Publications by authors named "Patrick Augustijns"

272 Publications

Investigating the Mechanisms behind the Positive Food Effect of Abiraterone Acetate: In Vitro and Rat In Situ Studies.

Pharmaceutics 2022 Apr 28;14(5). Epub 2022 Apr 28.

Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Gasthuisberg O&N II, Herestraat 49, P.O. Box 921, 3000 Leuven, Belgium.

The anticancer agent abiraterone suffers from an extensive positive food effect after oral intake of the prodrug abiraterone acetate (Zytiga). The underlying processes determining postprandial abiraterone absorption were investigated in this study. The impact of lipids and lipid digestion products on (i) the solubility of abiraterone acetate and abiraterone, (ii) the conversion of abiraterone acetate to abiraterone, and (iii) the passive permeation of abiraterone was determined in vitro. The interaction of abiraterone acetate and abiraterone with vesicles and colloidal structures in the simulated fed state media containing undigested lipids and lipid digestion products enhanced the solubility of both compounds but limited the esterase-mediated hydrolysis of abiraterone acetate and the potential of abiraterone to permeate. Rat in situ intestinal perfusion experiments with a suspension of abiraterone acetate in static fed state simulated media identified abiraterone concentrations in the perfusate as the main driving force for absorption. However, experiments with ongoing lipolysis in the perfusate highlighted the importance of including lipid digestion as a dynamic process when studying postprandial abiraterone absorption. Future research may employ the in situ perfusion model to study postprandial drug absorption from a dynamic lipolysis-mediated intestinal environment to provide reference data for the optimisation of relevant in vitro models to evaluate food effects.
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http://dx.doi.org/10.3390/pharmaceutics14050952DOI Listing
April 2022

Structured solubility behaviour in bioequivalent fasted simulated intestinal fluids.

Eur J Pharm Biopharm 2022 Jul 20;176:108-121. Epub 2022 May 20.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, United Kingdom. Electronic address:

Drug solubility in intestinal fluid is a key parameter controlling absorption after the administration of a solid oral dosage form. To measure solubility in vitro simulated intestinal fluids have been developed, but there are multiple recipes and the optimum is unknown. This situation creates difficulties during drug discovery and development research. A recent study characterised sampled fasted intestinal fluids using a multidimensional approach to derive nine bioequivalent fasted intestinal media that covered over 90% of the compositional variability. These media have been applied in this study to examine the equilibrium solubility of twenty one exemplar drugs (naproxen, indomethacin, phenytoin, zafirlukast, piroxicam, ibuprofen, mefenamic acid, furosemide, aprepitant, carvedilol, tadalafil, dipyridamole, posaconazole, atazanavir, fenofibrate, felodipine, griseofulvin, probucol, paracetamol, acyclovir and carbamazepine) to determine if consistent solubility behaviour was present. The bioequivalent media provide in the majority of cases structured solubility behaviour that is consistent with physicochemical properties and previous solubility studies. For the acidic drugs (pKa < 6.3) solubility is controlled by media pH, the profile is identical and consistent and the lowest and highest pH media identify the lowest and highest solubility in over 70% of cases. For weakly acidic (pKa > 8), basic and neutral drugs solubility is controlled by a combination of media pH and total amphiphile concentration (TAC), a consistent solubility behaviour is evident but with variation related to individual drug interactions within the media. The lowest and highest pH × TAC media identify the lowest and highest solubility in over 78% of cases. A subset of the latter category consisting of neutral and drugs non-ionised in the media pH range have been identified with a very narrow solubility range, indicating that the impact of the simulated intestinal media on their solubility is minimal. Two drugs probucol and atazanavir exhibit unusual behaviour. The study indicates that the use of two appropriate bioequivalent fasted intestinal media from the nine will identify in vitro the maximum and minimum solubility boundaries for drugs and due to the media derivation this is probably applicable in vivo. These media could be applied during discovery and development activities to provide a solubility range, which would assist placement of the drug within the BCS/DCS and rationalise drug and formulation decisions.
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http://dx.doi.org/10.1016/j.ejpb.2022.05.010DOI Listing
July 2022

Orlistat disposition in the human jejunum and the effect of lipolysis inhibition on bile salt concentrations and composition.

Int J Pharm 2022 Jun 6;621:121807. Epub 2022 May 6.

Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Gasthuisberg O&N II, Herestraat 49 - Box 921, 3000 Leuven, Belgium. Electronic address:

The lipolysis-mediated postprandial small intestinal environment is known to influence the solubilisation and subsequent absorption of lipophilic drugs. In a previously performed small-scale clinical study in healthy volunteers, co-administration of the lipase inhibitor orlistat increased jejunal solubilisation and systemic absorption of fenofibrate after intake of the lipid-based formulation Fenogal. In the present study, the jejunal disposition of the locally acting orlistat was assessed and linked to fenofibrate solubilisation. In addition, the effect of orlistat-induced lipolysis inhibition on bile salt concentrations and composition was evaluated. Orlistat was distributed predominantly in the lipid layer, as indicated by a 5- to 14-fold higher AUC in the total jejunal samples as compared to the micellar layers. No effect of orally administered orlistat on bile salt composition or total concentrations (ranging from 1.5 to 24.8 mM and 1.8 to 33.2 mM with and without orlistat co-administration, respectively) could be observed. The intraluminal presence of orlistat in the total jejunal samples correlated with the increased fenofibrate solubilisation in the jejunum (r = 0.9344) and enhanced absorption (r = 0.8184), highlighting the importance of the intraluminal lipid phase in lipophilic drug absorption.
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http://dx.doi.org/10.1016/j.ijpharm.2022.121807DOI Listing
June 2022

Application of In Vivo Imaging Techniques and Diagnostic Tools in Oral Drug Delivery Research.

