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BETA
Hammarlund-Udenaes, MargaretaORCID iD iconorcid.org/0000-0002-9181-1321
Alternative names
Publications (10 of 81) Show all publications
Gustafsson, S., Gustavsson, T., Roshanbin, S., Hultqvist, G., Hammarlund-Udenaes, M., Sehlin, D. & Syvänen, S. (2018). Blood-Brain Barrier Integrity in a Mouse Model of Alzheimer’s Disease With or Without Acute 3D6 Immunotherapy. Neuropharmacology, 143, 1-9
Open this publication in new window or tab >>Blood-Brain Barrier Integrity in a Mouse Model of Alzheimer’s Disease With or Without Acute 3D6 Immunotherapy
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2018 (English)In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 143, p. 1-9Article in journal (Refereed) Published
Abstract [en]

The blood-brain barrier (BBB) is suggested to be compromised in Alzheimer's disease (AD). The concomitant presence of vascular amyloid beta (AD) pathology, so called cerebral amyloid angiopathy (CAA), also predisposes impairment of vessel integrity. Additionally, immunotherapy against A beta may lead to further damage of the BBB. To what extent this affects the BBB passage of molecules is debated. The current study aimed to investigate BBB integrity to large molecules in transgenic mice displaying abundant A beta pathology and age matched wild type animals, with or without acute anti-A beta antibody treatment. Animals were administered a single i.v. injection of PBS or 3D6 (10 mg/kg), i.e. the murine version of the clinically investigated A beta antibody bapineuzumab, supplemented with [(125)]3D6. Three days post injections, a 4 kDa FITC and a 150 kDa Antonia Red dextran were administered i.v. to all animals. After termination, fluorescent detection in brain and serum was used for the calculation of dextran brain-to-blood concentration ratios. Further characterization of antibody fate and the presence of CAA were investigated using radioactivity measurements and Congo red staining. BBB passage of large molecules was equally low in wild type and transgenic mice, suggesting an intact BBB despite A beta pathology. Neither was the BBB integrity affected by acute 3D6 treatment. However, CAA was confirmed in the transgenes and local antibody accumulations were observed in the brain, indicating CAA-antibody interactions. The current study shows that independently of A beta pathology or acute 3D6 treatment, the BBB is intact, without extensive permeability to large molecules, including the 3D6 antibody.

National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
urn:nbn:se:uu:diva-347199 (URN)10.1016/j.neuropharm.2018.09.001 (DOI)000453493200001 ()30201212 (PubMedID)
Funder
Swedish Research Council, 2017-02413Magnus Bergvall FoundationGun och Bertil Stohnes StiftelseStiftelsen Gamla Tjänarinnor
Available from: 2018-03-27 Created: 2018-03-27 Last updated: 2019-01-11Bibliographically approved
Hu, Y., Gaillard, P. J., Rip, J., De lange, E. C. .. & Hammarlund-Udenaes, M. (2018). In Vivo Quantitative Understanding of PEGylated Liposome’s Influence on Brain Delivery of Diphenhydramine. Molecular Pharmaceutics, 15(12), 5493-5500
Open this publication in new window or tab >>In Vivo Quantitative Understanding of PEGylated Liposome’s Influence on Brain Delivery of Diphenhydramine
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2018 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 15, no 12, p. 5493-5500Article in journal (Refereed) Published
Abstract [en]

Despite the promising features of liposomes as brain drug delivery vehicles, it remains uncertain how they influence the brain uptake in vivo. In order to gain a better fundamental understanding of the interaction between liposomes and the blood–brain barrier (BBB), it is indispensable to test if liposomes affect drugs with different BBB transport properties (active influx or efflux) differently. The aim of this study was to quantitatively evaluate how PEGylated (PEG) liposomes influence brain delivery of diphenhydramine (DPH), a drug with active influx at the BBB, in rats. The brain uptake of DPH after 30 min intravenous infusion of free DPH, PEG liposomal DPH, or free DPH + empty PEG liposomes was compared by determining the unbound DPH concentrations in brain interstitial fluid and plasma with microdialysis. Regular blood samples were taken to measure total DPH concentrations in plasma. Free DPH was actively taken up into the brain time-dependently, with higher uptake at early time points followed by an unbound brain-to-plasma exposure ratio (Kp,uu) of 3.0. The encapsulation in PEG liposomes significantly decreased brain uptake of DPH, with a reduction of Kp,uu to 1.5 (p < 0.05). When empty PEG liposomes were coadministered with free drug, DPH brain uptake had a tendency to decrease (Kp,uu 2.3), and DPH was found to bind to the liposomes. This study showed that PEG liposomes decreased the brain delivery of DPH in a complex manner, contributing to the understanding of the intricate interactions between drug, liposomes, and the BBB.

