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Lennernäs, Hans
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Publications (10 of 106) Show all publications
Dahlgren, D. & Lennernäs, H. (2019). Intestinal Permeability and Drug Absorption: Predictive Experimental, Computational and In Vivo Approaches. Pharmaceutics, 11(8), Article ID 411.
Open this publication in new window or tab >>Intestinal Permeability and Drug Absorption: Predictive Experimental, Computational and In Vivo Approaches
2019 (English)In: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 11, no 8, article id 411Article, review/survey (Refereed) Published
Abstract [en]

The main objective of this review is to discuss recent advancements in the overall investigation and in vivo prediction of drug absorption. The intestinal permeability of an orally administered drug (given the value P-eff) has been widely used to determine the rate and extent of the drug's intestinal absorption (F-abs) in humans. Preclinical gastrointestinal (GI) absorption models are currently in demand for the pharmaceutical development of novel dosage forms and new drug products. However, there is a strong need to improve our understanding of the interplay between pharmaceutical, biopharmaceutical, biochemical, and physiological factors when predicting F-abs and bioavailability. Currently, our knowledge of GI secretion, GI motility, and regional intestinal permeability, in both healthy subjects and patients with GI diseases, is limited by the relative inaccessibility of some intestinal segments of the human GI tract. In particular, our understanding of the complex and highly dynamic physiology of the region from the mid-jejunum to the sigmoid colon could be significantly improved. One approach to the assessment of intestinal permeability is to use animal models that allow these intestinal regions to be investigated in detail and then to compare the results with those from simple human permeability models such as cell cultures. Investigation of intestinal drug permeation processes is a crucial biopharmaceutical step in the development of oral pharmaceutical products. The determination of the intestinal P-eff for a specific drug is dependent on the technique, model, and conditions applied, and is influenced by multiple interactions between the drug molecule and the biological membranes.

Place, publisher, year, edition, pages
MDPI, 2019
Keywords
intestinal permeability, intestinal drug absorption, experimental and computational permeability methods
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-395363 (URN)10.3390/pharmaceutics11080411 (DOI)000484515100053 ()31412551 (PubMedID)
Available from: 2019-10-22 Created: 2019-10-22 Last updated: 2019-10-22Bibliographically approved
Garcia, L. P., Janzen, D., Kanebratt, K., Ericsson, H., Lennernäs, H. & Lundahl, A. (2019). Physiologically based pharmacokinetic model predictions of ivosidenib (AG-120) as a victim and perpetrator of drug–drug interactions. Drug Metabolism and Pharmacokinetics, 34(1), S70-S71
Open this publication in new window or tab >>Physiologically based pharmacokinetic model predictions of ivosidenib (AG-120) as a victim and perpetrator of drug–drug interactions
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2019 (English)In: Drug Metabolism and Pharmacokinetics, ISSN 1347-4367, E-ISSN 1880-0920, Vol. 34, no 1, p. S70-S71Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
JAPANESE SOC STUDY XENOBIOTICS, 2019
National Category
Pharmaceutical Sciences Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-378239 (URN)10.1016/j.dmpk.2018.09.238 (DOI)000458519400233 ()
Available from: 2019-03-15 Created: 2019-03-15 Last updated: 2019-03-15Bibliographically approved
Eriksson, J., Thorn, H., Sjögren, E., Holmsten, L., Rubin, K. & Lennernäs, H. (2019). Pulmonary Dissolution of Poorly Soluble Compounds Studied in an ex Vivo Rat Lung Model. Molecular Pharmaceutics, 16(7), 3053-3064
Open this publication in new window or tab >>Pulmonary Dissolution of Poorly Soluble Compounds Studied in an ex Vivo Rat Lung Model
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2019 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 16, no 7, p. 3053-3064Article in journal (Refereed) Published
Abstract [en]