Pharmaceutics 2022 Apr 6;14(4). Epub 2022 Apr 6.

Department of Biopharmaceutics and Pharmaceutical Technology, Center of Drug Absorption and Transport, University of Greifswald, 17489 Greifswald, Germany.

Drug absorption following oral administration is determined by complex and dynamic interactions between gastrointestinal (GI) physiology, the drug, and its formulation. Since many of these interactions are not fully understood, the COST action on "Understanding Gastrointestinal Absorption-related Processes (UNGAP)" was initiated in 2017, with the aim to improve the current comprehension of intestinal drug absorption and foster future developments in this field. In this regard, in vivo techniques used for the characterization of human GI physiology and the intraluminal behavior of orally administered dosage forms in the GI tract are fundamental to gaining deeper mechanistic understanding of the interplay between human GI physiology and drug product performance. In this review, the potential applications, advantages, and limitations of the most important in vivo techniques relevant to oral biopharmaceutics are presented from the perspectives of different research fields.
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http://dx.doi.org/10.3390/pharmaceutics14040801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9025904PMC
April 2022

HIV protease inhibitors Nelfinavir and Lopinavir/Ritonavir markedly improve lung pathology in SARS-CoV-2-infected Syrian hamsters despite lack of an antiviral effect.

Antiviral Res 2022 06 4;202:105311. Epub 2022 Apr 4.

KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000, Leuven, Belgium; GVN, Global Virus Network, Baltimore, MD, USA. Electronic address:

Nelfinavir is an HIV protease inhibitor that has been widely prescribed as a component of highly active antiretroviral therapy, and has been reported to exert in vitro antiviral activity against SARS-CoV-2. We here assessed the effect of Nelfinavir in a SARS-CoV-2 infection model in hamsters. Despite the fact that Nelfinavir, [50 mg/kg twice daily (BID) for four consecutive days], did not reduce viral RNA load and infectious virus titres in the lung of infected animals, treatment resulted in a substantial improvement of SARS-CoV-2-induced lung pathology. This was accompanied by a dense infiltration of neutrophils in the lung interstitium which was similarly observed in non-infected hamsters. Nelfinavir resulted also in a marked increase in activated neutrophils in the blood, as observed in non-infected animals. Although Nelfinavir treatment did not alter the expression of chemoattractant receptors or adhesion molecules on human neutrophils, in vitro migration of human neutrophils to the major human neutrophil attractant CXCL8 was augmented by this protease inhibitor. Nelfinavir appears to induce an immunomodulatory effect associated with increasing neutrophil number and functionality, which may be linked to the marked improvement in SARS-CoV-2 lung pathology independent of its lack of antiviral activity. Since Nelfinavir is no longer used for the treatment of HIV, we studied the effect of two other HIV protease inhibitors, namely the combination Lopinavir/Ritonavir (Kaletra™) in this model. This combination resulted in a similar protective effect as Nelfinavir against SARS-CoV2 induced lung pathology in hamsters.
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http://dx.doi.org/10.1016/j.antiviral.2022.105311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8978445PMC
June 2022

The effect of esomeprazole on the upper GI tract release and systemic absorption of mesalazine from colon targeted formulations.

Int J Pharm 2022 May 23;619:121701. Epub 2022 Mar 23.

Drug Delivery and Disposition, KU Leuven, Gasthuisberg O&N II, Herestraat 49 - box 921, 3000 Leuven, Belgium. Electronic address:

The aim of the present study was to investigate the effect of coadministration of the proton pump inhibitor (PPI) esomeprazole on the upper GI tract behavior and systemic exposure of mesalazine from two mechanistically different colon targeted delivery systems: Claversal (pH-dependent release) and Pentasa (prolonged release). To this end, gastric, jejunal and systemic concentrations of mesalazine and its metabolite N-acetyl mesalazine were monitored in 5 healthy volunteers following oral intake of Pentasa or Claversal with or without PPI pre-treatment (cross-over study). Our exploratory study demonstrated that pre-treatment with a PPI may affect the release and absorption of mesalazine from formulations with different modified release mechanisms. Upon intake of Claversal, the onset of mesalazine absorption was accelerated substantially by PPI pre-treatment. While the PPI-induced increase in pH initiated the disintegration process already in the upper GI tract, the release of mesalazine started beyond the proximal jejunum. Upon intake of Pentasa, PPI pre-treatment seemed to increase the systemic exposure, even though the underlying mechanism could not be revealed yet. The faster release of mesalazine in the GI tract and/or the increased systemic absorption following PPI pre-treatment may reduce the ability of mesalazine to reach the colon. Future research assessing mesalazine disposition in the lower GI tract is warranted.
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http://dx.doi.org/10.1016/j.ijpharm.2022.121701DOI Listing
May 2022

Practical and operational considerations related to paediatric oral drug formulation: An industry survey.

Int J Pharm 2022 Apr 16;618:121670. Epub 2022 Mar 16.

Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium. Electronic address:

For over 15 years, US and EU regulations ensure that medicines developed for children are explicitly authorised for such use with age-appropriate forms and formulations, implying dedicated research. To shed light on how these regulations have been adopted by pharmaceutical companies and how various aspects of paediatric oral drug formulation development are currently handled, an exploratory survey was conducted. Topics included: general company policy, regulatory aspects, dosage form selection, in-vitro, in-silico and (non-)clinical in-vivo methods, and food effects assessment. The survey results clearly underline the positive impact of the paediatric regulations and their overall uptake across the pharmaceutical industry. Even though significant improvements have been made in paediatric product development, major challenges remain. In this respect, dosage form selection faces a discrepancy between the youngest age groups (liquid products preference) and older subpopulations (adult formulation preference). Additionally, concerted research is needed in the development and validation of in-vitro tools and physiology based pharmacokinetic models tailored to the paediatric population, and in estimating the effect of non-standard and paediatric relevant foods. The current momentum in paediatric drug development and research should allow for an evolution in standardised methodology and guidance to develop paediatric formulations, which would benefit pharmaceutical industry and regulators.
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http://dx.doi.org/10.1016/j.ijpharm.2022.121670DOI Listing
April 2022

The oral protease inhibitor (PF-07321332) protects Syrian hamsters against infection with SARS-CoV-2 variants of concern.

