No description available.

Formulation of local anaesthetics in different dosage forms, including those for oral, parenteral, and topical application have being widely investigated. All of these formulations include local anaesthetics in their salt forms. The lipophilic nature of the bases of local anaesthetics may influence the rate of the pharmacological effect. There has been very little research done towards this aspect of local anaesthetics. Prilocaine base and lignocaine base possess greater lipophilicity than their salts. The salt forms undergo dissociation in the body. To maximise the absorption rate lipophilicity plays an important role. The aim of the present study is to evaluate the potential of using prilocaine and lignocaine individually and in combination as bases for parenteral formulations using cyclodextrins as complexing agents. Cyclodextrins are widely used as complexing agents to increase the solubility of poorly soluble drugs. Hydroxypropyl-β-cyclodextrin (HPβCD) was the first choice amongst the different cyclodextrins to be evaluated as a solubility enhancer as it does not show nephrotoxicity and is more bio-available compared to other cyclodextrins. / Method: Prilocaine base was prepared from its salt and lignocaine base was obtained from Sigma Pharmaceuticals. Solubilities were examined individually and in combination by the phase solubility method and complex formation investigated. The mobile phase used was methanol:water (55:45) with phosphate buffer at pH 5.5. An AL type solubility isotherm was obtained for the influence of HPβCD on the solubilities of prilocaine and lignocaine. Complexation was investigated for both prilocaine and lignocaine to HPβCD by NMR. Results: The measured solubilities of prilocaine and lignocaine individually at 30% HPβCD from 25°C to 42°C were 1.96-7.91 moles/L and 1.69-4.55 moles/L respectively. The solubilities in combination were 0.91-3.68 moles/L for prilocaine and 1.03-8.35 moles/L for lignocaine respectively. The NMR data suggested that complexation involves the aromatic ring for both prilocaine and lignocaine apart from methene and methyl groups for prilocaine and ethyl amide and aromatic methyl groups for lignocaine.

No description available.

3 ABSTRACT Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of biophysics and physical chemistry Author: Magdaléna Pleváková Supervisor: Ing. Vladimír Kubíček, CSc. Thesis title: Determination of Lipophilicity of Drugs by HPLC In this thesis a RP-HPLC method for fast and reliable determination of lipophilicity was proposed and tested. Stationary phase was selected by using hydrophobic substraction model. Capacity factors of the chosen substances were initially measured on Zorbax ECLIPSE XDB C18 250x4,6 mm, 5µm column, which exhibits almost identical retention characteristics as the column used for this purpose until now. Then the capacity factors of the same substances were determined by using Zorbax ECLIPSE XDB-C18 50x4,6 mm, 1,8µm column that was selected to reduce retention times significantly. A group of newly synthesised drugs based on structure of pyrazine served as samples for the measurement. The reproducibility of the capacity factor values determined using both columns was compared and the independence of the capacity factor on the mobile phase flow was confirmed. The capacity factors of two homologous series and a group of benzimidazols were consequently determined on Zorbax ECLIPSE XDB-C18 50x4,6 mm, 1,8µm column using various compositions of mobile phases. Several...

The full text of this thesis/dissertation is not available online. Please <a href="mailto:upetd@up.ac.za">contact us</a> if you need access. Read the abstract in the section 00front of this document. / Dissertation (MSc (Medical Immunology))--University of Pretoria, 2006. / Immunology / unrestricted

Voltage sensitive dyes are a family of chemical sensors which enable optical recording of electrical activities from large populations of neurons, but nevertheless suffer from the lack of delivery and targeting strategies in brain tissue due to their generally high lipophilicity. In this dissertation, I present a purely chemical approach to target voltage sensitive dyes to natively expressed protein targets in live brain tissue and achieve functional voltage imaging with the limited photon budget afforded by the small number of sensors targeted to endogenous molecular targets. To our knowledge, this study represents the first example of functional optical recording from specific neuronal types and their axons in live brain tissue without any genetic manipulation. Such approach is vastly significant in the long run when we ultimately need to translate findings from model animals in research laboratories to benefit real human patients in clinical settings, to which imaging and diagnostic methods requiring genetic modification are and will remain problematic in the foreseeable future. In addition, we demonstrate the high modularity and versatility of our chemical approach in targeting different voltage sensitive dyes to various molecular targets in the brain. We believe that the same concept can be applied to the targeting and delivery of other important lipophilic cargos, such as drugs and other sensors, to enable genetic modification-free, cell- or molecule-specific imaging and pharmacology in the brain.

