| 1. |
- Ahmad, Amais, et al.
(författare)
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IMI – Oral biopharmaceutics tools project – Evaluation of bottom-up PBPK prediction success part 4 : Prediction accuracy and software comparisons with improved data and modelling strategies
- 2020
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : Elsevier BV. - 0939-6411 .- 1873-3441. ; 156, s. 50-63
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Tidskriftsartikel (refereegranskat)abstract
- Oral drug absorption is a complex process depending on many factors, including the physicochemical properties of the drug, formulation characteristics and their interplay with gastrointestinal physiology and biology. Physiological-based pharmacokinetic (PBPK) models integrate all available information on gastro-intestinal system with drug and formulation data to predict oral drug absorption. The latter together with in vitro-in vivo extrapolation and other preclinical data on drug disposition can be used to predict plasma concentration-time profiles in silico. Despite recent successes of PBPK in many areas of drug development, an improvement in their utility for evaluating oral absorption is much needed. Current status of predictive performance, within the confinement of commonly available in vitro data on drugs and formulations alongside systems information, were tested using 3 PBPK software packages (GI-Sim (ver.4.1), Simcyp® Simulator (ver.15.0.86.0), and GastroPlusTM (ver.9.0.00xx)). This was part of the Innovative Medicines Initiative (IMI) Oral Biopharmaceutics Tools (OrBiTo) project.Fifty eight active pharmaceutical ingredients (APIs) were qualified from the OrBiTo database to be part of the investigation based on a priori set criteria on availability of minimum necessary information to allow modelling exercise. The set entailed over 200 human clinical studies with over 700 study arms. These were simulated using input parameters which had been harmonised by a panel of experts across different software packages prior to conduct of any simulation. Overall prediction performance and software packages comparison were evaluated based on performance indicators (Fold error (FE), Average fold error (AFE) and absolute average fold error (AAFE)) of pharmacokinetic (PK) parameters.On average, PK parameters (Area Under the Concentration-time curve (AUC0-tlast), Maximal concentration (Cmax), half-life (t1/2)) were predicted with AFE values between 1.11 and 1.97. Variability in FEs of these PK parameters was relatively high with AAFE values ranging from 2.08 to 2.74. Around half of the simulations were within the 2-fold error for AUC0-tlast and around 90% of the simulations were within 10-fold error for AUC0-tlast. Oral bioavailability (Foral) predictions, which were limited to 19 APIs having intravenous (i.v.) human data, showed AFE and AAFE of values 1.37 and 1.75 respectively. Across different APIs, AFE of AUC0-tlast predictions were between 0.22 and 22.76 with 70% of the APIs showing an AFE > 1. When compared across different formulations and routes of administration, AUC0-tlast for oral controlled release and i.v. administration were better predicted than that for oral immediate release formulations. Average predictive performance did not clearly differ between software packages but some APIs showed a high level of variability in predictive performance across different software packages. This variability could be related to several factors such as compound specific properties, the quality and availability of information, and errors in scaling from in vitro and preclinical in vivo data to human in vivo behaviour which will be explored further. Results were compared with previous similar exercise when the input data selection was carried by the modeller rather than a panel of experts on each in vitro test. Overall, average predictive performance was increased as reflected in smaller AAFE value of 2.8 as compared to AAFE value of 3.8 in case of previous exercise.
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| 2. |
- Kanai, M, et al.
(författare)
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- 2023
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swepub:Mat__t
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| 3. |
- Bolger, Claire, et al.
(författare)
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Hyperpnea-Induced Bronchoconstriction and Urinary CC16 Levels in Athletes
- 2011
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Ingår i: Medicine & Science in Sports & Exercise. - 1530-0315. ; 43:7, s. 1207-1213
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Tidskriftsartikel (refereegranskat)abstract
- BOLGER, C., E. TUFVESSON, M. SUE-CHU, G. DEVEREUX, J. G. AYRES, L. BJERMER, and P. KIPPELEN. Hyperpnea-Induced Bronchoconstriction and Urinary CC16 Levels in Athletes. Med. Sci. Sports Exerc., Vol. 43, No. 7, pp. 1207-1213, 2011. Purpose: Exercise-induced bronchoconstriction (EIB) is a common condition in both individuals with asthma and otherwise healthy elite athletes. Although excessive water loss by peripheral airways during hyperpnea is regarded as the initial trigger for EIB, the cascade of events that follows remains unclear. Our goal was to establish whether transient disruption of the airway epithelial barrier occurs after a short period of hyperpnea of dry air in athletes with EIB. Methods: Urinary concentration of the pneumoprotein Clara cell (CC16) was used as an assumed biomarker of lung epithelial cell damage or dysfunction. Samples were collected at baseline and for 90 min after an 8-min eucapnic voluntary hyperpnea (EVH) test in 50 female individuals (28 athletes and 22 untrained). Results: Nineteen subjects (10 athletes) demonstrated a sustained bronchoconstriction after EVH (mean +/- SE forced expiratory volume in the first second (FEV1) fall from baseline = 23.4% +/- 2.6%). The remaining subjects had a negative challenge result with an FEV1 fall of 5.9% +/- 0.6%. An increase (P < 0.001) in urinary CC16 concentration was noticed after EVH in all but one subject, with no group difference (median CC16 increase before to after challenge: athletes EVH- 0.083 ng.mu mol(-1), athletes EVH+ 0.223 ng.mu mol(-1), untrained EVH- 0.074 ng.mu mol(-1), untrained EVH+ 0.571 ng.mu mol(-1); P > 0.05). Conclusions: Urinary levels of CC16 are increased after EVH in all individuals (trained and untrained, with and without EIB) suggestive of dehydration-induced perturbation of the distal respiratory epithelium during episodes of hyperventilation.
