Dissertations / Theses on the topic 'Drugs acting on the central nervous system'

Depression and stimulant drug addiction each result in massive losses of health, productivity and human lives every year. Despite decades of research, current treatment regimes for depression are ineffective in approximately half of all patients. Therapy available to stimulant drug addicts is largely ineffective and moreover, dedicated treatments for drug dependence (including abuse of cocaine) are non-existent. Thus, there is a pressing need to further understanding of the molecular mechanisms underlying these disorders in order to develop novel, targeted therapeutic strategies. Chromatin remodeling, including changes in histone acetylation, has been proposed to play a role in both the etiology and treatment of depression and stimulant abuse. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) regulate numerous cellular processes, including transcription, cell cycle progression and differentiation. Moreover, histone acetylation has been shown to regulate hippocampal neurogenesis, a cellular response associated with the pathogenesis and treatment of depression and stimulant abuse (Hsieh et al., 2004, Yamaguchi et al., 2004, Fischer et al., 2007). Ultimately, such basic cellular processes impact higher order function, namely cognition and emotion. Indeed, recent studies suggest that HDAC activity in selected forebrain regions, including ventral striatum and hippocampus, modulate stimulant- and antidepressantinduced behavior (Kumar et al., 2005, Tsankova et al., 2006a, Fischer et al., 2007). These reports highlight an association between chromatin remodeling and diverse behavioral changes, including changes induced by the pleiotropic HDAC inhibitor, sodium butyrate (SB), (Kumar et al., 2005, Tsankova et al., 2006a, Fischer et al., 2007). However, behavioral, brain-metabolic and molecular effects of SB treatment in the context of rodent models of depression, dopaminergic sensitization and repeated cocaine administration remained unclear. The work described in this thesis illustrates the potential for chromatin modifying drugs in mechanisms underlying the experimental pharmacology of depression and stimulant addiction. Specifically, the data presented here support the view that treatment with the short chain fatty acid, sodium butyrate enhances: (1) antidepressant-like behavioral effects of the selective serotonin reuptake inhibitor (SSRI), fluoxetine (2) locomotor sensitization induced by repeated administration of the dopamine D1/D5 receptor agonist SKF82958; and(3) brain metabolic activation upon repeated cocaine administration as evidenced by fMRI in awake rats. Furthermore, this report provides evidence that these treatment paradigms will result in chromatin modification changes associated with active transcription, in addition to increased mRNA levels of plasticity-associated genes, including brain-derived neurotrophic factor (BDNF) at key brain regions implicated in the pathogenesis of depression and stimulant addiction. To date, little is known regarding the underlying mechanisms of action mediating the enhancing effects of sodium butyrate on the various antidepressant- and stimulantrelated paradigms. Our findings underscore the potential of chromatin-modifying drugs to profoundly affect the behavioral response of an animal to antidepressant and stimulant drugs and warrants consideration in the context of developing novel therapeutic strategies.

The main theme of this thesis is that there is a common structural basis for drugs acting on the central nervous system (CNS), and that this concept may be used to design new CNS-active drugs which have greater specificity and hence less side-effects. To develop these ideas, the biological basis of how drugs modify CMS neurotransmission is described, and illustrated using dopaminergic pathways. An account is then given of the use of physicochemical concepts in contemporary drug design. The complete conformational analysis of several antipsychotic drugs is used to illustrate some of these techniques in the development of a model for antipsychotic drug action. After reviewing current structure-activity studies in several classes of CNS drugs (antipsychotics, anti-depressants, stimulants, hal1ucinogens, anticonvulsants and analgesics), a hypothesis for a common structural basis of CNS drug action is proposed- This is based on a topographical comparison of the X-ray structures of eight representative CNS-active drugs, and consists of three parts: 1.there is a common structural basis for the activity of many different CNS-active drug classes; 2. an aromatic ring and a nitrogen atom are the primary binding groups whose topographical arrangement is fundamental to the activity of these drug classes; 3. the nature and placement of secondary binding determines different classes of CNS drug activity. A four-Point model for this common structural basis is then defined using 14- CNS-active drug structures that include the original eight used in proposing the hypothesis. The coordinates of this model are: R1 (0. 3.5, 0), R2 (0, -3.5, O), N (4.8. -0.3, 1.4), and R3 (6.3, 1.3, 0), where R1 and R2 represent the point locations of a hydrophobic interaction of the common aromatic ring with a receptor, and R3 locates the receptor point for a hydrogen bond involving the common nitrogen, N. Extended structures were used to define the receptor points R1, R2 and R3, and the complete conformational space of each of the 14 molecules was considered. It is then shoun that the model may be used to predict whether a given structure is likely to show CNS activity: a search over 1,000 entries in the current Merck Index shows a high probability (82%) of CNS activity in compounds fitting the structural model. Analysis of CNS neurotransmitters and neuropeptides shows that these fit the common model well. Based on the available evidence supporting chemical evolution, protein evolution, and the evolution of neurotransmitter functions, it is surmised that the aromatic ring/nitrogen atom pharmacophore proposed in the common model supports the idea of the evolution of CNS receptors and their neurotransmitters, possibly from an aromatic amine or acety1cho1ine acting as a primaeval communicating molecule. The third point in the hypothesis trilogy is then addressed. The extensive conformation-activity analyses that have resulted in well-defined models for five separate CNS drug classes are used to map out the locations of secondary binding groups relative to the common model for anti-psychotics, antidepressants, analgesics, anticholinergics, and anticonvulsants. With this information, and knowledge derived from receptor-binding data, it is postulated that drugs having specified activity could be designed. In order to generate novel structures having a high probability of CNS-activity, a process of drug design is described in which known CNS structures are superimposed topographically using the common model as a template. Atoms regarded as superfluous may be selectively deleted and the required secondary binding groups added in predicted locations to give novel structures. It is concluded that this process provides the basis for the rational design of new lead compounds which could further be optimized for potent and specific CNS activity.

