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Preliminary pharmacokinetics of the bacterial virulence inhibitor N'-(3,5-dibromo-2-hydroxy-benzylidenene)-nicotinic acid hydrazide
Umeå University, Faculty of Science and Technology, Department of Chemistry. Department of Pharmacy, Quaid-i-Azam University, Islamabad, Pakistan . (Gerhard Gröbner)
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
Discovery Drug Metabolism, Pharmacokinetics, and Bioanalysis, AstraZeneca R&D Lund, Sweden.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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2012 (English)In: Advances in Yersinia Research, Springer, 2012, 349-356 p.Chapter in book (Other academic)
Abstract [en]

Bacterial virulence inhibitors are potential novel drugs that may be used to treat infections. N′-(3,5-dibromo-2-hydroxy-benzylidene)-nicotinic acid hydrazide, ME0052, has been shown to inhibit type III secretion (T3S) and virulence in several Gram-negative enteric pathogens including Yersinia pseudotuberculosis. In vitro data suggest that ME0052 may be developed into drugs against bacterial gastroenteritis. Here we describe preliminary pharmacokinetics of ME0052 after intraperitoneal and subcutaneous administration in mice. The aim of this work was to identify suitable formulations and to determine pharmacokinetic parameters prior to testing in animal infection models. Peak plasma concentrations above the IC50 for virulence inhibition were achieved with high dose formulations and the elimination half-life was prolonged from 0.5 to 3.4 h using a poloxamer 407-based slow-release formulation.

Place, publisher, year, edition, pages
Springer, 2012. 349-356 p.
, Advances in Experimental Medicine and Biology, ISSN 0065-2598 ; 954
Keyword [en]
salicylidene acylhydrazide, pharmacokinetics, preclinical testing, sustained release formulations, anti-chlamydial activity
National Category
Medicinal Chemistry Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Pharmaceutical Microbiology; Pharmaceutics
URN: urn:nbn:se:umu:diva-40486DOI: 10.1007/978-1-4614-3561-7_42ISI: 000333327900043ISBN: 978-1-4614-3560-0ISBN: 978-1-4614-3561-7OAI: diva2:400151

Originally published in thesis in manuscript form with the title: "Preliminary pharmacokinetics of the bacterial virulence inhibitor 3,5-dibromo-2-hydroxy-benzylidene nicotinic acid hydrazide"

Available from: 2011-02-24 Created: 2011-02-23 Last updated: 2015-06-10Bibliographically approved
In thesis
1. Controlled release gel formulations and preclinical screening of drug candidates
Open this publication in new window or tab >>Controlled release gel formulations and preclinical screening of drug candidates
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Simple gel formulations may be applied to enhance the systemic and local exposure of potential compounds. The aim of this thesis is the development and characterization of controlled release formulations based on thermo-reversible poloxamer gels, which are suitable for novel drug delivery applications.  In particular co-solvents (DMSO, ethanol), mucoadhesive polymers (chitosan, alginate) and salts (sodium tripolyphosphate, CaCl2) have been used to enhance the applications of poloxamer 407 (P407) formulations in preclinical animal studies. The impact of these additives on the micellization and gelation properties of P407 aqueous solutions was studied by calorimetric methods, nuclear magnetic resonance spectroscopy (NMR) and “tube inversion” experiments. The drug release behavior of hydrophobic and hydrophilic drugs was characterized by using a membrane/membrane-free experimental setup. Finally, preliminary pharmacokinetic studies using a mouse model were conducted for screening of selected inhibitors of bacterial type III secretion and for evaluation of different formulations including P407 gel. All additives, used here, reduced the CMTs (critical micelle temperature) of dilute P407 solutions, with the exception of ethanol. The gelation temperature of concentrated P407 solutions was lowered in the presence of CaCl2, DMSO, TPP and alginate. 1H MAS (Magic Angle Spinning) NMR studies revealed that DMSO influences the hydrophobicity of the PPO segment of P407 polymers. Low concentrations of DMSO did not show any major effect on the drug release from P407 gels and may be used to improve the exposure of lead compounds in poloxamer gels. A newly developed in situ ionotropic gelation of chitosan in combination with TPP in P407 gels showed an enhanced resistance to water and reduced the release rates of model drugs. From preliminary pharmacokinetic studies in mice it was revealed that poloxamer formulations resulted in an increased plasma half-life of the lead compound.

Place, publisher, year, edition, pages
Umeå: Department of Chemistry, 2011. 51 p.
poloxamer, drug delivery, micellization, DMSO, calorimetry, NMR. in situ gelation, chitosan, preclinical pharmacokinetics, type III secretion inhibitors
National Category
Physical Chemistry
Research subject
urn:nbn:se:umu:diva-40489 (URN)978-91-7459-161-3 (ISBN)
Public defence
2011-03-22, KBC-huset, KB3A9, Umeå universitet, Umeå, 10:00 (English)
Available from: 2011-03-01 Created: 2011-02-23 Last updated: 2011-03-01Bibliographically approved

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Ur-Rehman, TofeeqNordfelth, RolandZetterström, Caroline EElofsson, MikaelGylfe, Åsa
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Department of ChemistryDepartment of Molecular Biology (Faculty of Medicine)Umeå Centre for Microbial Research (UCMR)Molecular Infection Medicine Sweden (MIMS)Department of Clinical Microbiology
Medicinal ChemistryMedical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)

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