Many inhaled drugs are poorly water soluble, and the dissolution rate is often the rate-limiting step in the overall absorption process. To improve understanding of pulmonary drug dissolution, four poorly soluble inhalation compounds (AZD5423 (a developmental nonsteroidal glucocorticoid), budesonide, fluticasone furoate (FF), and fluticasone propionate (FP)) were administered as suspensions or dry powders to the well-established isolated perfused 4 rat lung (IPL) model. Two particle size distributions (d50 = 1.2 mu m and d50 = 2.8 mu m) were investigated for AZD5423. The pulmonary absorption rates of the drugs from the suspensions and dry powders were compared with historical absorption data for solutions to improve understanding of the effects of dissolution on the overall pulmonary absorption process for poorly soluble inhaled drugs. A physiologically based biopharmaceutical in silico model was used to analyze the experimental IPL data and to estimate a dissolution parameter (K-ex vivo). A similar in silico approach was applied to in vitro dissolution data from the literature to obtain an in vitro dissolution parameter (Kin vitro). When FF, FP, and the larger particles of AZD5423 were administered as suspensions, drug dissolution was the rate-limiting step in the overall absorption process. However, this was not the case for budesonide, which has the highest aqueous solubility (61 mu M), and the smaller particles of AZD5423, probably because of the increased surface area available for dissolution (d50 = 1.2 mu m). The estimated dissolution parameters were ranked in accordance with the solubility of the drugs, and there was good agreement between k(ex vivo) and k(in vitro). The dry powders of all the compounds were absorbed more slowly than the suspensions, indicating that wetting is an important parameter for the dissolution of dry powders. A wetting factor was introduced to the in silico model to explain the difference in absorption profiles between the suspensions and dry powders where AZD5423 had the poorest wettability followed by FP and FF. The IPL model in combination with an in silico model is a useful tool for investigating pulmonary dissolution and improving understanding of dissolution-related parameters for poorly soluble inhaled compounds.

Keywords
inhalation, lung dissolution, isolated perfused lung model, pulmonary drug delivery, pulmonary drug absorption
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-390996 (URN)10.1021/acs.molpharmaceut.9b00289 (DOI)000474475400020 ()31136181 (PubMedID)
Funder
AstraZeneca
Available from: 2019-08-19 Created: 2019-08-19 Last updated: 2019-08-19Bibliographically approved
Dahlgren, D., Roos, C., Lundqvist, A., Tannergren, C., Sjöblom, M., Sjögren, E. & Lennernäs, H. (2018). Effect of absorption-modifying excipients, hypotonicity, and enteric neural activity in an in vivo model for small intestinal transport.. International Journal of Pharmaceutics, 549(1-2), 239-248, Article ID S0378-5173(18)30532-5.
Open this publication in new window or tab >>Effect of absorption-modifying excipients, hypotonicity, and enteric neural activity in an in vivo model for small intestinal transport.
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2018 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 549, no 1-2, p. 239-248, article id S0378-5173(18)30532-5Article in journal (Refereed) Published
Abstract [en]

The small intestine mucosal barrier is physiologically regulated by the luminal conditions, where intestinal factors, such as diet and luminal tonicity, can affect mucosal permeability. The intestinal barrier may also be affected by absorption-modifying excipients (AME) in oral drug delivery systems. Currently, there is a gap in the understanding of how AMEs interact with the physiological regulation of intestinal electrolyte transport and fluid flux, and epithelial permeability. Therefore, the objective of this single-pass perfusion study in rat was to investigate the effect of three AMEs on the intestinal mucosal permeability at different luminal tonicities (100, 170, and 290 mOsm). The effect was also evaluated following luminal administration of a nicotinic receptor antagonist, mecamylamine, and after intravenous administration of a COX-2 inhibitor, parecoxib, both of which affect the enteric neural activity involved in physiological regulation of intestinal functions. The effect was evaluated by changes in intestinal lumen-to-blood transport of six model compounds, and blood-to-lumen clearance of 51Cr-EDTA (a mucosal barrier marker). Luminal hypotonicity alone increased the intestinal epithelial transport of 51Cr-EDTA. This effect was potentiated by two AMEs (SDS and caprate) and by parecoxib, while it was reduced by mecamylamine. Consequently, the impact of enteric neural activity and luminal conditions may affect nonclinical determinations of intestinal permeability. In vivo predictions based on animal intestinal perfusion models can be improved by considering these effects. The in vivo relevance can be increased by treating rats with a COX-2 inhibitor prior to surgery. This decreases the risk of surgery-induced ileus, which may affect the physiological regulation of mucosal permeability.