INTRODUCTION: With successful treatment and near-normal life expectancy of people living with HIV, the focus of care has shifted towards minimizing toxicity from long term exposure to antiretrovirals (ARVs) and preventing co-morbidities. The prevalence of neurocognitive abnormalities has been reported to remain high, including in patients treated with cART. A low level viral replication in the central nervous system (CNS) may persist even in patients presenting with HIV-1 suppression in plasma, leading to local inflammation, neuronal damage and a poorer neuropsychological performance. A poor penetration of ARV drugs into the CNS may allow local HIV replication and may be associated with asymptomatic and even symptomatic HIV-related neurocognitive impairment or neurologic symptoms, which may be severe and present as HIV encephalitis in some occasions. For this reason we consider it extremely important to conduct research in order to improve the knowledge of the newer antiretroviral drugs penetration into the CNS and so to carry out a pilot study based on these results. HYPOTHESIS: 1. Maraviroc may reach pharmacological concentrations above the IC50 range in the CSF. 2. Maraviroc in combination with other antiretroviral drugs may help to maintain HIV viral suppression in the CSF. 3. Etravirine concentrations in CSF may be low but higher than the IC50. 4. Etravirine in combination with other antiretroviral drugs may help to maintain HIV viral suppression in the CSF. 5. Amprenavir concentrations in CSF may be above the IC50. 6. Fosamprenavir/ritonavir monotherapy may be sufficient to maintain HIV viral suppression in CSF. 7. A treatment switch from tenofovir, emtricitabine and efavirenz to abacavir, lamivudine and maravicoc in patients with neurocognitive impairment may be associated with a reduction on CSF inflammatory markers, CSF HIV RNA and an improvement in their neurocognitive performance. CONCLUSIONS: 1. Maraviroc concentrations in CSF in HIV-infected patients. -In all except 1 CSF sample, MVC concentrations exceeded the median serum- adjusted IC90. -Our data suggest that MVC may contribute to inhibit HIV-1 replication in CNS. -Maraviroc in combination with nucleoside-sparing regimens, including new ARV drugs, seems to be locally active. 2. Etravirine concentrations in CSF in HIV-infected patients -In all samples Etravirine concentrations exceeded the IC50 range. -Our data suggest that Etravirine may contribute to inhibiting HIV-1 replication in the CNS and that combined nucleoside sparing regimens, including new antiretroviral drugs, seem to be locally active. 3. Viral response in stable patients switching to fosamprenavir/ritonavir monotherapy. -Although the high percentage of viral failure with FPV/r monotherapy found in our study, this study is a proof of concept that boosted PI monotherapy could be enough to suppress HIV viral replication in CSF. 4. Viral and inflammatory markers in cerebrospinal fluid of patients with HIV-1-associated neurocognitive impairment during antiretroviral treatment switch. -There was a non-statistically significant reduction on the CSF HIV viral load after six months. -A significant reduction on TNF-α would suggest a reduction on local inflammatory reaction following treatment switch. This could be related to a reduction in CSF viral load, the anti-inflammatory effect of Maraviroc or both. -A trend towards an improvement in neurocognitive performance could be related to the above mentioned effects. - A switch to a regimen with a higher CPE score containing MVC was associated with a trend towards an improvement in neuropsychological performance and a reduction in TNF-α. In CSF. GENERAL CONCLUSION. The study of the concentrations and antiviral activity in CSF of the antiretroviral drugs will make possible the design for more effective combinations to be implemented in patients with NCI. A treatment switch can contribute to clinical and virological improvement as well as a reduction in the inflammatory markers.
INTRODUCCIÓN: En los últimos años diversos estudios han puesto en evidencia la persistencia de trastornos neurocognitivos (TNC) asociados al VIH, siendo en su mayoría formas asintomáticas o leves y moderadas. Si bien son múltiples los factores que favorecen la presencia de TNC en individuos infectados por el VIH (hepatopatía crónica, enfermedad cardiovascular, alcoholismo, uso de drogas, psicofármacos, etc), el virus –que ingresa en el SNC desde los primeros días de la infección- parece jugar un papel importante y ser causa de TNC incluso severos y/o enfermedad neurológica en forma de encefalitis aguda que puede llevar al coma y la muerte. En este contexto, la diferente penetración de los fármacos ARV podría jugar un papel en la prevención, y tratamiento de estas alteraciones. OBJETIVO GENERAL: Generar conocimiento sobre la penetración y actividad de diferentes fármacos antirretrovirales. Utilizar dicha información para poner en práctica una intervención destinada a mejorar la eficacia de una combinación antirretroviral en SNC. HIPÓTESIS: 1. Maraviroc alcanzaría niveles farmacológicos en LCR superiores a la CI50. 2. Maraviroc en combinación con otros fármacos antirretrovirales ayudaría a mantener la supresión viral en LCR. 3. Las concentraciones de Etravirina en LCR serían bajas aunque superiores a la CI50. 4. Etravirina en combinación con otros fármacos antirretrovirales contribuiría a mantener la supresión viral en LCR. 5. Las concentraciones de Amprenavir en LCR serían superiores a la CI50. 6. Fosamprenavir/ritonavir en monoterapia sería suficiente para mantener la supresión viral en LCR. 7. En pacientes que reciben una pauta de emtricitabina/tenofovir/ efavirenz y presentan deterioro neurocognitivo, el cambio a abacavir/lamivudina/maraviroc se asociaría a una disminución de marcadores inflamatorios, carga viral en LCR y a una mejoría en los TNC. CONCLUSIÓN: El estudio de las concentraciones de fármacos antirretrovirales y su actividad en LCR permitirá diseñar con mayor eficacia las pautas a utilizar en pacientes con TNC. Aunque hacen falta estudios más amplios, nuestros datos sugieren un posible beneficio clínico, virológico y de parámetros inflamatorios en pacientes con TNC que cambian a un TAR con mayor penetrabilidad en SNC.