Nat Commun 2022 02 15;13(1):719. Epub 2022 Feb 15.

KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, 3000, Leuven, Belgium.

There is an urgent need for potent and selective antivirals against SARS-CoV-2. Pfizer developed PF-07321332 (PF-332), a potent inhibitor of the viral main protease (Mpro, 3CLpro) that can be dosed orally and that is in clinical development. We here report that PF-332 exerts equipotent in vitro activity against the four SARS-CoV-2 variants of concerns (VoC) and that it can completely arrest replication of the alpha variant in primary human airway epithelial cells grown at the air-liquid interface. Treatment of Syrian Golden hamsters with PF-332 (250 mg/kg, twice daily) completely protected the animals against intranasal infection with the beta (B.1.351) and delta (B.1.617.2) SARS-CoV-2 variants. Moreover, treatment of SARS-CoV-2 (B.1.617.2) infected animals with PF-332 completely prevented transmission to untreated co-housed sentinels.
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http://dx.doi.org/10.1038/s41467-022-28354-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8847371PMC
February 2022

The Influence of Fed State Lipolysis Inhibition on the Intraluminal Behaviour and Absorption of Fenofibrate from a Lipid-Based Formulation.

Pharmaceutics 2022 Jan 4;14(1). Epub 2022 Jan 4.

Drug Delivery and Disposition, KU Leuven, Gasthuisberg O&N II, Herestraat 49-Box 921, 3000 Leuven, Belgium.

The bioavailability of lipophilic drugs may or may not be increased when administered with food due to increased solubilisation in fed state gastrointestinal (GI) fluids. The in vivo interplay between drug solubilisation, lipid phase digestion and drug absorption is complex and remains poorly understood. This study aimed to investigate the role of fed state GI lipolysis on the intraluminal behaviour and absorption of fenofibrate, formulated as the lipid-based formulation Fenogal. Therefore, a crossover study was performed in healthy volunteers using orlistat as lipase inhibitor. Fenofibrate concentrations were determined in the proximal jejunum and linked to simultaneously assessed systemic fenofibric acid concentrations. Inhibition of lipolysis by orlistat resulted in a faster onset of absorption in 4 out of 6 volunteers, reflected by a decrease in systemic T between 20 and 140 min. In addition, the increase of undigested lipids present in the small intestine upon orlistat co-administration sustained drug solubilisation for a longer period, resulting in higher fenofibrate concentrations in the jejunum and improved absorption in 5 out of 6 volunteers (median AUC 8377 vs. 5832 μM.min). Sustaining drug solubilisation in the lipid phase may thus contribute to the absorption of lipophilic drugs. More research into the different mechanisms underlying lipophilic drug absorption from fed state media at different levels of digestion is warranted.
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http://dx.doi.org/10.3390/pharmaceutics14010119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8781256PMC
January 2022

Best practices in current models mimicking drug permeability in the gastrointestinal tract - An UNGAP review.

Eur J Pharm Sci 2022 Mar 22;170:106098. Epub 2021 Dec 22.

School of Pharmacy, University College Cork, Cork, Ireland.

The absorption of orally administered drug products is a complex, dynamic process, dependant on a range of biopharmaceutical properties; notably the aqueous solubility of a molecule, stability within the gastrointestinal tract (GIT) and permeability. From a regulatory perspective, the concept of high intestinal permeability is intrinsically linked to the fraction of the oral dose absorbed. The relationship between permeability and the extent of absorption means that experimental models of permeability have regularly been used as a surrogate measure to estimate the fraction absorbed. Accurate assessment of a molecule's intestinal permeability is of critical importance during the pharmaceutical development process of oral drug products, and the current review provides a critique of in vivo, in vitro and ex vivo approaches. The usefulness of in silico models to predict drug permeability is also discussed and an overview of solvent systems used in permeability assessments is provided. Studies of drug absorption in humans are an indirect indicator of intestinal permeability, but both in vitro and ex vivo tools provide initial screening approaches and are important tools for assessment of permeability in drug development. Continued refinement of the accuracy of in silico approaches and their validation with human in vivo data will facilitate more efficient characterisation of permeability earlier in the drug development process and will provide useful inputs for integrated, end-to-end absorption modelling.
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http://dx.doi.org/10.1016/j.ejps.2021.106098DOI Listing
March 2022

Duodenal Dysbiosis and Relation to the Efficacy of Proton Pump Inhibitors in Functional Dyspepsia.

Int J Mol Sci 2021 Dec 19;22(24). Epub 2021 Dec 19.

VIB Center for Microbiology, 3000 Leuven, Belgium.