Keywords
Absorption-modifying excipients, Biopharmaceutical classification system, In vivo predictions, Intestinal perfusion, Intestinal permeability, Intestinal physiology, Permeation enhancers
National Category
Pharmaceutical Sciences
Research subject
Biopharmaceutics
Identifiers
urn:nbn:se:uu:diva-358464 (URN)10.1016/j.ijpharm.2018.07.057 (DOI)000443255300022 ()30055302 (PubMedID)
Available from: 2018-08-29 Created: 2018-08-29 Last updated: 2018-11-19Bibliographically approved
Hens, B., Sinko, P. D., Job, N., Dean, M., Al-Gousous, J., Salehi, N., . . . Amidon, G. L. (2018). Formulation predictive dissolution (fPD) testing to advance oral drug product development: An introduction to the US FDA funded '21st Century BA/BE' project. International Journal of Pharmaceutics, 548(1), 120-127
Open this publication in new window or tab >>Formulation predictive dissolution (fPD) testing to advance oral drug product development: An introduction to the US FDA funded '21st Century BA/BE' project
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2018 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 548, no 1, p. 120-127Article, review/survey (Refereed) Published
Abstract [en]

Over the past decade, formulation predictive dissolution (fPD) testing has gained increasing attention. Another mindset is pushed forward where scientists in our field are more confident to explore the in vivo behavior of an oral drug product by performing predictive in vitro dissolution studies. Similarly, there is an increasing interest in the application of modern computational fluid dynamics (CFD) frameworks and high-performance computing platforms to study the local processes underlying absorption within the gastrointestinal (GI) tract. In that way, CFD and computing platforms both can inform future PBPK-based in silico frameworks and determine the GI-motility-driven hydrodynamic impacts that should be incorporated into in vitro dissolution methods for in vivo relevance. Current compendial dissolution methods are not always reliable to predict the in vivo behavior, especially not for biopharmaceutics classification system (BCS) class 2/4 compounds suffering from a low aqueous solubility. Developing a predictive dissolution test will be more reliable, cost-effective and less time-consuming as long as the predictive power of the test is sufficiently strong. There is a need to develop a biorelevant, predictive dissolution method that can be applied by pharmaceutical drug companies to facilitate marketing access for generic and novel drug products. In 2014, Prof. Gordon L. Amidon and his team initiated a far-ranging research program designed to integrate (1) in vivo studies in humans in order to further improve the understanding of the intraluminal processing of oral dosage forms and dissolved drug along the gastrointestinal (GI) tract, (2) advancement of in vitro methodologies that incorporates higher levels of in vivo relevance and (3) computational experiments to study the local processes underlying dissolution, transport and absorption within the intestines performed with a new unique CFD based framework. Of particular importance is revealing the physiological variables determining the variability in in vivo dissolution and GI absorption from person to person in order to address (potential) in vivo BE failures. This paper provides an introduction to this multidisciplinary project, informs the reader about current achievements and outlines future directions.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
In vivo dissolution, Bioequivalence, Bioavailability, Oral absorption, MRI, Manometry, Computational fluid dynamics
National Category
Pharmacology and Toxicology Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-366305 (URN)10.1016/j.ijpharm.2018.06.050 (DOI)000440552100013 ()29944899 (PubMedID)
Available from: 2018-11-20 Created: 2018-11-20 Last updated: 2018-11-20Bibliographically approved
Roos, C., Westergren, J., Dahlgren, D., Lennernäs, H. & Sjögren, E. (2018). Mechanistic modelling of intestinal drug absorption: the in vivo effects of nanoparticles, hydrodynamics, and colloidal structures. European journal of pharmaceutics and biopharmaceutics, 133, 70-76
Open this publication in new window or tab >>Mechanistic modelling of intestinal drug absorption: the in vivo effects of nanoparticles, hydrodynamics, and colloidal structures
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2018 (English)In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 133, p. 70-76Article in journal (Refereed) Published
Abstract [en]

Particle size reduction is a traditional approach to increase the intestinal absorption of active pharmaceutical ingredients with poor intestinal solubility, by increasing the particle dissolution rate. However, an increase in the dissolution rate cannot always fully explain the effects of nanoformulations, and a method of assessing the potential benefits of a nanoformulation in vivo would hence be of great value in drug development. A novel mathematical model of a nanoformulation, including interlinked descriptions of the hydrodynamics, particle dissolution and diffusion of particles and colloidal structures (CS), was developed to predict the combined in vivo effects of these mechanisms on drug absorption. The model successfully described previously reported in vivo observations of nanoformulated aprepitant in rats, at various drug concentrations and in the presence or absence of CS. The increase in absorption rate was explained as a direct consequence of the increased drug concentration at the membrane, caused by the contributing effects of the diffusion of both nanoparticles and CS into which the drug had partitioned. Further simulations supported the conclusion that the model can be applied during drug development to provide a priori assessments of the potential benefits of nanoformulations.