The blood-brain barrier restricts the access of many compounds, including therapeutic agents, to the brain. Several human studies indicate that nasal administration of hydrophilic compounds, such as peptides, can bypass the blood-brain barrier. The aims of this thesis were to develop and refine models for this direct nose-to-brain transfer.

In a mouse model, [³H]-dopamine was given as a unilateral nasal dose. The resulting radioactivity in the ipsilateral olfactory bulb was significantly higher than that in the contralateral bulb and peaked at 4 h. Tape section autoradiography showed that the radioactivity was concentrated in the olfactory nerve layer and the glomerular layer of the olfactory bulb. The olfactory transfer of dopamine was also studied in vitro. At a lower donor concentration, the mucosal-to-serosal dopamine permeability was higher than the serosal-to-mucosal permeability, but at a higher concentration, the permeability coefficients were similar. Together, these results suggest that the olfactory transfer of dopamine has an active component.

Olfactory transfer of fluorescein-labeled dextran through the epithelium and deeper tissues was studied in a rat model, which enabled visualization of the transfer using fluorescence microscopy. Although the epithelial transfer appeared to be mainly intracellular, transfer in the following deeper tissues was extracellular. Without altering the route of uptake, a gellan gum formulation enhanced the uptake of fluorescein dextran. The enhancing effect was considered likely to be the result of an increased residence time in the nasal cavity.

In conclusion, dopamine and fluorescein-labeled dextran were identified as suitable model compounds for the study of olfactory drug transfer mechanisms and the influence of drug formulation. Two new in vitro models of olfactory transfer were compared. Also, a rat model, which enabled the visualization of the entire nose-to-brain transfer, was developed.