Proton pump inhibitors (PPI) may improve symptoms in functional dyspepsia (FD) through duodenal eosinophil-reducing effects. However, the contribution of the microbiome to FD symptoms and its interaction with PPI remains elusive. Aseptic duodenal brushings and biopsies were performed before and after PPI intake (4 weeks Pantoprazole 40 mg daily, FD-starters and controls) or withdrawal (2 months, FD-stoppers) for 16S-rRNA sequencing. Between- and within-group changes in genera or diversity and associations with symptoms or duodenal factors were analyzed. In total, 30 controls, 28 FD-starters and 19 FD-stoppers were followed. Mucus-associated was lower in FD-starters vs. controls and correlated with symptoms in FD and duodenal eosinophils in both groups, while correlated with eosinophils in controls. Although clinical and eosinophil-reducing effects of PPI therapy were unrelated to microbiota changes in FD-starters, increased was associated with duodenal PPI effects in controls and remained higher despite withdrawal of long-term PPI therapy in FD-stoppers. Thus, duodenal microbiome analysis demonstrated differential mucus-associated genera, with a potential role of in FD pathophysiology. While beneficial effects of short-term PPI therapy were not associated with microbial changes in FD-starters, increased and its association with PPIeffects in controls suggest a role for duodenal dysbiosis after long-term PPI therapy.
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http://dx.doi.org/10.3390/ijms222413609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8708077PMC
December 2021

Integration of advanced methods and models to study drug absorption and related processes: An UNGAP perspective.

Eur J Pharm Sci 2022 May 20;172:106100. Epub 2021 Dec 20.

Division of Pharmacology and Pharmacotherapy, University of Helsinki, Finland. Electronic address:

This collection of contributions from the European Network on Understanding Gastrointestinal Absorption-related Processes (UNGAP) community assembly aims to provide information on some of the current and newer methods employed to study the behaviour of medicines. It is the product of interactions in the immediate pre-Covid period when UNGAP members were able to meet and set up workshops and to discuss progress across the disciplines. UNGAP activities are divided into work packages that cover special treatment populations, absorption processes in different regions of the gut, the development of advanced formulations and the integration of food and pharmaceutical scientists in the food-drug interface. This involves both new and established technical approaches in which we have attempted to define best practice and highlight areas where further research is needed. Over the last months we have been able to reflect on some of the key innovative approaches which we were tasked with mapping, including theoretical, in silico, in vitro, in vivo and ex vivo, preclinical and clinical approaches. This is the product of some of us in a snapshot of where UNGAP has travelled and what aspects of innovative technologies are important. It is not a comprehensive review of all methods used in research to study drug dissolution and absorption, but provides an ample panorama of current and advanced methods generally and potentially useful in this area. This collection starts from a consideration of advances in a priori approaches: an understanding of the molecular properties of the compound to predict biological characteristics relevant to absorption. The next four sections discuss a major activity in the UNGAP initiative, the pursuit of more representative conditions to study lumenal dissolution of drug formulations developed independently by academic teams. They are important because they illustrate examples of in vitro simulation systems that have begun to provide a useful understanding of formulation behaviour in the upper GI tract for industry. The Leuven team highlights the importance of the physiology of the digestive tract, as they describe the relevance of gastric and intestinal fluids on the behaviour of drugs along the tract. This provides the introduction to microdosing as an early tool to study drug disposition. Microdosing in oncology is starting to use gamma-emitting tracers, which provides a link through SPECT to the next section on nuclear medicine. The last two papers link the modelling approaches used by the pharmaceutical industry, in silico to Pop-PK linking to Darwich and Aarons, who provide discussion on pharmacometric modelling, completing the loop of molecule to man.
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http://dx.doi.org/10.1016/j.ejps.2021.106100DOI Listing
May 2022

Fasted intestinal solubility limits and distributions applied to the biopharmaceutics and developability classification systems.

Eur J Pharm Biopharm 2022 Jan 16;170:160-169. Epub 2021 Dec 16.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, United Kingdom. Electronic address:

After oral administration, a drug's solubility in intestinal fluid is an important parameter influencing bioavailability and if the value is known it can be applied to estimate multiple biopharmaceutical parameters including the solubility limited absorbable dose. Current in vitro measurements may utilise fasted human intestinal fluid (HIF) or simulated intestinal fluid (SIF) to provide an intestinal solubility value. This single point value is limited since its position in relation to the fasted intestinal solubility envelope is unknown. In this study we have applied a nine point fasted equilibrium solubility determination in SIF, based on a multi-dimensional analysis of fasted human intestinal fluid composition, to seven drugs that were previously utilised to investigate the developability classification system (ibuprofen, mefenamic acid, furosemide, dipyridamole, griseofulvin, paracetamol and acyclovir). The resulting fasted equilibrium solubility envelope encompasses literature solubility values in both HIF and SIF indicating that it measures the same solubility space as current approaches with solubility behaviour consistent with previous SIF design of experiment studies. In addition, it identifies that three drugs (griseofulvin, paracetamol and acyclovir) have a very narrow solubility range, a feature that single point solubility approaches would miss. The measured mid-point solubility value is statistically equivalent to the value determined with the original fasted simulated intestinal fluid recipe, further indicating similarity and that existing literature results could be utilised as a direct comparison. Since the multi-dimensional approach covered greater than ninety percent of the variability in fasted intestinal fluid composition, the measured maximum and minimum equilibrium solubility values should represent the extremes of fasted intestinal solubility and provide a range. The seven drugs all display different solubility ranges and behaviours, a result also consistent with previous studies. The dose/solubility ratio for each measurement point can be plotted using the developability classification system to highlight individual drug behaviours. The lowest solubility represents a worst-case scenario which may be useful in risk-based quality by design biopharmaceutical calculations than the mid-point value. The method also permits a dose/solubility ratio frequency distribution determination for the solubility envelope which permits further risk-based refinement, especially where the drug crosses a classification boundary. This novel approach therefore provides greater in vitro detail with respect to possible biopharmaceutical performance in vivo and an improved ability to apply risk-based analysis to biopharmaceutical performance. Further studies will be required to expand the number of drugs measured and link the in vitro measurements to in vivo results.
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http://dx.doi.org/10.1016/j.ejpb.2021.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8769049PMC
January 2022

Specific contributions of segmental transit times to gut microbiota composition.