Keywords
biopharmaceutics, colloidal structures, intestinal absorption, modelling, nanoparticles, nanosuspension, permeability
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-363163 (URN)10.1016/j.ejpb.2018.10.006 (DOI)000451489400007 ()30300720 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme
Available from: 2018-10-15 Created: 2018-10-15 Last updated: 2019-01-28Bibliographically approved
Garcia, L. P., Janzen, D., Kanebratt, K. P., Ericsson, H., Lennernäs, H. & Lundahl, A. (2018). Physiologically Based Pharmacokinetic Model of Itraconazole and Two of Its Metabolites to Improve the Predictions and the Mechanistic Understanding of CYP3A4 Drug-Drug Interactions. Drug Metabolism And Disposition, 46(10), 1420-1433
Open this publication in new window or tab >>Physiologically Based Pharmacokinetic Model of Itraconazole and Two of Its Metabolites to Improve the Predictions and the Mechanistic Understanding of CYP3A4 Drug-Drug Interactions
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2018 (English)In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 46, no 10, p. 1420-1433Article in journal (Refereed) Published
Abstract [en]

Physiologically based pharmacokinetic (PBPK) modeling for itraconazole using a bottom-up approach is challenging, not only due to complex saturable pharmacokinetics (PK) and the presence of three metabolites exhibiting CYP3A4 inhibition, but also because of discrepancies in reported in vitro data. The overall objective of this study is to provide a comprehensive mechanistic PBPK model for itraconazole in order to increase the confidence in its drug-drug interaction (DDI) predictions. To achieve this, key in vitro and in vivo data for itraconazole and its major metabolites were generated. These data were crucial to developing a novel bottom-up PBPK model in Simcyp (Simcyp Ltd., Certara, Sheffield, United Kingdom) for itraconazole and two of its major metabolites: hydroxy-itraconazole (OH-ITZ) and keto-itraconazole (keto-ITZ). Performance of the model was validated using prespecified acceptance criteria against different dosing regimens, formulations for 29 PK, and DDI studies with midazolam and other CYP3A4 substrates. The main outcome is an accurate PBPK model that simultaneously predicts the PK profiles of itraconazole, OH-ITZ, and keto-ITZ. In addition, itraconazole DDIs with midazolam and other CYP3A4 substrates were successfully predicted within a 2-fold error. Prediction precision and bias of DDI expressed as geometric mean fold error were for the area under the concentration-time curve and peak concentration, 1.06 and 0.96, respectively. To conclude, in this paper a comprehensive data set for itraconazole and its metabolites is provided that enables bottom-up mechanism-based PBPK modeling. The presented model is applicable for studying the contribution from the metabolites and allows improved assessments of itraconazole DDI.

Place, publisher, year, edition, pages
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS, 2018
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-366719 (URN)10.1124/dmd.118.081364 (DOI)000444895200006 ()30068519 (PubMedID)
Available from: 2018-12-13 Created: 2018-12-13 Last updated: 2018-12-13Bibliographically approved
Dubbelboer, I. R., Sjögren, E. & Lennernäs, H. (2018). Porcine and Human In Vivo Simulations for Doxorubicin-Containing Formulations Used in Locoregional Hepatocellular Carcinoma Treatment. AAPS Journal, 20(6), Article ID 96.
Open this publication in new window or tab >>Porcine and Human In Vivo Simulations for Doxorubicin-Containing Formulations Used in Locoregional Hepatocellular Carcinoma Treatment
2018 (English)In: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 20, no 6, article id 96Article in journal (Refereed) Published
Abstract [en]

It is important to be able to simulate and predict formulation effects on the pharmacokinetics of a drug in order to optimize effectivity in clinical practice and drug development. Two formulations containing doxorubicin are used in the treatment of hepatocellular carcinoma (HCC): a Lipiodol-based emulsion (LIPDOX) and a loadable microbead system (DEBDOX). Although equally effective, the formulations are vastly different, and little is known about the parameters affecting doxorubicin release in vivo. However, mathematical modeling can be used to predict doxorubicin release properties from these formulations and its in vivo pharmacokinetic (PK) profiles. A porcine semi-physiologically based pharmacokinetic (PBPK) model was scaled to a human physiologically based biopharmaceutical (PBBP) model that was altered to include HCC. DOX in vitro and in vivo release data from LIPDOX or DEBDOX were collected from the literature and combined with these in silico models. The simulated pharmacokinetic profiles were then compared with observed porcine and human HCC patient data. DOX pharmacokinetic profiles of LIPDOX-treated HCC patients were best predicted from release data sets acquired by in vitro methods that did not use a diffusion barrier. For the DEBDOX group, the best predictions were from the in vitro release method with a low ion concentration and a reduced loading dose. The in silico modeling combined with historical release data was effective in predicting in vivo plasma exposure. This can give useful insights into the release method properties necessary for correct in vivo predictions of pharmacokinetic profiles of HCC patients dosed with LIPDOX or DEBDOX.

