The tendency of the majority of active pharmaceutical ingredients (APIs) to exist in different solid forms with keeping their chemical structures is called polymorphism. This phenomenon has gained a lot of interest in the pharmaceutical industry, hoping to avoid producing unexpected transformations of compounds during and after synthesis. The optimal way to avoid that is to subject the API, at the early stage of development, under various conditions in order to obtain an elegant (safe, effective, and stable) drug for the next formulation step. The aim of this thesis was to investigate some factors that affect the appearance of different polymorphs during screening of some APIs. Four model drugs were selected: paracetamol; carbamazepine; mefenamic acid; and flufenamic acid. All have been well-characterised previously in terms of solid-state forms. Piezoelectric, or 2D inkjet printing technique was used as a main technique in fabrication of nanoarrays of APIs onto predefined design on a solid tunable substrates because of its ability to control the delivered quantities of the the printed materials accurately, without any direct contact with the used substrate that may cause a sample cross-contamination. Light optical microscope was used to investigate the behaviour of the printed droplets during and after solvent evaporation and turn to dried spots, and to confirm the crystalline state of some spots by using the polarised light in the same microscope. Raman spectroscopy at low-wavenumber, or phonon region (40-400 cm-1) was used for the first time to identify the resulted polymorphs after the printing process as its ability to probe the alterations that happen in the molecular skeleton inside the crystal lattice , in addition to molecular region (400-1800 cm-1) to analyse the resulting spots. In chapter three, the piezoelectric inkjet printing technique was successfully used for the first time to miniaturise, screen, and study the stability of the APIs at nano quantities in the range of (1-500 ng), about six-ordered magnification less than the reported studies. It was found that the variation in the printed quantities can produce different states and polymorphs. Stability with time was also studied for all the printed samples and it was noticed the variation in time for some printed drugs to convert from solid amorphous to crystalline state. In chapter four, the advantage of the ability of the gold-coated slide to undergo further chemical modifications was exploited to create new substrates. Chemical modification of the gold substrates was carried out by treating them with two types of thiols to form self-assembly monolayers (SAMs) and use them as substrates in polymorph screening of some APIs. The new prepared SAMs were examined by preliminary tests like atomic force microscope (AFM) and water contact angle (WCA) measurements to investigate the texture of the new substrates before using them in printing process. It was found that changing the chemical structure of the substrate can lead to different polymorphs. In chapter five, an attempt to create highly hydrophobic substrates was done to investigate whether it can affect the propensity of APIs for polymorphism. Fluorinated compounds were used in this chapter as they are considered more hydrophobic than the substrates used in the previous part of the work The effect of the fluorinated substrates on appearance of new polymorphs was studied. Two fluorinated compounds were selected for preparation of high-water repellent surfaces and using them as substrates as they have the ability to limit the spreading of the printed droplets of the API, and allow the molecules to be constructed layer by layer and form a condense spot. The new fluorinated substrates were examined before using them in printing, and they exhibited high WCA. Another FLUF polymorph (VI) was investigated in addition to the two reference (I and III) polymorphs used in FLUF polymorphic screening. It was found that the intensity of the Raman peaks of the printed spots of APIs was good and clear to recognise when using fluorinated SAMs as a substrate, while the fluorinated substrate prepared from Flutec LE15 exhibited fluorescence effect due to the interactions between the glass and the drug’s spot spectrum.

As poor solubility continues to be problem for new chemical entities (NCEs) in medicines development the use and interest in solid dispersions as a formulation-based solution has grown. Solid dispersions, where a drug is typically dispersed in a molecular state within an amorphous water-soluble polymer, present a good strategy to significantly enhance the effective drug solubility and hence bioavailability of drugs. The main drawback of this formulation strategy is the inherent instability of the amorphous form. With the right choice of polymer and manufacturing method, sufficient stability can be accomplished. However, finding the right combination of carrier and manufacturing method can be challenging, being labour, time and material costly. Therefore, a knowledge based support tool based upon a statistically significant data set to help with the formulation process would be of great value in the pharmaceutical industry. Here, 60 solid dispersion formulations were produced using ten, poorly soluble, chemically diverse APIs, three commonly used polymers and two manufacturing methods (spray drying and hot-melt extrusion). A long term stability study, up to one year, was performed on all formulations at accelerated conditions. Samples were regularly checked for the onset of crystallisation during the period, using mainly, polarised light microscopy. The stability data showed a large variance in stability between, methods, polymers and APIs. No obvious trends could be observed. Using statistical modelling, the experimental data in combination with calculated and predicted physicochemical properties of the APIs, several multiple linear regression (MLR) models were built. These had a good adjusted R2 and most showed good predictability in leave-one-out cross validations. Additionally, a validation on half of the models (eg. those based on spray-drying models) using an external dataset showed excellent predictability, with the correct ranking of formulations and accurate prediction of stability. In conclusion, this work has provided important insight into the complex correlations between the physical stability of amorphous solid dispersions and factors such as manufacturing method, carrier and properties of the API. Due to the expansive number of formulations studied here, which is far greater than previously published in the literature in a single study, more general conclusions can be drawn about these correlations than has previously been possible. This thesis has shown the potential of using well-founded statistical models in the formulation development of solid dispersion and given more insight into the complexity of these systems and how stability of these is dependent on multiple factors.

