flood simulations are important for flood (fatality) risk assessment. This article provides insight into the sensitivity of flood fatality risks to the model resolution of flood simulations and to ...several uncertain parameters in the loss of life model used. A case study is conducted for river flooding in a polder in the Netherlands (the Bommelerwaard) where the Dutch approach for loss of life estimation is applied. Flood models with resolutions of 100, 25, and 5 m are considered. Results show locally increased mortality rates in higher resolution simulations nearby structures including road embankments, dikes, and culverts. This causes a larger maximum individual risk value (annual probability of death for a person due to flooding) which has consequences for safety standards based on the individual risk criterion. Mortality rate in the breach zone is also affected by representations of buildings as solid objects versus as roughness elements. Furthermore, changes in the loss of life estimation approach via alternative ways of including people's behaviour, building characteristics, and age of the population, have a significant impact on flood fatality risk. Results from this study can be used to support future risk assessments and decision making with respect to safety standards.
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