The ALHAMBRA survey: An empirical estimation of the cosmic variance for merger fraction studies based on close pairs

Aims. Our goal is to estimate empirically the cosmic variance that affects merger fraction studies based on close pairs for the first time. Methods. We compute the merger fraction from photometric redshift close pairs with 10 h-1 kpc ≤ rp ≤ 50 h-1 kpc and Δv ≤ 500 km s-1 and measure it in the 48 sub-fields of the ALHAMBRA survey. We study the distribution of the measured merger fractions that follow a log-normal function and estimate the cosmic variance σv as the intrinsic dispersion of the observed distribution. We develop a maximum likelihood estimator to measure a reliable σv and avoid the dispersion due to the observational errors (including the Poisson shot noise term). Results. The cosmic variance σv of the merger fraction depends mainly on (i) the number density of the populations under study for both the principal (n1) and the companion (n2) galaxy in the close pair and (ii) the probed cosmic volume Vc. We do not find a significant dependence on either the search radius used to define close companions, the redshift, or the physical selection (luminosity or stellar mass) of the samples. Conclusions. We have estimated the cosmic variance that affects the measurement of the merger fraction by close pairs from observations. We provide a parametrisation of the cosmic variance with n1, n2, and Vc, σv ∝ n1-0.54Vc-0.48 (n_2/n_1)-0.37 . Thanks to this prescription, future merger fraction studies based on close pairs could properly account for the cosmic variance on their results

Discovery of fevipiprant (NVP-QAW039), a potent and selective DP2 receptor antagonist for treatment of asthma

Further optimization of an initial DP2 receptor antagonist clinical candidate NVPQAV680 led to the discovery of a follow-up molecule 2-(2-methyl-1-(4-(methylsulfonyl)-2- (trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetic acid (compound 11, NVP-QAW039, fevipiprant), which exhibits improved potency on human eosinophils and Th2 cells, together with a longer receptor residence time, and is currently in clinical trials for severe asthma

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS

Title Page 1-aminobenzotriazole modulates oral drug pharmacokinetics through cytochrome P450 inhibition and delay of gastric emptying in rats

Non-standard abbreviations: ABT, 1-aminobenzotriazole; AUC, area under the concentration-time curve; C max , Highest drug concentration observed in plasma after administration of extravascular dose; P450, cytochrome P450; LC-MS/MS, liquid chromatography tandem mass spectrometry; T max , Time at which highest concentration occurs after extravascular dose. DMD#056408 3 Abstract The simultaneous effect of the cytochrome P450 inhibitor 1-aminobenzotriazole (ABT) on inhibition of in vivo metabolism and gastric emptying was evaluated with the test compound NVS-CRF38, a novel CRF 1 antagonist with low water solubility, and the reference compound midazolam with high water solubility in rats. Pre-treatment of rats with 100 mg/kg oral ABT administered 2 hours prior to a semi-solid caloric test meal, markedly delayed gastric emptying. ABT increased stomach weights by 2-fold, this is likely to be attributed to a prosecretory effect because stomach concentrations of bilirubin were comparable in ABT and control groups. ABT administration decreased the initial systemic exposure of orally administered NVS-CRF38 and increased T max 40-fold, suggesting gastric retention and delayed oral absorption. ABT increased the initial systemic exposure of midazolam, however for orally (but not subcutaneously) administered midazolam, extensive variability in plasmaconcentration time profiles was apparent. Careful selection of administration routes is recommended for ABT use in vivo, variable oral absorption of co-administered compounds can be expected due to a disturbance of gastrointestinal transit. DMD#05640

Application of osmotic pumps for sustained release of 1-aminobenzotriazole and inhibition of cytochrome P450 enzymes in mice: Model comparison with the hepatic P450 reductase null mouse

The effectiveness of controlled release 1-aminobenzotriazole (ABT) administration to inhibit cytochrome P450 (P450) enzymes has been evaluated in mice. To maximize the duration of P450 inhibition in vivo, ABT was administered via an osmotic pump. The degree of P450 inhibition was compared with that achieved with a single bolus dose of ABT. Two-hour prior subcutaneous treatment of mice with ABT (50 mg/kg) inhibited antipyrine clearance by 88%. A less pronounced inhibitory effect (29% reduction in clearance) was observed when ABT was administered 24-hours before antipyrine administration, indicating partial restoration of P450 activity during this longer pretreatment time. The duration of ABT in mice was very short (mean residence time = 1.7 hours) after subcutaneous bolus administration. When the inhibitor was delivered by an osmotic pump, maximum blood concentrations of the inhibitor were observed 24 hours after device implantation and were maintained at steady state for 6 days. Inhibition of P450 activity, as measured by antipyrine clearance, was confirmed at 24 hours and 120 hours after pump implantation, highlighting the utility of this method as a longer-term model for P450 inhibition in mice. The magnitude of P450 inhibition in ABT-treated mice was compared with that in hepatic P450 reductase null mice and both models were comparable. In vivo ABT administration by an osmotic pump offers an effective approach for longer-term P450 inhibition in mice and avoids the necessity for multiple dosing of the inhibitor

Evaluation of the GastroPlus™ Advanced Compartmental and Transit (ACAT) Model in Early Discovery