Natural products play a pivotal role in the exploration of new cancer therapies of which the plant kingdom is a substantial source. Conofolidine is a novel bisindole alkaloid isolated from Malayan plant Tabernaemontana Corymbosa and belongs to the family of the known vinca alkaloid conophylline. To our knowledge, no published work existed at the time of commencement of this project. Herein, we report for the first time recognition of conofolidine’s exceptional anticancer activity, from a panel of Malayan bisindoles (namely leucophyllidine, bipleiophylline and alstonia macroline-sarpagine bisindoles) that were indiscriminately screened against various human-derived carcinoma cell lines. Preliminary data showed that conofolidine exerted remarkable inhibition of cell proliferation and colony formation of cancer cells (e.g. GI50 = 0.054 and IC50 < 0.1 μM in MCF-7) through either induction of apoptosis or senescence. Apoptosis was confirmed by accumulation of cleaved PARP and activation of caspases 3/7. Alternatively, increased β-galactosidase positive cells accompanied by transformation of cell shape to spindle like with enlarged cell size ascertained senescence induction. G1 cell cycle arrest and S-phase depletion were observed in the majority of tested cell lines. These cell cycle perturbations were confirmed by decreased expression of positive regulators (CDK2, cyclin A2 and c-Myc) and increased expression of CDK inhibitors p21WAF1/CIP1, p27KIP1 and p15INK4b. Conofolidine caused several aberrant mitotic phenotypes exemplified by multi-nucleation, mitotic slippage, changed polarity, membrane blebbing and DNA fragmentation. Compromised DNA integrity was confirmed by increased γ-H2AX foci and/or level indicating DNA double strand breaks. Conofolidine increased ROS production, which partly contributed to DNA damage, apoptosis- and senescence-induction. A proteomic study conducted following exposure of HT-29 cells to conofolidine (72 h; 0.602 μM) corroborated ROS generation by the increased expression of several ROS scavengers e.g. NQO1. Phospho-proteomics analyses revealed significant suppression of p-EGFR, p-Akt, p-ERK and p-STAT signal transduction. Such suppression caused c-Myc destabilisation with consequent eliciting of either apoptotic or senescent phenotypes. The variation in the basal phosphorylation levels of these signalling proteins in the different tested cell lines determined their fates. Additionally conofolidine down-regulated mutant-p53 at transcription, expression and post-translational levels in mutant-p53 (R273H) cell lines which could partly contribute to its suppressive actions on signalling pathways and cell cycle. Proteomic analyses showed decreased expressions of MCM (2-7) including MCM4 through which mutant-p53 (R273H) could drive initiation of DNA replication. Conofolidine’s ability to suppress MCM family (together with ROS production) provides an additional mechanism for conofolidine to induce DNA damage and genomic instability. Taken together, we present conofolidine in this study as potential anticancer candidate and provide mechanistic insight to its molecular targets and pathways, which encourage further future work.

