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Preliminary pharmacokinetics of the bacterial virulence inhibitor N'-(3,5-dibromo-2-hydroxy-benzylidenene)-nicotinic acid hydrazide
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Department of Pharmacy, Quaid-i-Azam University, Islamabad, Pakistan . (Gerhard Gröbner)
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
Discovery Drug Metabolism, Pharmacokinetics, and Bioanalysis, AstraZeneca R&D Lund, Sweden.
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
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2012 (Engelska)Ingår i: Advances in Yersinia Research, Springer, 2012, s. 349-356Kapitel i bok, del av antologi (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Springer, 2012. s. 349-356
Serie
Advances in Experimental Medicine and Biology, ISSN 0065-2598 ; 954
Nyckelord [en]
salicylidene acylhydrazide, pharmacokinetics, preclinical testing, sustained release formulations, anti-chlamydial activity
Nationell ämneskategori
Läkemedelskemi Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)
Forskningsämne
farmaceutisk mikrobiologi; galenisk farmaci
Identifikatorer
URN: urn:nbn:se:umu:diva-40486DOI: 10.1007/978-1-4614-3561-7_42ISI: 000333327900043Scopus ID: 2-s2.0-84868160252ISBN: 978-1-4614-3560-0 (tryckt)ISBN: 978-1-4614-3561-7 (tryckt)OAI: oai:DiVA.org:umu-40486DiVA, id: diva2:400151
Anmärkning

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"

Tillgänglig från: 2011-02-24 Skapad: 2011-02-23 Senast uppdaterad: 2024-07-02Bibliografiskt granskad
Ingår i avhandling
1. Controlled release gel formulations and preclinical screening of drug candidates
Öppna denna publikation i ny flik eller fönster >>Controlled release gel formulations and preclinical screening of drug candidates
2011 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Umeå: Department of Chemistry, 2011. s. 51
Nyckelord
poloxamer, drug delivery, micellization, DMSO, calorimetry, NMR. in situ gelation, chitosan, preclinical pharmacokinetics, type III secretion inhibitors
Nationell ämneskategori
Fysikalisk kemi
Forskningsämne
galenisk farmaci
Identifikatorer
urn:nbn:se:umu:diva-40489 (URN)978-91-7459-161-3 (ISBN)
Disputation
2011-03-22, KBC-huset, KB3A9, Umeå universitet, Umeå, 10:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2011-03-01 Skapad: 2011-02-23 Senast uppdaterad: 2024-07-02Bibliografiskt granskad

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Ur-Rehman, TofeeqNordfelth, RolandZetterström, Caroline EElofsson, MikaelGylfe, Åsa

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Ur-Rehman, TofeeqNordfelth, RolandZetterström, Caroline EElofsson, MikaelGylfe, Åsa
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Kemiska institutionenInstitutionen för molekylärbiologi (Medicinska fakulteten)Umeå Centre for Microbial Research (UCMR)Molekylär Infektionsmedicin, Sverige (MIMS)Institutionen för klinisk mikrobiologi
LäkemedelskemiMedicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)

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