Introduction. HIV-associated neurocognitive disorders appear to remain common despite access to antiretroviral therapy (ART). Penetration of ART into the central nervous system (CNS) is highly variable between drugs and between individuals. Cerebrospinal fluid (CSF) concentrations of many antiretroviral medications fall below the minimum inhibitory concentration for wild type virus. HIV-1 RNA can be detected in the CSF at greater levels than in plasma (CSF/plasma discordance), however the clinical significance of this is unclear, and the degree of difference considered pathological varies. Whether the CNS can act as a sanctuary site leading to persistent HIV detection in plasma is not known. Methods. The PARTITION study recruited HIV positive adults from 13 UK clinical sites. Paired CSF and plasma was collected from patients undergoing LP for clinical indication (group A) and subjects with unexplained viraemia despite ART (group B). The study aimed to determine a) the prevalence of CSF/plasma discordance and factors associated with this occurrence, and b) the prevalence of HIV-1 RNA detection in CSF in those with HIV-1 RNA persistence in plasma. A sensitive assay detected HIV-1 RNA below 50 copies/ml in a subgroup and a cytometric bead array determined CSF biomarkers. A matrix of clinical features and CSF/plasma biomarkers was related to cognitive decline in subjects from the CHARTER study. Drug concentrations in CSF and plasma were measured by mass spectrometry assays and related to host genetic factors in subjects in the PARTITION study and a Vietnamese cohort with tuberculous meningitis. Results. CSF/plasma HIV discordance occurred in 13% of this cohort and was associated with nadir, but not current, CD4 cell count. CSF/plasma discordance occurred in 7 of 40 (18%) of subjects with ongoing viral detection in plasma vs. 0 of 39 of those without. Residual HIV-1 RNA detection below 50 copies/ml was also associated with CSF HIV-1 RNA detection. Resistance associated HIV mutations were detected in CSF of subjects with CSF/plasma discordance. CSF/plasma discordance above 0.5log10 was associated with raised profiles of inflammatory CSF proteomic biomarkers compared to those without discordance. In the CHARTER cohort, cognitive decline over 18 months was associated with lower concentrations of CSF TNFa and plasma IGF1/2. CSF concentrations of efavirenz were associated with the CYP2B6 c.516G>T single nucleotide polymorphism. Efavirenz metabolites were mainly glucuronidated in CSF, were present at neurotoxic levels, and were related to degree of blood brain barrier permeability. Host genetic factors were did not relate to CSF DRV concentrations. Conclusions. CSF/plasma discordance is a frequent occurrence, likely related to processes established during advanced immunosuppression not fully reversed by ART. It is associated with CSF HIV resistance and raised CSF biomarkers, even at levels 0.5-1log10 which have been considered non-significant in some studies. Potentially neurotoxic CSF concentrations of efavirenz relate to host genetic factors.

Introduction: Aging, comorbid conditions, and use of medications render older adults more susceptible to alcohol-disease or alcohol-drug interactions that may lead to harmful outcomes. In this dissertation project the risk profile of alcohol and medications use among older adults was investigated. Considering the rise in CNS-acting medication use and the adverse effect profile linked to CNS-acting medications, it was also of interest to find if older adults were at risk of falling due to interactions between alcohol and CNS-acting medication. Objectives: The objectives were as follows: 1) to determine the prevalence, pattern and factors associated with at-risk drinking, 2) to determine the prevalence and pattern of potential concurrent use of CNS-acting medication and alcohol, and to identify factors associated with alcohol use among CNS-acting medication users, 3) to assess the effects of potential concurrent use of CNS-acting medications and alcohol on the risk for falls in older adults. Methods: The study population comprised a nationally representative sample of community-dwelling older adults aged 65 years or older. The 2009 Medicare Current Beneficiary Survey (MCBS) data (n=7163) were employed to determine at-risk drinking based on the Comorbidity Alcohol Risk Evaluation Tool (CARET) and to assess the effects of potential concurrent use of CNS-acting medication and alcohol on the risk for falls. The National Health and Nutrition Examination Survey (NHANES) 2005-2010 data (n=3220) were employed to determine potential concurrent use of alcohol and CNS-acting medications. The effect of combined use of alcohol and CNS-acting medications on risk of falls was assessed using logistic regression modeling and adjusting for confounders. Alcohol consumption was measured by the quantity-frequency method and the National Institute on Alcohol Abuse and Alcoholism (NIAAA) recommended drinking limits were utilized in all analyses. Results: In the MCBS study, 5.6% of the older adults were identified as at-risk drinkers. Adults aged between 65-74 years, being male, non-married, former or current smoker, and having no comorbid conditions were factors associated with at-risk drinking. In the NHANES study, 8.9% reported potential concurrent use of alcohol and CNS-acting medication. Use of at least one CNS-acting medication and drinking excessive alcohol, or binge drinking, was significantly associated with odds of falling. Conclusion: Hazardous alcohol use is common among older adults. A substantial proportion of older adults may concomitantly consume alcohol and CNS-acting medications. Odds of falling are greater in the presence of high alcohol intake and CNS-acting medication use. It is important for health care professionals to warn patients against excessive alcohol consumption. Increasing awareness of this issue among older adults and caregivers may help prevent falls. Contributions from healthcare professionals in the form of screening for potentially harmful alcohol use, prescription monitoring, and initiating counseling may help to reduce older adults’ risk for falls or other adverse effects.