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| 4. |
- Bolger, Claire, et al.
(författare)
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Urinary cc16 levels in winter versus summer sport athletes after eucapnic voluntary hyperpnoea
- 2009
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Konferensbidrag (refereegranskat)abstract
- Exercise induced bronchoconstriction (EIB) is highly prevalent in elite athletes, especially in those training in cold dry environments. Dehydration of the airways plays a key role in this process. EIB has recently been linked to airway epithelial injury in asthmatic individuals. The aim of the study is to determine whether a short period of hyperpnoea of dry air causes airway epithelial disruption in winter and/or summer sport athletes. We hypothesise that urinary level of the Clara cell protein (CC16) – an indirect marker of permeability/cellular integrity of the lung epithelial barrier – will be increased after a eucapnic voluntary hyperpnoea (EVH) test and that this increase will be larger in winter compared to summer athletes. Forty two female athletes – 28 summer athletes (age 31.1+/-1.7yr (SEM), training volume 9+/-1.1h/wk) and 14 winter athletes (age 21.4+/-0.8yr, training volume 12.0 ± 1.10h/wk) – took part in this study. They all performed an 8-min EVH test at a target ventilation rate of 30 times their baseline forced expiratory volume in one second (FEV1). After the challenge, FEV1 was measured in duplicate at 2, 5, 10, 15, 20, 30, 60 and 90min. A sustained decrease in FEV1 of at least 10% from baseline was considered positive. Urine samples were collected at baseline and at 30, 60 and 90min recovery. CC16 concentration was measured by enzyme immunoassay. Ten summer athletes had a positive test (max FEV1 fall = 19.6+/-2.4%), whilst eighteen of the summer athletes and all the winter athletes were negative (max FEV1 fall = 5.7+/-0.7% and 5.3+/-0.7%, respectively). CC16 increased significantly after the challenge in all three groups (P<0.01) with no difference between groups: delta CC16 (max post-EVH minus baseline) in summer EVH negative athletes was 0.241+/-0.1 ng/μmol creatinine, 0.292+/-0.085 ng/μmol creatinine in summer EVH positive athletes, and 0.123+/-0.047ng/μmol creatinine in winter EVH negative athletes (P=0.415)In conclusion, a short period of hyperpnoea of dry air is associated with an increased rate of CC16 excretion in urine in both winter and summer athletes. This suggests that the integrity of the airway epithelium might be compromised by loss of airway surface lining fluid when athletes inhale dry air at high flow rates. This appears to occur irrespective of the degree of bronchoconstriction or regular training environment.
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| 5. |
- Greene, Chris, et al.
(författare)
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Microvascular stabilization via blood-brain barrier regulation prevents seizure activity
- 2022
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Blood-brain barrier (BBB) dysfunction is associated with worse epilepsy outcomes however the underlying molecular mechanisms of BBB dysfunction remain to be elucidated. Tight junction proteins are important regulators of BBB integrity and in particular, the tight junction protein claudin-5 is the most enriched in brain endothelial cells and regulates size-selectivity at the BBB. Additionally, disruption of claudin-5 expression has been implicated in numerous disorders including schizophrenia, depression and traumatic brain injury, yet its role in epilepsy has not been fully deciphered. Here we report that claudin-5 protein levels are significantly diminished in surgically resected brain tissue from patients with treatment-resistant epilepsy. Concomitantly, dynamic contrast-enhanced MRI in these patients showed widespread BBB disruption. We show that targeted disruption of claudin-5 in the hippocampus or genetic heterozygosity of claudin-5 in mice exacerbates kainic acid-induced seizures and BBB disruption. Additionally, inducible knockdown of claudin-5 in mice leads to spontaneous recurrent seizures, severe neuroinflammation, and mortality. Finally, we identify that RepSox, a regulator of claudin-5 expression, can prevent seizure activity in experimental epilepsy. Altogether, we propose that BBB stabilizing drugs could represent a new generation of agents to prevent seizure activity in epilepsy patients.
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