Keywords
nanocarrier, liposome, blood-brain barrier, brain uptake, microdialysis, diphenhydramine
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science; Pharmacokinetics and Drug Therapy
Identifiers
urn:nbn:se:uu:diva-365857 (URN)10.1021/acs.molpharmaceut.8b00611 (DOI)000452344600006 ()30376346 (PubMedID)
Available from: 2018-11-14 Created: 2018-11-14 Last updated: 2019-01-22Bibliographically approved
Gustafsson, S., Lindström, V., Ingelsson, M., Hammarlund-Udenaes, M. & Syvänen, S. (2018). Intact blood-brain barrier transport of small molecular drugs in animal models of amyloid beta and alpha-synuclein pathology. Neuropharmacology, 128, 482-491
Open this publication in new window or tab >>Intact blood-brain barrier transport of small molecular drugs in animal models of amyloid beta and alpha-synuclein pathology
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2018 (English)In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 128, p. 482-491Article in journal (Refereed) Published
Abstract [en]

Pathophysiological impairment of the neurovascular unit, including the integrity and dynamics of the blood-brain barrier (BBB), has been denoted both a cause and consequence of neurodegenerative diseases. Pathological impact on BBB drug delivery has also been debated. The aim of the present study was to investigate BBB drug transport, by determining the unbound brain-to-plasma concentration ratio (K-p,K-uu,K-brain), in aged A beta PP-transgenic mice, alpha-synuclein transgenic mice, and wild type mice. Mice were dosed with a cassette of five compounds, including digoxin, levofloxacin (1 mg/kg, s.c.), paliperidone, oxycodone, and diazepam (0.25 mg/kg, s.c.). Brain and blood were collected at 0.5,1, or 3 h after dosage. Drug concentrations were measured using LC-MS/MS. The total brain-to-plasma concentration ratio was calculated and equilibrium dialysis was used to determine the fraction of unbound drug in brain and plasma for all compounds. Together, these three measures were used to determine the Kp,uu,brain value. Despite A beta or alpha-synuclein pathology in the current animal models, no difference was observed in the extent of drug transport across the BBB compared to wild type animals for any of the compounds investigated. Hence, the present study shows that the concept of a leaking barrier within neurodegenerative conditions has to be interpreted with caution when estimating drug transport into the brain. The capability of the highly dynamic BBB to regulate brain drug exposure still seems to be intact despite the presence of pathology. (C) 2017 The Authors. Published by Elsevier Ltd.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
Blood-brain barrier, Pharmacokinetics, Drug transport, Disease, Amyloid beta, Alpha-synuclein
National Category
Neurology Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-340458 (URN)10.1016/j.neuropharm.2017.08.002 (DOI)000418977200043 ()28797721 (PubMedID)
Available from: 2018-02-15 Created: 2018-02-15 Last updated: 2018-03-27Bibliographically approved
Mihajlica, N., Betsholtz, C. & Hammarlund-Udenaes, M. (2018). Pharmacokinetics of Pericyte Involvement in Small-Molecular Drug Transport Across the Blood-Brain Barrier. European Journal of Pharmaceutical Sciences, 122, 77-84
Open this publication in new window or tab >>Pharmacokinetics of Pericyte Involvement in Small-Molecular Drug Transport Across the Blood-Brain Barrier
2018 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 122, p. 77-84Article in journal (Refereed) Published
Abstract [en]