Dans ce travail de thèse, plusieurs groupes de nouveaux complexes d'or(I) à base de carbènes N-hétérocyclique (NHC)contenant des bras amino-aliphatiques et aromatiques avec un potentiel intéressant dans des applications biomédicales ont été synthétisés et entièrement caractérisés. En outre, une série de complexes d'iridium(III) contenant des ligands NHC avec des activités anticancéreuses prononcées pour une application en thérapie photodynamique, a étépréparée et entièrement caractérisée. Le premier groupe représente une famille de complexes cationiques or(I) bis(NHC) contenant des bras latéraux amino-aliphatiques. Ces complexes ont étésynthétisés et étudiés pour leurs activités antiprolifératives vis-à-vis de quatre lignées cellulaires cancéreuses humaines et de la lignée cellulaire non cancéreuse MDCK. Dans cette série, la lipophilie est directement liée àl'activitécytotoxique contre les cellules cancéreuses. La deuxième famille de composés concerne les complexes cationiques or(I) bis(NHC) contenant des bras latéraux amino-aromatiques. La cytotoxicitéin vitro de ces complexes et de leurs proligands sur les lignées cellulaires représentatives du cancer de la prostate PC-3 et de la vessie T24 a étéévaluée. Tous ces complexes présentent des valeurs de Log P (lipophilie) supérieures àcelles de la première série de complexes en accord avec leur cytotoxicité plus élevée, mais une lipophilie trop élevée peut également conduire àune sélectivitéplus faible. Afin de développer un candidat-médicament avec une activitéet une sélectivité optimisées, nous avons conçu et synthétisé la troisième famille de complexes cationiques or(I) bis(NHC). Les valeurs de log P de cette série se situent entre la première série et la deuxième série. Ces complexes moins lipophiles sont moins cytotoxiques envers les lignées cellulaires saines (NIH3T3) et montre des activités anticancéreuses un peu plus faibles sur les cellules PC-3 que la deuxième série, avec néanmoins des valeurs de GI50 dans la gamme du nanomolaire. Les études mécanistiques sur deux complexes d'or(I) ont été réalisées. Les mesures d'absorption cellulaire ont montré une accumulation cellulaire rapide et une bonne biodisponibilitédes complexes, en accord avec l'activitéantiproliférative de ces deux complexes. De plus, les deux complexes inhibent la thiorédoxine reductase (TrxR), une cible commune pour les complexes d'or(I). La mort cellulaire induite par ces deux complexes est dépendante des espèces réactives de l'oxygène. En plus des activités anticancéreuses, nous avons également testédes complexes d'or(I) mono-NHC pour une autre application biomédicale, la leishmaniose, maladie parsitaire. Ils ont été testés in vitro sur les formes promastigotes et amastigotes axéniques de L. infantum. De plus, leur cytotoxicitéa étéévaluée sur les macrophages murins J774A.1 afin de déterminer leur sélectivitéd'action. Un autre sujet de cette thèse concerne les complexes d'iridium(III)-NHC. Trois familles de complexes ont étépréparées et caractérisées. La cytotoxicitéin vitro de tous les complexes sur les cellules cancéreuses de la prostate PC-3 et de la vessie T24, et les cellules non cancéreuses NIH3T3 a étéévaluée. De plus, tous les complexes sont des agents théranostiques, et les expériences de microscopie confocale d'un complexe ont montréqu'il pouvait être rapidement et efficacement absorbédans les cellules PC-3 et se localiser spécifiquement dans les mitochondries. De manière intéressante, ces complexes peuvent agir comme des photosensibilisateurs efficaces. La cytotoxicitéde ces complexes a étéaugmentée substantiellement après une irradiation lumineuse de 365 nm, ce qui suggère le potentiel élevéde ces agents anticancéreux théranostiques ciblant les mitochondries pour la thérapie photodynamique. / In this work of thesis, several groups of novel NHC-based gold(I) complexes containing aliphatic and aromatic amino-side arms with interesting potential in biomedical applications have been synthesized and fully characterized. Also, a series of iridium(III) complexes containing NHC ligands with pronounced PDT anticancer activities has been prepared and fully characterized. The first group represents a family of cationic bis(NHC)-gold(I) complexes containing aliphatic amino-side arms. These complexes have been synthesized and investigated for their antiproliferative activities towards four human cancer cell lines and the non-cancerous MDCK cell line. In this series, the lipophilicity correlates directly with the cytotoxic activity against cancer cells. The second family of compounds concerns cationic gold(I) bis(NHC) complexes containing aromatic amino-side arms. The in vitro cytotoxicity of these complexes and proligands on the representative PC-3 prostate and T24 bladder cancer cell lines has been evaluated. All these complexes show higher Log P values (lipophilicity) than the first series of complexes, and in line with this higher cytotoxicity, nevertheless too high lipophilicity can also lead to lower selectivity. In order to develop a drug candidate with optimized activity and selectivity, we designed and synthesized the third family of cationic gold(I) bis(NHC) complexes. The Log P values of this series were between the first series and the second series. The lower cytotoxicity towards non-cancerous NIH3T3 cells was found for this series of complexes whereas they also displayed less activities towards cancer cells than the second series. The mechanistic studies on two gold complexes by monitoring the cellular uptake showed the rapid cellular accumulation of the intact gold bis(NHC) and a good bioavailability, in good agreement with the antiproliferative activity of these two complexes. Moreover, both complexes inhibit TrxR, a common target for gold(I) complexes. The cell death induced by these two complexes was ROS-dependent. Besides anticancer activities, we also tested gold(I) mono-NHC complexes for other biomedical applications in parasite disease Leishmaniasis. They were screened in vitro against both promastigote and axenic amastigote forms of L. infantum. Moreover, their cytotoxicity was evaluated on the murine J774A.1 macrophages in order to determine their selectivity of action. Another topic of this thesis concerns iridium(III)-NHC complexes. Three families of theranostic iridium(III)-NHC complexes were prepared and characterized. The in vitro cytotoxicity of all the complexes against PC-3 prostate, T24 bladder cancer cells and non-cancerous NIH3T3 cells was evaluated. Moreover, all complexes are theranostic agents, and the confocal microscopy experiments of one complex showed that it can be quickly and effectively taken up into PC-3 cells and specifically localize into mitochondria. Interestingly, these complexes can act as efficient photosensitizers. The cytotoxicity of these complexes was increased substantially upon 365 nm light irradiation, which suggested the high potential to be mitochondria-targeting theranostic anticancer agents for photodynamic therapy.