Biological medicinal products (BMPs) are medicinal products extracted from, or synthesised by, a biological system. While BMPs have been proven to be effective in treating chronic and life-threatening diseases, the utilisation of these medicines was associated with creating financial burdens for healthcare systems worldwide. Expiry of patents and marketing exclusivity rights offers an opportunity to develop similar and not identical follow-on copies called ‘biosimilar medicinal products’ (BSPs). The inability to produce an identical copy of the original product is related to the heterogenic molecular nature of BMPs and the complexity of the manufacturing processes involved. The United Kingdom (UK) was frequently reported to have only a limited uptake of BSPs. Factors related to prescribers’ reservations and lack of encouraging national policies were reported to limit BSPs’ utilisation in the UK. In February 2015, the first high-cost monoclonal antibody (mAb), ‘infliximab’ (IFX-BSP), was launched; it was the first BSP to be commissioned locally compared to the previously nationally commissioned BSPs. Since its launch, there have been several encouraging national initiatives led by NHS-England and NICE. These conditions created new market daynamics that might affect uptake rates of BSPs, particularly IFX-BSP. This thesis explores factors affecting BSPs’ utilisation and integration in clinical practice in England. The aim and objectives were actualised following an explanatory sequential mixed methods design. The study’s first component assessed BSPs’ integration levels in local medicines formularies and investigated the prescribing practices of IFX-BSPs by English Acute Trusts. Guided by first component results, the second explanatory component investigated factors that led to the observed utilisation rates of IFX-BSPs. The explanatory study was achieved through 59 in-depth semi-structured interviews with healthcare professionals, who were involved in assessing, commissioning, introducing, managing and prescribing IFX-BSPs. In general, formularies screening showed that the integration levels of targeted BSPs were less than expected from a generic medicines driven market. Data showed variations in the uptake levels between therapeutic and geographical areas within Great Britain; a phenomenon which needs to be further investigated and explained. In England, assessing prescribing practice showed that with time Acute Trusts were becoming more accepting of utilising IFX-BSPs and were beginning to switch their R-BMP stabilised patients over to the BSPs. Interviews suggested that prescribers’ knowledge, experience, common medical practice, professional societies and ethical obligations had influenced prescribers’ acceptance and attitudes toward BSPs, in general, and to the switching of stabilised patients in particular. Data showed BSPs’ utilisation was not only affected by prescribers’ attitudes, but it was also influenced by pull-push dynamics between providing Acute Trusts and commissioning CCGs. The knowledge gained from this research could be used to inform the future implementation of upcoming BSPs. Insights acquired from this research regarding interactions between providers and commissioners might be extrapolated to implementing interventions locally, especially when there is an absence of nationally specific policies or guidelines.

No description available.

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / Neste trabalho estudamos, atravÃs de abordagen de primeiros princÃpios, algumas forÂmas de obtermos monÃmeros e dÃmeros de Ti substitucionados em nanotubos de carbono metÃlicos ou semicondutores. Apresentamos possÃveis rotas substitucionais para as imÂpurezas se agregarem à superfÃcie dos nanotubos, observando a relaÃÃo entre o nÃmero de vacÃncias sobre as paredes e a quantidade de impurezas metÃlicas colocadas em cada sÃtio! Encontramos que essa forma sistemÃtica de realizarmos a dopagem gera mudanÃas pronunciÃveis sobre as principais propriedades eletrÃnicas e estruturais dos tubos. Desde modo, à possÃvel a confecÃÃo de complexos metais-ligantes, dependendo como os defeitos nos tubos sÃo produzidos e de que forma os metais estabelecem a sua configuraÃÃo mais estÃvel sobre a lamela. Podendo servir de centro reativo para agregaÃÃo de novas estruÂturas sobre os titÃnios e a formaÃÃo de estruturas hÃbridas, tÃo em evidÃncia nos mais amplos cenÃrios da funcionalizaÃÃo. Os cÃlculos de energia total com polarizaÃÃo de spin foram realizados com o programa SIESTA- Spanish Initiative fOT EletTOnic Simulations with Thousands of Atoms, que consiste hoje no estado da arte em termos; de cÃlculos computacionais ab initio para orbitais em base numÃrica que escalonam linearmente com o tamanho do sistema. O que possibilita à obtenÃÃo de resultados tÃo bons quanto aos melhores cÃlculos, em ondas; planas, sà que de forma mais rÃpida e barata computaciÂonalmente. Um detalhado estudo da estrutura eletrÃnica de bandas, da densidade de estados, do contouT plot da densidade de carga localizada sobre cada nÃvel do sistema, da populaÃÃo de Mullikcn e da configuraÃÃo geomÃtrica mais estÃvel que o sistema alcanÃou à realizado.