Purpose: The aim of this study was to evaluate the oral exposure predictions obtained early in drug discovery with a generic GastroPlus Advanced Compartmental And Transit (ACAT) model based on the in vivo intravenous blood concentration-time profile, in silico properties (lipophilicity, pKa) and in vitro high-throughput absorption-distribution-metabolism-excretion (ADME) data (as determined by PAMPA, solubility, liver microsomal stability assays). Methods: The model was applied to a total of 623 discovery molecules and their oral exposure was predicted in rats and/or dogs. The predictions of Cmax, AUClast and Tmax were compared against the observations. Results: The generic model proved to make predictions of oral Cmax, AUClast and Tmax within 3-fold of the observations for rats in respectively 65%, 68% and 57% of the 537 cases. For dogs, it was respectively 77%, 79% and 85% of the 124 cases. Statistically, the model was most successful at predicting oral exposure of Biopharmaceutical Classification System (BCS) class 1 compounds compared to classes 2 and 3, and was worst at predicting class 4 compounds oral exposure. Conclusion: The generic GastroPlus ACAT model provided reasonable predictions especially for BCS class 1 compounds. For compounds of other classes, the model may be refined by obtaining more information on solubility and permeability in secondary assays. This increases confidence that such a model can be used in discovery projects to understand the parameters limiting absorption and extrapolate predictions across species. Also, when predictions disagree with the observations, the model can be updated to test hypotheses and understand oral absorption

1-aminobenzotriazole modulates oral drug pharmacokinetics through cytochrome P450 inhibition and delay of gastric emptying in rats

The simultaneous effect of the cytochrome P450 inhibitor 1-aminobenzotriazole (ABT) on inhibition of in vivo metabolism and gastric emptying was evaluated with the test compound NVS308, a novel CRF1 antagonist with low water solubility, and the reference compound midazolam with high water solubility in rats. Pre-treatment of rats with 100 mg/kg oral. ABT administered 2 hours prior to a semi-solid caloric test meal, markedly delayed gastric emptying. ABT increased stomach weights by 2-fold, this is likely to be attributed to a pro-secretory effect because stomach concentrations of bilirubin were comparable in ABT and control groups. ABT administration decreased the initial systemic exposure of orally administered NVS308 and increased Tmax 40-fold, suggesting gastric retention and delayed oral absorption. ABT increased the initial systemic exposure of midazolam, however for orally (but not subcutaneously) administered midazolam, extensive variability in plasma-concentration time profiles was apparent. Careful selection of administration routes is recommended for ABT use in vivo, variable oral absorption of co-administered compounds can be expected due to a disturbance of gastrointestinal transit

Prediction of drug clearance by glucuronidation from in vitro data: Use of combined cytochrome P450 and UDP-glucuronosyltransferase cofactors in alamethicin-activated human liver microsomes

Glucuronidation via UDP-glucuronosyltransferase (UGT) is an increasingly important clearance pathway. In this study intrinsic clearance (CL(int)) values for buprenorphine, carvedilol, codeine, diclofenac, gemfibrozil, ketoprofen, midazolam, naloxone, raloxifene, and zidovudine were determined in pooled human liver microsomes using the substrate depletion approach. The in vitro clearance data indicated a varying contribution of glucuronidation to the clearance of the compounds studied, ranging from 6 to 79% for midazolam and gemfibrozil, respectively. The CL(int) was obtained using either individual or combined cofactors for cytochrome P450 (P450) and UGT enzymes with alamethicin activation and in the presence and absence of 2% bovine serum albumin (BSA). In the presence of combined P450 and UGT cofactors, CL(int) ranged from 2.8 to 688 microl/min/mg for zidovudine and buprenorphine, respectively; the clearance was approximately equal to the sum of the CL(int) values obtained in the presence of individual cofactors. The unbound intrinsic clearance (CL(int, u)) was scaled to provide an in vivo predicted CL(int); the data obtained in the presence of combined cofactors resulted in 5-fold underprediction on average. Addition of 2% BSA to the incubation with both P450 and UGT cofactors reduced the bias in the clearance prediction, with 8 of 10 compounds predicted within 2-fold of in vivo values with the exception of raloxifene and gemfibrozil. The current study indicates the applicability of combined cofactor conditions in the assessment of clearance for compounds with a differential contribution of P450 and UGT enzymes to their elimination. In addition, improved predictability of microsomal data is observed in the presence of BSA, in particular for UGT2B7 substrates

Application of a deuterium replacement strategy to modulate the pharmacokinetics of NVS-CRF38, a novel CRF1 antagonist

Deuterium isotope effects were evaluated as a strategy to optimize the pharmacokinetics of NVS-CRF38, a novel CRF1 receptor antagonist. In an attempt to supress O-demethylation of NVS-CRF38 without losing activity against the CRF1 receptor, the protons at the site of metabolism were replaced with deuterium. For in vitro and in vivo studies intrinsic primary isotope effects (KH/KD) were determined by the ratio of CLint obtained from the nondeuterated and deuterated substrate. In vitro isotope effects were more pronounced when CLint values were calculated based on the rate of formation of the O-desmethyl metabolite (KH/KD ~7), compared to the substrate depletion method (KH/KD ~2). In vivo isotope effects were measured in the rat after intravenous (1 mg/kg) and oral (10 mg/kg) administration. For both administration routes isotope effects calculated from in vivo CLint corresponding to all biotransformation pathways were lower (KH/KD ~2) compared to CLint values calculated from the O-demethylation reaction alone (KH/KD ~7). Comparative metabolite identification studies were undertaken using rat and human microsomes to explore the potential for metabolic switching. As expected a marked reduction of the O-demethylated metabolite was observed for the nondeuterated substrate, however levels of NVS-CRF38’s other metabolites increased, compensating to some extent for the isotope effect