Keywords
DC bead, doxorubicin, hepatocellular carcinoma, in vitro-in vivo correlation, Lipiodol, physiologically based pharmacokinetic modeling, physiologically based biopharmaceutical modeling, TACE
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-364156 (URN)10.1208/s12248-018-0251-4 (DOI)000443459100001 ()30167825 (PubMedID)
Available from: 2018-11-07 Created: 2018-11-07 Last updated: 2018-11-20Bibliographically approved
Eriksson, J., Sjögren, E., Thörn, H., Rubin, K., Bäckman, P. & Lennernäs, H. (2018). Pulmonary absorption - estimation of effective pulmonary permeability and tissue retention of ten drugs using an ex vivo rat model and computational analysis. European journal of pharmaceutics and biopharmaceutics, 124, 1-12
Open this publication in new window or tab >>Pulmonary absorption - estimation of effective pulmonary permeability and tissue retention of ten drugs using an ex vivo rat model and computational analysis
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2018 (English)In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 124, p. 1-12Article in journal (Refereed) Published
Abstract [en]

Permeation of inhaled drugs across the pulmonary epithelium can regulate the rate and extent of local drug absorption and hence the pulmonary tissue concentration. Therefore, understanding pulmonary epithelial transport could be important for successful design of novel inhaled medicines. To enhance understanding of pulmonary epithelial transport, drug transport data were generated for a set of inhaled compounds (n = 10) in the single-pass, isolated perfused rat lung model. A compartmental in silica model was used to estimate pulmonary permeability and tissue retention. The theoretical model was also used to re-analyze previously obtained historical drug transport data from the isolated perfused lung (n = 10) with re-circulating buffer. This was performed to evaluate the re-circulating model for assessing tissue retention measurements and to increase the number of data points. The tissue retention was an important parameter to estimate to be able to describe the drug transport profiles accurately of most of the investigated compounds. A relationship between the pulmonary permeability and the intrinsic (carrier-mediated transport inhibited) permeability of Caco-2 cell monolayers (n = 1-6) was also established. This correlation (R-2 = 0.76, p < .0001) suggests that intrinsic Caco-2 permeability measurements could offer early predictions of the passive transcellular permeability of lung epithelium to candidate drugs. Although, for some compounds a deviation from the correlation suggests that other transport mechanisms may coexist. The compartmental in silica model was successful in describing the pulmonary drug transport profiles of the investigated compounds and has potential for further development to investigate the effects of formulations with different features on the pulmonary overall absorption rate.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV, 2018
Keywords
Inhalation, Lung permeability, Isolated perfused lung model, Pulmonary drug delivery, Pulmonary drug absorption
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-350060 (URN)10.1016/j.ejpb.2017.11.013 (DOI)000425839500001 ()29191716 (PubMedID)
Funder
AstraZeneca
Available from: 2018-05-04 Created: 2018-05-04 Last updated: 2018-05-04Bibliographically approved
Dubbelboer, I. R., Lilienberg, E., Karalli, A., Axelsson, R., Brismar, T. B., Ebeling Barbier, C., . . . Lennernäs, H. (2018). Reply to "Comment on 'In Vivo Drug Delivery Performance of Lipiodol-Based Emulsion or Drug-Eluting Beads in Patients with Hepatocellular Carcinoma'". Molecular Pharmaceutics, 15(1), 336-340
Open this publication in new window or tab >>Reply to "Comment on 'In Vivo Drug Delivery Performance of Lipiodol-Based Emulsion or Drug-Eluting Beads in Patients with Hepatocellular Carcinoma'"
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2018 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 15, no 1, p. 336-340Article in journal (Refereed) Published
Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018
Keywords
Lipiodol, doxorubicin, drug-eluting beads, hepatocelluar carcinoma, image-guided transarterial tumor therapy, interventional radiology, liver cancer, local therapy, transarterial chemoembolization (TACE)
National Category
Pharmacology and Toxicology Pharmaceutical Sciences Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-335507 (URN)10.1021/acs.molpharmaceut.7b00840 (DOI)000419419800033 ()29185767 (PubMedID)
Available from: 2017-12-06 Created: 2017-12-06 Last updated: 2018-05-04Bibliographically approved
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