Lam, Ming Yiu. / "September 2011." / Thesis (M.Phil.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 149-169). / Abstracts in English and Chinese. / Thesis / Assessment Committee --- p.ii / Abstract (English) --- p.iii / Abstract (Chinese) --- p.vi / Acknowledgements --- p.viii / Table of contents --- p.x / List of figures --- p.xvi / List of tables --- p.xix / Abbreviations --- p.xx / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Cerebral stroke --- p.1 / Chapter 1.2 --- Epidemiology --- p.2 / Chapter 1.3 --- Risk factors and symptoms --- p.5 / Chapter 1.3.1 --- Non-modifiable risks --- p.5 / Chapter 1.3.2 --- Modifiable risks --- p.6 / Chapter 1.3.3 --- Symptoms --- p.9 / Chapter 1.4 --- Mechanisms of cell injury --- p.10 / Chapter 1.4.1 --- Energy failure and loss of ionic homeostasis --- p.10 / Chapter 1.4.2 --- Excitotoxicity and calcium-modulated cell damage --- p.11 / Chapter 1.4.3 --- Oxidative stress --- p.13 / Chapter 1.4.4 --- Inflammation --- p.16 / Chapter 1.4.5 --- Apoptosis --- p.18 / Chapter 1.5 --- Current treatment of ischemia --- p.19 / Chapter 1.6 --- Chinese herbal medicine --- p.21 / Chapter 1.6.1 --- Traditional Chinese medicine theory on stroke --- p.21 / Chapter 1.6.2 --- Danshen --- p.22 / Chapter 1.6.3 --- Gegen --- p.25 / Chapter 1.6.4 --- Danshen-Gegen formula --- p.28 / Chapter 1.7 --- Aim of study --- p.30 / Chapter Chapter 2 --- General methodology --- p.31 / Chapter 2.1 --- Induction of transient focal cerebral ischemia by middle cerebral artery occlusion (MCAO) --- p.31 / Chapter 2.1.1 --- Intraluminal filament production --- p.32 / Chapter 2.1.2 --- Cerebral blood flow measurement by laser Doppler flowmetry --- p.33 / Chapter 2.1.3 --- Middle cerebral artery occlusion --- p.35 / Chapter 2.2 --- Neurological scoring --- p.38 / Chapter 2.3 --- Brain infarction measurement by triphenyltetrazolium chloride (TTC) staining --- p.40 / Chapter 2.4 --- Statistical analyses --- p.42 / Chapter Chapter 3 --- Preparation of herbal medicine --- p.43 / Chapter 3.1 --- Authentication of Chinese herbs --- p.43 / Chapter 3.1.1 --- Morphological authentication --- p.43 / Chapter 3.1.2 --- Chemical authentication using thin layer chromatography --- p.44 / Chapter 3.1.2.1 --- Danshen --- p.44 / Chapter 3.1.2.2 --- Gegen --- p.48 / Chapter 3.2 --- Danshen-Gegen (DG) extract preparation --- p.50 / Chapter 3.3 --- Chemical analysis of DG extract --- p.51 / Chapter 3.3.1 --- TLC --- p.51 / Chapter 3.3.2 --- HPLC --- p.54 / Chapter 3.4 --- Conclusion --- p.57 / Chapter Chapter 4 --- Protective effect of DG extract on cerebral ischemia --- p.58 / Chapter 4.1 --- Introduction --- p.58 / Chapter 4.1.1 --- Different models of ischemia --- p.58 / Chapter 4.1.2 --- Anti-oxidative enzymes in cerebral ischemia --- p.61 / Chapter 4.1.2.1 --- Superoxide dismutase (SOD) --- p.61 / Chapter 4.1.2.2 --- Catalase --- p.62 / Chapter 4.1.2.3 --- Glutathione peroxidase (GPX) --- p.62 / Chapter 4.2 --- Materials and methods --- p.64 / Chapter 4.2.1 --- "DG extract treatment, neurological deficit and brain infarction" --- p.64 / Chapter 4.2.2 --- Anti-oxidative enzymes activity determination --- p.65 / Chapter 4.2.2.1 --- Treatment with DG extract and induction of cerebral ischemia --- p.65 / Chapter 4.2.2.2 --- Extraction of enzymes from the brain --- p.66 / Chapter 4.2.2.3 --- Determination of protein concentration --- p.66 / Chapter 4.2.2.4 --- Assay kits --- p.67 / Chapter 4.3 --- Results --- p.70 / Chapter 4.4 --- Discussion --- p.80 / Chapter 4.4.1 --- Neurological score and percentage brain infarction --- p.80 / Chapter 4.4.2 --- Anti-oxidative enzyme induction --- p.82 / Chapter Chapter 5 --- Behavioral assessment using the shuttle box avoidance test on rats suffering from cerebral ischemia: effect of DG extract treatment --- p.86 / Chapter 5.1 --- Introduction --- p.86 / Chapter 5.1.1 --- Behavioral tests --- p.86 / Chapter 5.1.2 --- Theory of the test --- p.90 / Chapter 5.2 --- Materials and methods --- p.91 / Chapter 5.2.1 --- DG extract treatment --- p.91 / Chapter 5.2.2 --- Shuttle box training and MCAO --- p.92 / Chapter 5.2.3 --- Shuttle box