Pericytes are perivascular cells that play important roles in the regulation of the blood-brain barrier (BBB) properties. Pericyte-deficiency causes compromised BBB integrity and increase in permeability to different macromolecules mainly by upregulated transcytosis. The aim of the present study was to investigate pericyte involvement in the extent of small-molecular drug transport across the BBB. This was performed with five compounds: diazepam, digoxin, levofloxacin, oxycodone and paliperidone. Compounds were administered at low doses via subcutaneous injections as a cassette (simultaneously) to pericyte-deficient Pdgfb(ret/ret) mice and corresponding WT controls. Total drug partitioning across the BBB was calculated as the ratio of total drug exposures in brain tissue and plasma (K-p,K-brain). In addition, equilibrium dialysis experiments were performed to estimate unbound drug fractions in brain (f(u,brain)) and plasma (f(u,plasma)). This enabled estimation of unbound drug partitioning coefficients (K-p,K-uu,K-brain). The results indicated slight tendencies towards increase of total brain exposures in Pdgfb(ret/ret) mice as reflected in K-p,K-brain values, which were within the 2-fold limit. Part of these differences could be explained by differences in plasma protein binding. No difference was found in brain tissue binding. The combined in vivo and in vitro data resulted in no differences in BBB transport in pericyte-deficiency, as described by similar K-p,K-uu,K-brain Values in Pdgfb(ret/ret) and control mice. In conclusion, these findings imply no influence of pericytes on the extent of BBB transport of small-molecular drugs, and suggest preserved BBB features relevant for handling of this type of molecules irrespective of pericyte presence at the brain endothelium.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
Pericytes, Blood-brain barrier, Small-molecular drugs, Drug partitioning, Extent of transport, Unbound drug fractions
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-345932 (URN)10.1016/j.ejps.2018.06.018 (DOI)000439564000009 ()29933077 (PubMedID)
Available from: 2018-03-13 Created: 2018-03-13 Last updated: 2018-10-17Bibliographically approved
Mihajlica, N., Betsholtz, C. & Hammarlund-Udenaes, M. (2018). Rate of Small-Molecular Drug Transport Across the Blood-Brain Barrier in a Pericyte-Deficient State. European Journal of Pharmaceutical Sciences, 124, 182-187
Open this publication in new window or tab >>Rate of Small-Molecular Drug Transport Across the Blood-Brain Barrier in a Pericyte-Deficient State
2018 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 124, p. 182-187Article in journal (Refereed) Published
Abstract [en]

Close interactions between pericytes and brain endothelial cells are essential for keeping the blood-brain barrier (BBB) functional and to restrict the transport of various xenobiotics from blood circulation to the brain parenchyma. Profound understanding of pericyte roles at the BBB and underlying mechanisms for the regulation of BBB transport are important as a potential strategy to improve drug delivery in treatment of CNS disorders. The aim of the present study was to investigate pericyte role in the rate of small-molecular drug transport across the BBB, by examining three model compounds in a pericyte-deficient state. Diazepam, oxycodone and paliperidone were selected for this purpose based on utilization of different transport mechanisms at the BBB. The rate of brain uptake was assessed by implementing the trans-cardiac in situ brain perfusion technique. Radiolabeled 14C-sucrose was used as a vascular marker. Pericyte-deficient mice (Pdgfb(ret/ret)) exhibited significantly larger brain vascular volumes (V-vasc) 1.72 +/- 0.13 mL/100 g brain, compared to littermate controls with normal pericyte coverage (Pdgfb(ret/+)) 1.15 +/- 0.13 mL/100 g brain (p < 0001). However, the unidirectional transfer coefficient Kin, which describes the rate of brain uptake, was not different between Pdgfb(ret/ret) and Pdgfb(ret/+) mice for all three tested compounds. Taken together the present results indicate no pericyte influence in the rate of small-molecular drug transport at the BBB, despite the larger brain vascular volumes that were observed in a pericyte-deficient state.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-345939 (URN)10.1016/j.ejps.2018.08.009 (DOI)000447981200018 ()30098392 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 317250
Available from: 2018-03-13 Created: 2018-03-13 Last updated: 2019-01-07Bibliographically approved
Gustafsson, S., Eriksson, J., Syvänen, S., Eriksson, O., Hammarlund-Udenaes, M. & Antoni, G. (2017). Combined PET and microdialysis for in vivo estimation of drug blood-brain barrier transport and brain unbound concentrations. NeuroImage, 155, 177-186
Open this publication in new window or tab >>Combined PET and microdialysis for in vivo estimation of drug blood-brain barrier transport and brain unbound concentrations
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2017 (English)In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 155, p. 177-186Article in journal (Refereed) Published
Abstract [en]