Gut 2022 Jul 12;71(7):1443-1444. Epub 2021 Oct 12.

Department of Chronic Diseases and Metabolism, Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium

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http://dx.doi.org/10.1136/gutjnl-2021-325916DOI Listing
July 2022

The combined treatment of Molnupiravir and Favipiravir results in a potentiation of antiviral efficacy in a SARS-CoV-2 hamster infection model.

EBioMedicine 2021 Oct 24;72:103595. Epub 2021 Sep 24.

KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium; Global Virus Network, GVN, Baltimore, MD 21201, USA.

Background: Favipiravir and Molnupiravir, orally available antivirals, have been reported to exert antiviral activity against SARS-CoV-2. First efficacy data have been recently reported in COVID-19 patients.

Methods: We here report on the combined antiviral effect of both drugs in a SARS-CoV-2 Syrian hamster infection model. The infected hamsters were treated twice daily with the vehicle (the control group) or a suboptimal dose of each compound or a combination of both compounds.

Findings: When animals were treated with a combination of suboptimal doses of Molnupiravir and Favipiravir at the time of infection, a marked combined potency at endpoint is observed. Infectious virus titers in the lungs of animals treated with the combination are reduced by ∼5 log10 and infectious virus are no longer detected in the lungs of >60% of treated animals. When start of treatment was delayed with one day a reduction of titers in the lungs of 2.4 log10 was achieved. Moreover, treatment of infected animals nearly completely prevented transmission to co-housed untreated sentinels. Both drugs result in an increased mutation frequency of the remaining viral RNA recovered from the lungs of treated animals. In the combo-treated hamsters, an increased frequency of C-to-T mutations in the viral RNA is observed as compared to the single treatment groups which may explain the pronounced antiviral potency of the combination.

Interpretation: Our findings may lay the basis for the design of clinical studies to test the efficacy of the combination of Molnupiravir/Favipiravir in the treatment of COVID-19.

Funding: stated in the acknowledgment.
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http://dx.doi.org/10.1016/j.ebiom.2021.103595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8461366PMC
October 2021

An Assessment of Occasional Bio-Inequivalence for BCS1 and BCS3 Drugs: What are the Underlying Reasons?

J Pharm Sci 2022 01 4;111(1):124-134. Epub 2021 Aug 4.

Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium. Electronic address:

Despite having adequate solubility properties, bioequivalence (BE) studies performed on immediate release formulations containing BCS1/3 drugs occasionally fail. By systematically evaluating a set of 17 soluble drugs where unexpected BE failures have been reported and comparing to a set of 29 drugs where no such reports have been documented, a broad assessment of the risk factors leading to BE failure was performed. BE failures for BCS1/3 drugs were predominantly related to changes in C rather than AUC. C changes were typically modest, with minimal clinical significance for most drugs. Overall, drugs with a sharp plasma peak were identified as a key factor in BE failure risk. A new pharmacokinetic term (t½C) is proposed to identify drugs at higher risk due to their peak plasma profile shape. In addition, the analysis revealed that weak acids, and drugs with particularly high gastric solubility are potentially more vulnerable to BE failure, particularly when these features are combined with a sharp C peak. BCS3 drugs, which are often characterised as being more vulnerable to BE failure due to their potential for permeation and transit to be altered, particularly by excipient change, were not in general at greater risk of BE failures. These findings will help to inform how biowaivers may be optimally applied in the future.
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http://dx.doi.org/10.1016/j.xphs.2021.08.001DOI Listing
January 2022

Chloroquine, an Anti-Malaria Drug as Effective Prevention for Hantavirus Infections.

Front Cell Infect Microbiol 2021 15;11:580532. Epub 2021 Mar 15.

Laboratory of Clinical Virology, Zoonotic Infectious Diseases Unit, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium.

We investigated whether chloroquine can prevent hantavirus infection and disease and , using the Hantaan virus newborn C57BL/6 mice model and the Syrian hamster model for Andes virus. antiviral experiments were performed using Vero E6 cells, and Old World and New World hantavirus species. Hantavirus RNA was detected using quantitative RT-PCR. For all hantavirus species tested, results indicate that the IC of chloroquine (mean 10.2 ± 1.43 μM) is significantly lower than the CC (mean 260 ± 2.52 μM) yielding an overall selectivity index of 25.5. We also investigated the potential of chloroquine to prevent death in newborn mice after Hantaan virus infection and its antiviral effect in the hantavirus Syrian hamster model. For this purpose, C57Bl/6 mother mice were treated subcutaneously with daily doses of chloroquine. Subsequently, 1-day-old suckling mice were inoculated intracerebrally with 5 x 10 Hantaan virus particles. In litters of untreated mothers, none of the pups survived challenge. The highest survival rate (72.7% of pups) was found when mother mice were administered a concentration of 10 mg/kg chloroquine. Survival rates declined in a dose-dependent manner, with 47.6% survival when treated with 5 mg/kg chloroquine, and 4.2% when treated with 1 mg/kg chloroquine. Assessing the antiviral therapeutic and prophylactic effect of chloroquine in the Syrian hamster model was done using two different administration routes (intraperitoneally and subcutaneously using an osmotic pump system). Evaluating the prophylactic effect, a delay in onset of disease was noted and for the osmotic pump, 60% survival was observed. Our results show that chloroquine can be highly effective against Hantaan virus infection in newborn mice and against Andes virus in Syrian hamsters.
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http://dx.doi.org/10.3389/fcimb.2021.580532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006394PMC
June 2021

Impact of gastrointestinal tract variability on oral drug absorption and pharmacokinetics: An UNGAP review.