testing --- p.96 / Chapter 5.2.4 --- Neurological score and brain infarction --- p.96 / Chapter 5.3 --- Results --- p.97 / Chapter 5.3.1 --- Shuttle box performance --- p.97 / Chapter 5.3.2 --- Neurological score --- p.105 / Chapter 5.3.3 --- Brain infarction --- p.109 / Chapter 5.4 --- Discussion --- p.112 / Chapter 5.4.1 --- The shuttle box protocol --- p.112 / Chapter 5.4.2 --- Shuttle box performance --- p.114 / Chapter 5.4.2.1 --- Pretreatment groups --- p.114 / Chapter 5.4.2.2 --- Pre + post treatment groups --- p.115 / Chapter 5.4.2.3 --- Comparison of pretreatment and pre + post treatment groups --- p.116 / Chapter 5.4.3 --- Neurological score --- p.117 / Chapter 5.4.4 --- Brain infarction --- p.118 / Chapter 5.4.5 --- Conclusion --- p.119 / Chapter Chapter 6 --- Anti-blood coagulation effect of DG extract --- p.121 / Chapter 6.1 --- Introduction --- p.121 / Chapter 6.2 --- Materials and methods --- p.125 / Chapter 6.2.1 --- Treatment with DG extract and warfarin --- p.125 / Chapter 6.2.2 --- Tail bleeding time and volume --- p.126 / Chapter 6.2.3 --- Prothrombin time --- p.127 / Chapter 6.2.4 --- Platelet aggregation --- p.127 / Chapter 6.3 --- Results --- p.128 / Chapter 6.4 --- Discussion --- p.138 / Chapter Chapter 7 --- General discussion --- p.141 / Chapter 7.1 --- General discussion and conclusion --- p.141 / Chapter 7.2 --- Clinical significance of the study --- p.145 / Chapter 7.3 --- Limitations of the study --- p.146 / Chapter 7.4 --- Future work --- p.147 / References --- p.149 / Publications --- p.170

Publicación a texto completo no autorizada por el autor / Los temas de investigación de esta tesis son muestras de meteoritos que han sido poco estudiadas en el Perú por técnicas físicas de caracterización. Esto motiva la elaboración de un proyecto con objetivos definidos para las muestras seleccionadas, enfatizando la determinación de su composición elemental, mineralógica y morfológica, así como de sus fases estructurales. En parte, estas muestras son recolectadas in situ en el área de impacto de un meteorito en Carancas, Puno, desde el cráter y el área adyacente. Las otras muestras estudiadas pertenecen a una colección del Museo de Historia Natural de la Universidad Nacional Mayor de San Marcos (UNMSM), Lima, Perú. Los resultados de los análisis de las muestras relacionadas con el meteorito de Carancas mediante fluorescencia de rayos X en energía dispersiva (FRXED) permiten contrastar la composición elemental de los residuos del propio meteorito con las muestras de suelo del cráter. Mediante difractometría de rayos X (DRX) se observa la presencia de fases mineralógicas como troilita (FeS), ringwoodita (Rw, (Mg, Fe)2 SiO4), olivino (Fe, Mg) 2SiO4 y piroxeno ((Mg, Ca, Mn, Fe) Si2O6). Los análisis por espectroscopía Mössbauer de transmisión (EMT) a temperatura ambiente (TA) permiten observar dos sextetos magnéticos, uno de ellos asignado a taenita (Fe-Ni) y el otro a troilita, y dos dobletes paramagnéticos asignados a Fe2 +: D1, asignados a olivino, y el otro, D2, a piroxeno. Los análisis de los espectros tomados a temperatura de helio líquido (THL) son una tarea compleja y permiten resolver la presencia de: a) dos componentes magnéticos de Fe3 + asociados a troilita (I) y troilita (II), dos componentes metálicos atribuidos a fases de Fe-Ni, que se asocian por una parte a la taenita cristalográficamente ordenada (tetrataenita) con Bhf= 34,5 T, y por otra parte a la taenita en una fase desordenada con Bhf = 38,8 T respectivamente, y c) una singlete S1 que es asignado a la antitaenite. Los resultados de los análisis de las muestras de suelo recogidas del cráter de Carancas y área adyacente (M1, M2 y M3) por el FRXED, DRX y EMT (TA y THL) informan transformaciones de fase que indican la presencia de elementos y minerales de impacto como coesita y stishovita (fases de SiO2). La presencia de estas fases de SiO2 en el suelo del cráter refuerza la hipótesis de su origen por el metamorfismo inducido por el impacto del meteorito. Además, se observa la presencia de sextetos magnéticos asignados al óxido de hierro: hematita y tres dobletes paramagnéticos, dos