Methods to investigate blood-brain barrier transport and pharmacologically active drug concentrations in the human brain are limited and data translation between species is challenging. Hence, there is a need to further develop the read-out of techniques like positron emission tomography ( PET) for studying neuropharmacokinetics. PET has a high translational applicability from rodents to man and measures total drug concentrations in vivo. The aim of the present study was to investigate the possibility of translating total drug concentrations, acquired through PET, to unbound concentrations, resembling those measured in the interstitial fluid by microdialysis sampling. Simultaneous PET scanning and brain microdialysis sampling were performed in rats throughout a 60 min infusion of [N-methyl-C-11] oxycodone in combination with a therapeutic dose of oxycodone and during a 60 min follow up period after the end of infusion. The oxycodone concentrations acquired with PET were converted into unbound concentrations by compensating for brain tissue binding and brain intracellular distribution, using the unbound volume of distribution in brain (Vu, brain), and were compared to microdialysis measurements of unbound concentrations. A good congruence between the methods was observed throughout the infusion. However, an accumulating divergence in the acquired PET and microdialysis data was apparent and became more pronounced during the elimination phase, most likely due to the passage of radioactive metabolites into the brain. In conclusion, the study showed that PET can be used to translate non-invasively measured total drug concentrations into unbound concentrations as long as the contribution of radiolabelled metabolites is minor or can be compensated for.

Keywords
Blood-brain barrier, Unbound concentration, Positron emission tomography, Microdialysis, Pharmacokinetics, Oxycodone
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-332421 (URN)10.1016/j.neuroimage.2017.04.068 (DOI)000405460900015 ()28467891 (PubMedID)
Available from: 2017-11-02 Created: 2017-11-02 Last updated: 2018-03-27Bibliographically approved
Greenwood, J., Hammarlund-Udenaes, M., Jones, H. C., Stitt, A. W., Vandenbrouke, R. E., Romero, I. A., . . . Khrestchatisky, M. (2017). Current research into brain barriers and the delivery of therapeutics for neurological diseases: a report on CNS barrier congress London, UK, 2017. Fluids and Barriers of the CNS, 14, Article ID 31.
Open this publication in new window or tab >>Current research into brain barriers and the delivery of therapeutics for neurological diseases: a report on CNS barrier congress London, UK, 2017
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2017 (English)In: Fluids and Barriers of the CNS, ISSN 2045-8118, E-ISSN 2045-8118, Vol. 14, article id 31Article, review/survey (Refereed) Published
Abstract [en]

This is a report on the CNS barrier congress held in London, UK, March 22-23rd 2017 and sponsored by Kisaco Research Ltd. The two 1-day sessions were chaired by John Greenwood and Margareta Hammarlund-Udenaes, respectively, and each session ended with a discussion led by the chair. Speakers consisted of invited academic researchers studying the brain barriers in relation to neurological diseases and industry researchers studying new methods to deliver therapeutics to treat neurological diseases. We include here brief reports from the speakers.

Keywords
Blood-brain barrier, Blood-CSF barrier, Blood-retinal barrier, Neuroinflammation, Viral vectors, Drug delivery, Antibody therapy, MicroRNA, Liposomal technology, Protein capsules
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-346611 (URN)10.1186/s12987-017-0079-9 (DOI)000414755100001 ()
Note

Correction in: Fluids and Barriers of the CNS, 2018, 15:3

https://doi.org/10.1186/s12987-017-0086-x

Available from: 2018-03-22 Created: 2018-03-22 Last updated: 2018-04-26Bibliographically approved
Chen, X., Keep, R. F., Liang, Y., Zhu, H.-J., Hammarlund-Udenaes, M., Hu, Y. & Smith, D. E. (2017). Influence of peptide transporter 2 (PEPT2) on the distribution of cefadroxil in mouse brain: A microdialysis study. Biochemical Pharmacology, 131, 89-97
Open this publication in new window or tab >>Influence of peptide transporter 2 (PEPT2) on the distribution of cefadroxil in mouse brain: A microdialysis study
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2017 (English)In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 131, p. 89-97Article in journal (Refereed) Published
Abstract [en]