Thesis (MSc.(Pharmacology)--Faculty of Health Sciences)-University of Pretoria, 2008.

Thesis (Ph.D.)--Flinders University, School of Medicine, Dept. of Clinical Pharmacology. / Typescript bound. Includes bibliographical references: (leaves 172-189) Also available online.

Exposure to halogenated phenols and pyridinols is of increasing concern because of their wide use and distribution. This research was initiated to determine the distribution, accumulation, and depletion of a group of halogenated phenols and a pyridinol in selected tissues of male weanling rats at different time intervals following a single oral dose of 0.33 or 1.66 m moles per kg body weight. The halogenated phenols and pyridinol were distributed differently in every tissue sampled following their administration, even though the amount administered was the same in each case. The concentrations in tissue were found in the order: 2,4,5-trichloro-phenol > 4-bromo-2,5-dichlorophenol > 4-iodo-2,5-dichlorophenol > 3,5,6-trichloro-2-pyridonol in kidney and fat, whereas the series 3,5,6-trichloro-2-pyridinol > 4-iodo-2,5-dichlorophenol > 4-bromo-2,5-dichlorophenol > 3,5,6-trichlorophenol occurred in liver. No structurally significant series was observed for their concentrations in blood. All halogenated phenols and pyridinol concentrations in tissues declined rapidly with time but not always in an apparently log linear fashion. Rates were greatest for clearance from blood. The highest concentration of halogenated phenols was in kidney among the tissues studied, whereas the highest concentration of halogenated pyridinol was in liver. Relationships were found between the relative lipophilicity, as indicated by the chromatographic Rm value, and the concentrations of these compounds in tissues. The RH (i.e., relative lipophilicity) was generally very well correlated with the log concentration of compounds in tissues observed 24 h after dosing. The correlation coefficients ranged between .517 and .995 among tissues. Correlations were positive between the Rm values and 24 h concentrations in adipose tissue, and kidney, but negative for the relationship between the Rm and 24 h concentrations in blood and liver.