Thesis (MSc (Hons.)Health) -- University of Western Sydney, Macarthur, 2000.
"March 2000" "A thesis presented to the University of Western Sydney Macarthur in partial fulfilment of the requirements for the Degree of Master of Science (Hons) Health" Bibliography: leaves 90-101.

Notre étude s'est intéressée aux effets de l'alcoolisation chronique sur la production de monoxyde d'azote dans le système nerveux central. L'activité de la NOS a été mesurée avec un dosage des nitrites (avec le réactif de Griess) ainsi qu'un dosage de la [3H]L-citrulline qui a permis de déterminer les paramètres cinétiques de l'enzyme. Les taux d'ARN messagers (ARNm) ont été mesurés par des techniques de RT-PCR quantitative et semi-quantitative, utilisant respectivement des ARN délétés et les ARNm de la G3PDH comme standards. Nos résultats ont montré que l'éthanol potentialise l'induction de la NOS 2 (NOS inductible) par les lipopolysaccharides et l'IL-1 (activité et taux de messagers), dans un modèle cellulaire de barrière hémato-encéphalique (cellules RBE4). Cette surproduction de NO qui altère la perméabilité de la barrière pourrait contribuer aux effets neurotoxiques de l'alcool. Chez le rat alcoolisé, l'activité et les taux d'ARNm de la NOS 1 sont modifiés de façon différente selon l'aire cérébrale étudiée (cortex frontal, hippocampe et striatum) ; suggérant une différence de sensibilité à l'alcool entre les structures cérébrales. Le traitement chronique par le MK-801 (0,1 mg/kg/j) antagonise l'effet de l'alcoolisation sur les taux d'ARNm dans l'hippocampe et le striatum, montrant que les récepteurs NMDA régulent l'expression de la NOS 1 dans les processus d'alcoolisation. Ni la nitrendipine (20 mg/kg/j), ni le 7-nitroindazole (25 mg/kg/j) n'ont modifié les effets de l'alcoolisation chronique sur les taux d'ARNm de la NOS 1. L'injection par voie intracérébroventriculaire d'un oligodéoxynucléotide antisens dirigé spécifiquement contre les ARNm de la NOS 1 diminue significativement la consommation d'alcool et la préférence, sans modification de l'évolution pondérale des animaux relativement aux animaux non traités. L'injection d'un oligodéoxynucléotide mismatch diminue la consommation d'alcool mais aussi la prise de poids des rats, imputable à un effet toxique de cet oligodéoxynucléotide. Au total, nous avons, pour la première fois clairement démontré que l'alcoolisation chronique était associée à une modification de l'activité et de l'expression de la NOS 1. Cet effet est lié à l'activité des récepteurs NMDA. Ces deux voies de production centrale de NO devront être explorées dans la recherche d'outils thérapeutiques de la dépendance alcoolique.

Nasal administration of analgesics for achieving rapid pain relief is currently a topic of great interest. The blood-brain barrier (BBB) restricts access to the central nervous system (CNS) for several central-acting drugs, such as morphine and dihydroergotamine, which results in a substantial effect delay. Evidence for the olfactory transfer of drugs from the nasal cavity to the CNS after nasal administration, bypassing the BBB, is available for both animals and humans. The aims of this thesis were to study the olfactory transfer of morphine to the CNS after nasal administration, and to compare the nasal transport of analgesic drugs across nasal respiratory and olfactory mucosa. In vivo studies in rodents demonstrated that morphine is transferred via olfactory pathways to the olfactory bulbs and the longitudinal fissure of the brain after nasal administration. Further, olfactory transfer of morphine significantly contributed to the early high morphine brain hemisphere concentrations seen after nasal administration to rats. Olfactory transfer was tracked by collecting and analysing brain tissue and blood samples after right-sided nasal administration and comparing the results to the situation after i.v. administration. The olfactory transfer was also visualised by brain autoradiography. In vitro studies indicated that the olfactory mucosa should not be a major barrier to the olfactory transfer of dihydroergotamine or morphine, since transport of these drugs was no more restricted across the olfactory mucosa than across the nasal respiratory mucosa. The in vitro studies were performed using the horizontal Ussing chamber method. This method was further developed to enable comparison of drug transport across nasal respiratory and olfactory mucosa which cannot be achieved in vivo. In conclusion, these analgesic drugs showed potential for olfactory transfer, and access to the CNS by this route should be further investigated in humans, especially for the drugs with central effects that are currently under development for nasal administration.