Peptide transporter 2 (PEPT2) is a high-affinity low-capacity transporter belonging to the proton-coupled oligopeptide transporter family. Although many aspects of PEPT2 structure-function are known, including its localization in choroid plexus and neurons, its regional activity in brain, especially extracellular fluid (ECF), is uncertain. In this study, the pharmacokinetics and regional brain distribution of cefadroxil, a beta-lactam antibiotic and PEN 2 substrate, were investigated in wildtype and Pept2 null mice using in vivo intracerebral microdialysis. Cefadroxil was infused intravenously over 4 h at 0.15 mg/min/kg, and samples obtained from plasma, brain ECF, cerebrospinal fluid (CSF) and brain tissue. A permeability surface area experiment was also performed in which 0.15 mg/min/kg cefadroxil was infused intravenously for 10 min, and samples obtained from plasma and brain tissues. Our results showed that PEPT2 ablation significantly increased the brain ECF and CSF levels of cefadroxil (2- to 2.5-fold). In contrast, there were no significant differences between wildtype and Pept2 null mice in the amount of cefadroxil in brain cells. The unbound volume of distribution of cefadroxil in brain was 60% lower in Pept2 null mice indicating an uptake function for PEPT2 in brain cells. Finally, PEPT2 did not affect the influx clearance of cefadroxil, thereby, ruling out differences between the two genotypes in drug entry across the blood-brain barriers. These findings demonstrate, for the first time, the impact of PEPT2 on brain ECF as well as the known role of PEPT2 in removing peptide-like drugs, such as cefadroxil, from the CSF to blood.

Place, publisher, year, edition, pages
PERGAMON-ELSEVIER SCIENCE LTD, 2017
Keywords
Microdialysis, Peptide transporter 2, Blood-cerebrospinal fluid barrier, Cefadroxil, Brain extracellular fluid
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-321784 (URN)10.1016/j.bcp.2017.02.005 (DOI)000399256700008 ()28192085 (PubMedID)
Available from: 2017-05-11 Created: 2017-05-11 Last updated: 2018-01-13Bibliographically approved
Hammarlund-Udenaes, M. (2017). Microdialysis as an Important Technique in Systems Pharmacology: a Historical and Methodological Review. AAPS Journal, 19(5), 1294-1303
Open this publication in new window or tab >>Microdialysis as an Important Technique in Systems Pharmacology: a Historical and Methodological Review
2017 (English)In: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 19, no 5, p. 1294-1303Article, review/survey (Refereed) Published
Abstract [en]

Microdialysis has contributed with very important knowledge to the understanding of target-specific concentrations and their relationship to pharmacodynamic effects from a systems pharmacology perspective, aiding in the global understanding of drug effects. This review focuses on the historical development of microdialysis as a method to quantify the pharmacologically very important unbound tissue concentrations and of recent findings relating to modeling microdialysis data to extrapolate from rodents to humans, understanding distribution of drugs in different tissues and disease conditions. Quantitative microdialysis developed very rapidly during the early 1990s. Method development was in focus in the early years including development of quantitative microdialysis, to be able to estimate true extracellular concentrations. Microdialysis has significantly contributed to the understanding of active transport at the blood-brain barrier and in other organs. Examples are presented where microdialysis together with modeling has increased the knowledge on tissue distribution between species, in overweight patients and in tumors, and in metabolite contribution to drug effects. More integrated metabolomic studies are still sparse within the microdialysis field, although a great potential for tissue and disease-specific measurements is evident.

Keywords
microdialysis, pharmacodynamics, pharmacokinetics, pharmacology, recovery methods, systems
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-345884 (URN)10.1208/s12248-017-0108-2 (DOI)000408407300006 ()28762127 (PubMedID)
Available from: 2018-03-13 Created: 2018-03-13 Last updated: 2018-03-13Bibliographically approved
Kusuhara, H., Obach, R. S., Rostami-Hodjegan, A., Pang, K. S., Hammarlund-Udenaes, M., Derendorf, H., . . . Terasaki, T. (2017). Professor Yuichi Sugiyama: A Brilliant, Creative, Amicable, Charming, and Humorous Pharmaceutical Scientist. Journal of Pharmaceutical Sciences, 106(9), 2188-2194
Open this publication in new window or tab >>Professor Yuichi Sugiyama: A Brilliant, Creative, Amicable, Charming, and Humorous Pharmaceutical Scientist
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2017 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 106, no 9, p. 2188-2194Article in journal, Editorial material (Other academic) Published
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-345604 (URN)10.1016/j.xphs.2017.04.072 (DOI)000417339900002 ()28479350 (PubMedID)
Available from: 2018-03-09 Created: 2018-03-09 Last updated: 2018-03-09Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-9181-1321

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