Eur J Pharm Sci 2021 Jul 20;162:105812. Epub 2021 Mar 20.

Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium; Chairperson of the UNGAP network, COST CA 16205. Electronic address:

The absorption of oral drugs is frequently plagued by significant variability with potentially serious therapeutic consequences. The source of variability can be traced back to interindividual variability in physiology, differences in special populations (age- and disease-dependent), drug and formulation properties, or food-drug interactions. Clinical evidence for the impact of some of these factors on drug pharmacokinetic variability is mounting: e.g. gastric pH and emptying time, small intestinal fluid properties, differences in pediatrics and the elderly, and surgical changes in gastrointestinal anatomy. However, the link of colonic factors variability (transit time, fluid composition, microbiome), sex differences (male vs. female) and gut-related diseases (chronic constipation, anorexia and cachexia) to drug absorption variability has not been firmly established yet. At the same time, a way to decrease oral drug pharmacokinetic variability is provided by the pharmaceutical industry: clinical evidence suggests that formulation approaches employed during drug development can decrease the variability in oral exposure. This review outlines the main drivers of oral drug exposure variability and potential approaches to overcome them, while highlighting existing knowledge gaps and guiding future studies in this area.
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http://dx.doi.org/10.1016/j.ejps.2021.105812DOI Listing
July 2021

Leveraging Oral Drug Development to a Next Level: Impact of the IMI-Funded OrBiTo Project on Patient Healthcare.

Front Med (Lausanne) 2021 5;8:480706. Epub 2021 Mar 5.

Oral Product Development, Pharmaceutical Technology and Development, Operations, AstraZeneca Gothenburg, Mölndal, Sweden.

A thorough understanding of the behavior of drug formulations in the human gastrointestinal (GI) tract is essential when working in the field of oral drug development in a pharmaceutical company. For orally administered drug products, various GI processes, including disintegration of the drug formulation, drugrelease, dissolution, precipitation, degradation, dosage form transit and permeation, dictate absorption into the systemic circulation. These processes are not always fully captured in predictive and tools, as commonly applied in the pre-clinical stage of formulation drug development. A collaborative initiative focused on the science of oral biopharmaceutics was established in 2012 between academic institutions and industrial companies to innovate, optimize and validate these and biopharmaceutical tools. From that perspective, the predictive power of these models can be revised and, if necessary, optimized to improve the accuracy toward predictions of the performance of orally administered drug products in patients. The IMI/EFPIA-funded "Oral Bioavailability Tools (OrBiTo)" project aimed to improve our fundamental understanding of the GI absorption process. The gathered information was integrated into the development of new (or already existing) laboratory tests and computer-based methods in order to deliver more accurate predictions of drug product behavior in a real-life setting. These methods were validated with the use of industrial data. Crucially, the ultimate goal of the project was to set up a scientific framework (i.e., decision trees) to guide the use of these new tools in drug development. The project aimed to facilitate and accelerate the formulation development process and to significantly reduce the need for animal experiments in this area as well as for human clinical studies in the future. With respect to the positive outcome for patients, high-quality oral medicines will be developed where the required dose is well-calculated and consistently provides an optimal clinical effect. In a first step, this manuscript summarizes the setup of the project and how data were collected across the different work packages. In a second step, case studies of how this project contributed to improved knowledge of oral drug delivery which can be used to develop improved products for patients will be illustrated.
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http://dx.doi.org/10.3389/fmed.2021.480706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973356PMC
March 2021

Current challenges and future perspectives in oral absorption research: An opinion of the UNGAP network.

Adv Drug Deliv Rev 2021 04 18;171:289-331. Epub 2021 Feb 18.

College of Pharmaceutical Sciences, Ritsumeikan University, Shiga, Japan.

Although oral drug delivery is the preferred administration route and has been used for centuries, modern drug discovery and development pipelines challenge conventional formulation approaches and highlight the insufficient mechanistic understanding of processes critical to oral drug absorption. This review presents the opinion of UNGAP scientists on four key themes across the oral absorption landscape: (1) specific patient populations, (2) regional differences in the gastrointestinal tract, (3) advanced formulations and (4) food-drug interactions. The differences of oral absorption in pediatric and geriatric populations, the specific issues in colonic absorption, the formulation approaches for poorly water-soluble (small molecules) and poorly permeable (peptides, RNA etc.) drugs, as well as the vast realm of food effects, are some of the topics discussed in detail. The identified controversies and gaps in the current understanding of gastrointestinal absorption-related processes are used to create a roadmap for the future of oral drug absorption research.
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http://dx.doi.org/10.1016/j.addr.2021.02.001DOI Listing
April 2021

Adaptations in gastrointestinal physiology after sleeve gastrectomy and Roux-en-Y gastric bypass.

Lancet Gastroenterol Hepatol 2021 03;6(3):225-237

Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium. Electronic address:

Linked to the growing obesity epidemic, demand for bariatric and metabolic surgery has increased, the most common procedures being sleeve gastrectomy and Roux-en-Y gastric bypass. Originally, bariatric procedures were described as purely restrictive, malabsorptive, or combined restrictive-malabsorptive procedures limiting food intake, nutrient absorption, or both. Nowadays, anatomical alterations are known to affect gastrointestinal physiology, which in turn affects the digestion and absorption of nutrients and drugs. Therefore, understanding gastrointestinal physiology is crucial to prevent postoperative nutritional deficiencies and to optimise postoperative drug therapy. Preclinical and clinical research indicates that sleeve gastrectomy accelerates liquid and solid gastric emptying and small intestinal transit, and increases bile acid serum levels, whereas its effects on gastrointestinal acidity, gastric and pancreatic secretions, surface area, and colonic transit remain largely unknown. Roux-en-Y gastric bypass diminishes gastric acid secretion, accelerates liquid gastric emptying, and increases bile acid serum levels, but its effects on intestinal pH, solid gastric emptying, intestinal transit time, gastric enzyme secretions, and surface area remain largely unknown. In this Review, we summarise current knowledge of the effects of these two procedures on gastrointestinal physiology and assess the knowledge gaps.
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http://dx.doi.org/10.1016/S2468-1253(20)30302-2DOI Listing
March 2021

Drug Disposition in the Lower Gastrointestinal Tract: Targeting and Monitoring.