Methylenedioxymethamphetamine (MDMA) popularly known as "Ecstasy" continues to gain popularity as a recreational drug that has been shown to increase serotonin and dopamine levels. The present study has demonstrated that repeated exposure to MDMA produces long-term damage to serotonergic and dopaminergic neurons in various regions of the rat brain.

Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências Farmacêuticas
Os neurotransmissores e neuromoduladores, são moléculas do sistema nervoso que desempenham um papel fundamental na comunicação intercelular. Quando estimulados os neurónios libertam estas moléculas que posteriormente vão atuar em recetores pré e/ou pós-sinápticos, desencadeando uma resposta biológica. A comunicação intercelular no sistema nervoso central exige um controlo rigoroso da duração e intensidade da ação de um neurotransmissor num determinado alvo. Os neurotransmissores podem ser excitatórios ou inibitórios dependendo do recetor que é ativado. As drogas de abuso, como o álcool, as metanfetaminas, a cocaína, a heroína, o LDS e a cannabis, influenciam a comunicação entre as células nervosas ao alterar a forma como os neurotransmissores transmitem sinais (informação) de neurónio para neurónio. As drogas possuem diversas ações psicotrópicas que vão desde a supressão de sensações negativas à potenciação de emoções positivas. Além disso, estão associadas a diferentes graus de toxidade, bem como a efeitos adversos graves, a nível mental e físico, e dependência. Grande parte da ação das drogas de abuso deve-se a alterações na transmissão sináptica. Neurotransmitters and neuromodulators are molecules that are part of the nervous system and play a fundamental role in the intercellular communication. When stimulated, the neurons release these molecules that will then act on pre or post-synaptic receptors, triggering a biological response. The intercellular communication in the central nervous system requires a rigorous control on the duration an intensity of a neurotransmitter action on a determined target. Neurotransmitters may be excitatory or inhibitory depending on the receptor that is activated. Drug abuse, such as alcohol, methamphetamines, cocaine, heroin, LSD and cannabis influence the communication between nervous cells by altering the way neurotransmitters transmit signals (information) between neurons. Drugs have different psychotropic actions, from the suppression of negative sensations to the potentiation of positive emotions. Besides, they are associated to different levels of toxicity as well as to severe adverse physical and mental effects and dependency. A major part of the abuse drugs action is due to alterations in the synaptic transmission.

碩士
國立臺灣大學
藥學研究所
93
Compounds of tricyclic structure play a role in the development of antidepression and antipsychotic drugs. These drugs possess similar structural characteristics but have different targets. Therefore, the issue of selectivity of these drugs still remains to be improved. The pharmaceutical chemistry and the action mechanism of these drugs have been clarified to a great extent. Based on these, this study was aimed to add pharmacophores to a naturally abundant new tricyclic-like skeleton by appropriate chemical reactions to produce some unique compounds for further pharmacological study. The tricyclic-like compound used as starting material in this study is a pavine alkaloid (-)-caryachine N-metho salt, which is abundant in Cryptocarya chinensis. This quaternary ammonium salt was converted into the key intermediate (-)-O-benzylnorcaryachine via three steps, i.e. O-benzylation, and two successive N-demethylation reactions (4oN → 3oN, 3oN → 2oN). Some pharmacophores such as 3-(4-alkylpiperazin-1-yl)propyl group were selected from clinically used drugs. They were synthesized starting from piperazine or morpholine by appropriate N-alkylation procedure. Coupling of (-)-O-benzyl norcaryachine with these halogenated pharmacophores via N-alkylation followed by deprotection yielded two types of products, i.e. (-)-N-3-piperazin-1-yl propylnorcaryachine (48-53) and (-)-N-3-morpholinopropylnorcaryachine (55). During this study, (-)-N,N’-alkenylbisnorcaryachine (59 and 60) were also prepared unexpectedly by reacting the secondary amine with 1,2-dihaloethane or 1,3-dihalopropane in moderate yields. The CNS activity of these prepared compounds will be elucidated using the clinically used drugs as positive control. Hopefully, some SAR will be drawn and the result will be served as a reference for further exploration of CNS drugs.

