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Pre-clinical pharmacokinetics and anti-chlamydial activity of salicylidene acylhydrazide inhibitors of bacterial type III secretion
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. (Gerhard Gröbner)
Discovery Drug Metabolism, Pharmacokinetics, and Bioanalysis, AstraZeneca R&D Lund, Sweden.
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.ORCID-id: 0000-0001-8632-7087
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nyckelord [en]
Type III secretion inhibitors, pharmacokintics, anti-chlamydial activity, salicylidene acylhdrazides, preclinical screening
Nationell ämneskategori
Läkemedelskemi
Forskningsämne
galenisk farmaci; farmaceutisk mikrobiologi
Identifikatorer
URN: urn:nbn:se:umu:diva-40485OAI: oai:DiVA.org:umu-40485DiVA, id: diva2:400153
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, TofeeqElofsson, MikaelGylfe, Åsa

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Ur-Rehman, TofeeqElofsson, MikaelGylfe, Åsa
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