Pharmaceutics 2021 Jan 26;13(2). Epub 2021 Jan 26.

Drug Delivery and Disposition, KU Leuven, Gasthuisberg O&N II, Herestraat 49-Box 921, 3000 Leuven, Belgium.

The increasing prevalence of colonic diseases calls for a better understanding of the various colonic drug absorption barriers of colon-targeted formulations, and for reliable in vitro tools that accurately predict local drug disposition. In vivo relevant incubation conditions have been shown to better capture the composition of the limited colonic fluid and have resulted in relevant degradation and dissolution kinetics of drugs and formulations. Furthermore, drug hurdles such as efflux transporters and metabolising enzymes, and the presence of mucus and microbiome are slowly integrated into drug stability- and permeation assays. Traditionally, the well characterized Caco-2 cell line and the Ussing chamber technique are used to assess the absorption characteristics of small drug molecules. Recently, various stem cell-derived intestinal systems have emerged, closely mimicking epithelial physiology. Models that can assess microbiome-mediated drug metabolism or enable coculturing of gut microbiome with epithelial cells are also increasingly explored. Here we provide a comprehensive overview of the colonic physiology in relation to drug absorption, and review colon-targeting formulation strategies and in vitro tools to characterize colonic drug disposition.
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http://dx.doi.org/10.3390/pharmaceutics13020161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912393PMC
January 2021

Local immune response to food antigens drives meal-induced abdominal pain.

Nature 2021 02 13;590(7844):151-156. Epub 2021 Jan 13.

Laboratory of Immunoregulation, VIB Center for Inflammation Research, Ghent, Belgium.

Up to 20% of people worldwide develop gastrointestinal symptoms following a meal, leading to decreased quality of life, substantial morbidity and high medical costs. Although the interest of both the scientific and lay communities in this issue has increased markedly in recent years, with the worldwide introduction of gluten-free and other diets, the underlying mechanisms of food-induced abdominal complaints remain largely unknown. Here we show that a bacterial infection and bacterial toxins can trigger an immune response that leads to the production of dietary-antigen-specific IgE antibodies in mice, which are limited to the intestine. Following subsequent oral ingestion of the respective dietary antigen, an IgE- and mast-cell-dependent mechanism induced increased visceral pain. This aberrant pain signalling resulted from histamine receptor H-mediated sensitization of visceral afferents. Moreover, injection of food antigens (gluten, wheat, soy and milk) into the rectosigmoid mucosa of patients with irritable bowel syndrome induced local oedema and mast cell activation. Our results identify and characterize a peripheral mechanism that underlies food-induced abdominal pain, thereby creating new possibilities for the treatment of irritable bowel syndrome and related abdominal pain disorders.
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http://dx.doi.org/10.1038/s41586-020-03118-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610810PMC
February 2021

Exploring the Impact of Intestinal Fluid Components on the Solubility and Supersaturation of Danazol.

J Pharm Sci 2021 06 9;110(6):2479-2488. Epub 2021 Jan 9.

Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark; Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland.

Eleven simulated intestinal fluids (SIF) were designed using a Design of Experiment (DoE) approach. The DoE SIF covered a range of compositions of fasted state human intestinal fluid (FaHIF) with regard to pH, bile salt (BS), and phospholipid (PL). Using the model compound danazol, the apparent crystalline solubility (aCS) and apparent amorphous solubility (aAS), as well as the supersaturation propensity was determined in the DoE SIF media. The aCS of danazol was dependent on the composition of the SIF, with PL as the main factor, and a small effect from BS and an interaction between BS and PL. From the DoE solubility data a model was derived, which could predict aCS in commercially available SIF (FaSSIF-V1 and -V2) and in a range of FaHIF. The aAS of danazol was differently affected by the SIF composition than the aCS; PL was again the main factor influencing the aAS, but interactions between BS and pH, as well as pH and PL were also important. The supersaturation propensities of danazol in the DoE SIF media were affected by the same factors as the aCS. Hence, the supersaturation behaviour and aCS of danazol, were found to be closely related.
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http://dx.doi.org/10.1016/j.xphs.2020.12.039DOI Listing
June 2021

Correction: López-Yerena, A., et al. "Absorption and Intestinal Metabolic Profile of Oleocanthal in Rats" 2020, , 134.

Pharmaceutics 2020 Dec 17;12(12). Epub 2020 Dec 17.

CIBER Physiopathology of Obesity and Nutrition (CIBEROBN), Institute of Health Carlos III, 28029 Madrid, Spain.

The authors would like to make the following corrections to this paper [...].
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http://dx.doi.org/10.3390/pharmaceutics12121220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766302PMC
December 2020

Reply to "Comment on López-Yerena et al. 'Absorption and Intestinal Metabolic Profile of Oleocanthal in Rats' 2020, , 134".

Pharmaceutics 2020 Dec 17;12(12). Epub 2020 Dec 17.

CIBER Physiopathology of Obesity and Nutrition (CIBEROBN), Institute of Health Carlos III, 28029 Madrid, Spain.