碩士
國立臺灣大學
藥學研究所
97
According to molecular modeling analysis, compounds which have characteristic linkage with definite distance between nitrogen and oxygen play an important role in the development of anti-acetylcholinesterase drugs. These drugs possess similar structural characteristics but have different targets. Therefore, the issue of activity and selectivity of these drugs still remains to be verified. The pharmaceutical chemistry and the action mechanism of these drugs have not been explorded to a great extent. Based on these, this study aimed to modify the pharmacophores of the naturally abundant compounds exhibiting anti-acetylcholinesterase activity by unique appropriate chemical reactions to produce some unique compounds for further pharmacological study. The target compounds used as starting material in this article are pavine alkaloid, including (-)-caryachine N-metho salt (1) and (-)-crychine (7) which are abundant in Cryptocarya chinensis Hemsl. and lycorine which is abundant in C.asiaticumvar. sinicum. (-)-caryachine N-metho salt (1) was converted into 6R-iodo-N,O-dimethyl-6 secocaryachine (5) via three steps. (-)-crychine (7) was converted into the key intermediate dihydrosecocrychine (10) in three steps, including N-benzylation, Hofmann degradation and catalytic hydrogenation (3°N → 4°N, 4°N → 3°N, 3°N → 2°N). And also, N,N-cycloethano salt (11a), N,N-cyclobutano salt (11b) and N,N-cyclohaxano salt (11c) of dihydrosecocrychine (10) were prepared unexpectedly by reacting the secondary amine with 1,2-dihaloethane, 1,4-dihalobutane or 1,5-dihalopentane respectively. The lycorine (15), tertiary amine, from C. asiaticumvar. sinicum was converted into 4,5-dihydrohippadine (18) in three steps. The activities of these prepared compounds need to be assayed by comparing with the clinically used drug, glanthamine as veritive control. Hopefully, from these studies some SAR will be drawn and the result will be served as a reference for further exploration.

The majority of the population in South Africa use traditional health care to treat various mental conditions. This thesis has two main objectives; to bring together a comprehensive and detailed record of psychotropic plants used in southern Africa by indigenous peoples for medicinal or cultural purposes. Secondly, this research attempts to investigate the validity and rationale of the use of these plants by screening them in various biological assays for psychotropic activity. Plants were selected, based on their traditional use and availability, and were screened in four assays, which detect biological activity of a useful nature. A number of in vitro enzymatic and neuronal signal transduction assays were employed in this thesis, the inhibition of the serotonin reuptake transporter protein (SERT); inhibition of catabolic enzymes (e.g. acetylcholinesterase, monoamine oxidase); GABAA- benzodiazepine receptor binding. The influence of legislation, past and present, on the state of traditional medicine is highlighted. Aspects of the philosophies and practises of the various practitioners of South African traditional medicine will be discussed. An annotated list compiled from available ethnobotanical literature of plants traditionally used for central nervous system-related purposes is provided. It contains more than 330 species, from 94 families, which are currently used or have been used for cultural, medicinal and recreational purposes related to the central nervous system (CNS). Where available, information pertaining to plant part used, preparation method, dosage, route of administration, known and potentially active constituents are included. Seventy five extracts from 34 indigenous plant species used in South African traditional medicine or taxonomically related to these were investigated for their affinity to the serotonin reuptake transport protein, making use of an in vitro [3H]-citalopram serotonin reuptake transport protein binding assay. Aqueous and 70% ethanolic extracts of various plant parts were screened and 45 extracts derived from 15 plant species showed affinity. The affinity of 12 extracts from four plants was characterized as high (more than 50% inhibition at 5, 1, and 0.5 mg/ml). Plant species with high affinity to the serotonin reuptake transport protein included Agapanthus campanulatus, Boophone disticha, Datura ferox and Xysmalobium undulatum. Agapanthus campanulatus yielded high activity in aqueous extracts from leaves and flowers. B. disticha showed high activity both in aqueous and ethanolic extracts of leaves and bulbs. D. ferox showed high activity in aqueous extracts from the seeds and X. undulatum showed high activity in the ethanolic extract of the whole plant. Two compounds, buphanadrine and buphanamine, were isolated by bioassay-guided fractionation on vacuum-liquid-chromatography (VLC) and preparative thin-layer-chromatography (TLC) from B. disticha. The structures of the compounds were determined by 1H and 13C NMR. Fractions were tested for affinity to the serotonin transporter in a binding assay using [3H]-citalopram as a ligand. The IC50 values of buphanidrine and buphanamine were 274 ìM (Ki = 132 ìM) and 1799 ìM (Ki = 868 ìM), respectively. The two alkaloids were also tested for affinity to the 5HT1A receptor, but only showed slight affinity. Aqueous and ethanol extracts of 43 plants that are traditionally used to treat against epilepsy and convulsions were initially tested in the GABAA-benzodiazepine receptor binding assay, where the binding of 3H-Ro 15-1788 (flumazenil) to the