de ellos, D1 y D2, asignados a sitios de catión de Fe2 + y Fe3 + en illita y / o montmorillonita, respectivamente, y D3 asignado a un Fe3 + sitio de cationes aún no identificado. Los resultados de los análisis de ocho muestras de posibles meteoritos recogidos del Museo de Historia Natural (MHN) por las técnicas citadas revelan que no corresponden a muestras meteoriticas, sin embargo algunas de las muestras corresponden a piedras pelíticas magnéticas y otras son de impacto debido a la presencia de coesita y stishovita, así como de ringwoodita, que son polimorfo de olivino. Todos estos minerales se originan solo a través de un proceso de impacto meteorítico. Cabe mencionar que para una de éstas muestras del MHN-03 hubo necesidad de aplicar la técnica de Mössbauer por la modalidad de dispersión. / Universidad Nacional Mayor de San Marcos (Lima). Vicerrectorado de Investigación y Posgrado / Tesis

Cerebral ischaemia, traumatic injury to the brain, inflammatory neurological disorders and HIV infections are amongst the most prevalent causes of neurodegeneration. Neuroprotective strategies are usually to limit the progressive secondary injury that generally occurs, thus limiting overall tissue damage. Neuroprotective strategies are usually to limit the progressive secondary injury that generally occurs, thus limiting overall tissue damage. Sodium channel blockers have been often used for this matter as they prevent the cascade of events culminating in free radical generation and eventually neuronal apoptosis. Newer compounds, such as antiperoxidants and free radical scavengers, show encouraging experimental results, but their clinical use is still very limited. Phenytoin being a popular drug in the treatment of epilepsy has also been used as a neuroprotectant during certain neurological emergencies and in pharmacological prophylaxis of post-traumatic epilepsy. Furthermore this agent functions by prolonging inactivation of voltage gated sodium channels. In these sets of experiment the neuroprotective properties of phenytoin were examined. The histological study revealed that phenytoin confers protection to the CA1 and CA3 regions of the hippocampus under the insult of QUIN. Cells maintain their characteristic shape and minimal tissue necrosis occurs in the presence of this agent. The in vitro effect of this antiepileptic drug on free radicals generation shows that phenytoin does not reduce or prevent the formation of these reactive species. Lipid peroxidation was induced using QUIN and iron (II), two known neurotoxins. The study reveals that only lipid peroxidation induced using iron (II) is reduced by phenytoin. These experiments were carried out in whole rat brain homogenate. These studies show that phenytoin possesses poor free radical scavenging properties. However, the dose-related reduction of iron-induced lipid peroxidation allows for speculation that phenytoin interacts with iron in order to reduce neuronal damage. Metal binding studies were performed using UV, IR and electrochemical analysis to examine the interaction of phenytoin with iron (II) and iron (III). Phenytoin, when added to iron (II) in solution, first oxidises the latter to iron (III) and maintains it in that form. A shift in the peak was observed in the UV spectrum when iron was added to phenytoin. Moreover, electrochemical studies indicate that the interaction between the metal and the ligand is very weak. The IR analysis it shows that phenytoin may be coordinating with iron through the Nitrogen atom on the phenytoin molecule. These studies show that phenytoin maintains iron in its oxidised form, which is a good property to possess as a neuroprotectants. Pineal organ culture showed that phenytoin does not increase melatonin production but slightly and non-significantly reduces the levels of this pineal hormone. However there is a significant rise in precursor NAS levels. As melatonin is known to possess antioxidant and free radical scavenging properties, this could mean that this drug can cause the CNS to become more susceptible to attacks by reactive oxygen species.

No description available.