Recently, in February 2020, we published a study exploring the intestinal absorption and metabolism of oleocanthal (OLC) in rats. A single-pass intestinal perfusion technique (SPIP) was used, involving simultaneous sampling from the luminal perfusate and mesenteric blood. Later, comments on our published paper were released, requesting clarification of specific data. In this detailed reply, we hope to have addressed and clarified all the concerns of A. Kaddoumi and K. El Sayed and that the scientific community will benefit from both the study and the comments it has generated.
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http://dx.doi.org/10.3390/pharmaceutics12121221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765908PMC
December 2020

Proton Pump Inhibitors Reduce Duodenal Eosinophilia, Mast Cells, and Permeability in Patients With Functional Dyspepsia.

Gastroenterology 2021 04 18;160(5):1521-1531.e9. Epub 2020 Dec 18.

Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium; Translational Research in Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven, Leuven, Belgium. Electronic address:

Background & Aims: Despite the growing recognition of duodenal alterations in the pathophysiology of functional dyspepsia (FD), the effect and mechanism of proton pump inhibitors (PPIs) or first-line therapy remain unclear. We studied duodenal and systemic alterations in relation to PPI therapy in patients with FD and healthy volunteers (HVs).

Methods: We performed a prospective interventional study assessing symptoms (Patient Assessment of Gastrointestinal Symptom Severity Index), duodenal alterations, and systemic factors in patients with FD ("FD-starters") and HVs before and after PPI therapy (pantoprazole 40 mg once daily for 4 weeks). Duodenal mucosal eosinophils, mast cells and permeability were quantified. Luminal pH and bile salts were determined in duodenal aspirates. Procedures were also performed in PPI-refractory patients with FD ("FD-stoppers") before and 8 weeks after PPI withdrawal. Between- and within-group changes from baseline and associations with duodenal or systemic factors were analyzed using linear mixed models.

Results: The study was completed by 30 HV, 27 FD-starters, and 18 FD-stoppers. Symptoms and duodenal eosinophils, mast cells (all, P < .0001), and paracellular passage (P = .02) were significantly higher in FD-starters vs HVs and reduced with PPI therapy. Symptoms and duodenal immune cells also decreased in FD-stoppers off PPIs. In contrast, immune cells and permeability increased in HVs on PPIs. Dyspeptic symptoms correlated with eosinophils before and during PPI therapy, and increased eosinophils and permeability in HVs on PPIs were associated with changes in bile salts.

Conclusions: We provide the first prospective evidence for eosinophil-reducing effects as a therapeutic mechanism of PPIs in FD, with differential effects in HVs pointing to a role of luminal changes. ClinicalTrials.gov, Number: NCT03545243.
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http://dx.doi.org/10.1053/j.gastro.2020.12.016DOI Listing
April 2021

Erratum: Hens, B.; et al. Application of the Gastrointestinal Simulator (GIS) Coupled with In Silico Modeling to Measure the Impact of Coca-Cola on the Luminal and Systemic Behavior of Loratadine (BCS Class 2b). , 2020, , 566.

Pharmaceutics 2020 Nov 25;12(12). Epub 2020 Nov 25.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109-1065, USA.

The authors make the following correction to this paper after the final publication of the work [...].
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http://dx.doi.org/10.3390/pharmaceutics12121137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761310PMC
November 2020

Association between duodenal bile salts and gastric emptying in patients with functional dyspepsia.

Gut 2021 11 25;70(11):2208-2210. Epub 2020 Nov 25.

Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium

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http://dx.doi.org/10.1136/gutjnl-2020-323598DOI Listing
November 2021

Codeine induces increased resistance at the esophagogastric junction but has no effect on motility and bolus flow in the pharynx and upper esophageal sphincter in healthy volunteers: A randomized, double-blind, placebo-controlled, cross-over trial.

Neurogastroenterol Motil 2021 05 24;33(5):e14041. Epub 2020 Nov 24.

Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium.

Background: Chronic opioid use can induce esophageal dysfunction with symptoms resembling achalasia and a manometric pattern of esophagogastric junction-outflow obstruction (EGJ-OO). However, the effect of opioids in acute setting on pharyngeal function and esophageal body contractility has not been investigated.

Methods: After positioning the high-resolution impedance manometry (HRiM) catheter, codeine (60 mg) or placebo (glucose syrup) was infused intragastrically. Forty-five minutes post-infusion, participants received liquid, semi-solid, and solid boluses to assess esophageal and pharyngeal function. HRiM analysis was performed adhering to the Chicago classification v3.0. (CC v3.0). Pressure flow analysis (PFA) for the esophageal body and the pharynx was performed using the SwallowGateway™ online platform.

Key Results: Nineteen healthy volunteers (HV) [5 male; age 38.3] were included. After codeine administration, higher integrated relaxation pressure 4 s values resulted in significantly reduced deglutitive EGJ relaxation and distal latency was significantly shorter. Distal contractility was similar in both conditions. Bolus flow resistance at the EGJ and distention pressures increased significantly after codeine infusion. Based on CC v3.0, acute infusion of codeine induced EGJ-OO in six HV (p = 0.0003 vs. placebo). Codeine administration induced no significant alterations in any of the pharyngeal PFA metrics.

Conclusions & Inferences: In HV, acute administration of codeine increased bolus resistance at the EGJ secondary to induced incomplete EGJ relaxation leading to major motility disorders in a subset of subjects including EGJ-OO. However, an acute single dose of codeine did not affect motility or bolus flow in pharynx and UES. ClinicalTrials.gov number, NCT03784105.
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http://dx.doi.org/10.1111/nmo.14041DOI Listing
May 2021
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