benzodiazepine site is measured. The GABAA-benzodiazepine receptor complex is involved in epilepsy and convulsions. Out of the 118 extracts tested, one aqueous and 18 ethanol extracts showed activity. The most active extracts were the ethanolic leaf extracts of Searsia tridentata, Searsia rehmanniana and Hoslundia opposita and the ethanolic corm extract of Hypoxis colchicifolia, which all showed good dose-dependent activity. A further forty-six ethanol extracts from another 35 species, both indigenous and exotic that are traditionally used predominantly as sedatives or to treat various CNS-related ailments were tested in the GABAA-benzodiazepine receptor-binding assay. Out of the 46 extracts tested, seven showed good activity and 10 showed moderate activity. The most active extracts were the ethanolic leaf extracts of Arctopus echinatus, Artemisa afra, four Helichrysum species and Mentha aquatica which all showed good dose-dependent activity. Two biflavonoids with activity in the 3H-Ro 15-1788 (flumazenil) binding assay were isolated by high pressure liquid chromatography (HPLC) fractionation of the ethanol extract of the leaves from Searsia pyroides. The structures of the two biflavonoids were elucidated by nuclear magnetic resonance spectroscopy (NMR) to be agathisflavone and amentoflavone. Agathisflavone and amentoflavone competitively inhibited the binding of 3H-Ro 15-1788 with a Ki of 28 and 37 nM, respectively. Extracts of Searsia dentata and Searsia pentheri were not as active as the extract from Searsia pyroides; both were found to contain apigenin and agathisflavone. The monomer apigenin, agathisflavone and amentoflavone were fitted into a pharmacophore model for ligands binding to the GABAA receptor benzodiazepine site. This reflected the affinities of the compounds in the [3H]-flumazenil binding assay. Mentha aquatica, a mint that is found in Europe and Africa, is used in Zulu traditional medicine for spiritual purposes. The ethanolic leaf extract showed a strong affinity to the GABA-benzodiazepine receptor. Viridiflorol from the essential oil and (S)-naringenin from an ethanolic extract was isolated by bioassay-guided fractionation using binding to the GABA-benzodiazepine site. Viridiflorol had an IC50 of 0.19 M and (S)-naringenin of 0.0026 M. Twenty plants used in Zulu traditional medicine for several CNS-related ailments were screened for MAO inhibition and specific MAO-B inhibition activity. MAO-B inhibitors are currently employed in the treatment of neurodegenerative related illnesses such as Parkinson's and Alzheimer's diseases. A photometric peroxidase linked assay was used to determine the inhibition of the oxidative deamination of tyramine by MAO isolated from rat liver. Ruta graveolens exhibited the best MAO inhibitory activity (ethyl acetate leaf extract = IC50 5 ± 1 ìg/ml, petroleum ether extract = 3 ± 1 ìg/ml) and specific MAO-B inhibition (ethyl acetate leaf extract = IC50 7 ± 6 ìg/ml petroleum ether extract = 3 ± 1 ìg/ml). Schotia brachypetala, Mentha aquatica and Gasteria croucheri also exhibited good MAO-B inhibition activity. Six extracts of varying polarity of Mentha aquatica were tested in a photometric peroxidase linked MAO bioassay. The 70% ethanol extract had highest inhibitory activity. (S)-Naringenin was isolated from the extract by bioassay guided fractionation on VLC and preparative TLC. The structure of the compound was determined by 1H, 13C and 13C-DEPT NMR and optical rotation. The IC50 values for MAO inhibition by naringenin were 342 ± 33 ìM for the rat liver mitochondrial fraction, 955 ± 129 ìM for MAO-A and 288 ± 18 ìM for MAO-B respectively. South African traditional medicine clearly utilizes many botanical species with CNS-related activity. Only a small number of the more than 330 southern African plant species reported to treat or alter the CNS have been scientifically evaluated. To date very few of the active compounds have been isolated and identified.
Thesis (Ph.D.)-University of KwaZulu-Natal, Pietermaritzburg, 2009.

The World Health Organization (WHO) estimates that one billion people worldwide suffer from central nervous system (CNS) disorders [1]. One major issue in treating these disorders is inadequate drug penetration which can be attributed to an effective blood-brain-barrier that limits passage across blood vessels. Low diffusivity of large classes of drug compounds restricts transport across blood vessel walls and subsequent passage through surrounding brain tissues. Tissue transport is emerging as an increasingly important area of research in drug delivery since the vast majority of therapeutic agents must traverse this space before reaching their targets.

Brain stroke is considered as one of the three diseases that threaten human health all over the world. Hypertension and cerebral arteriosclerosis are thought to be the most dangerous risk factors of brain stroke, and they frequently occur together, leading to ischemia of brain tissue. Unfortunately, it is not clear whether the pathological changes resulting from hypertension are related to those resulting from cerebral arteriosclerosis. There have been no ideal animal models mimicking the pathological changes in such a combined condition. In this thesis, an animal model of hypertension combined with cerebral arteriosclerosis in rats was established by occlusion of both the left and right common carotid arteries in spontaneous hypertension rats. Pien Tze Huang (PTH), a reputed traditional Chinese medicinal complex, contains Radix notoginseng, snake bile, calculus bovis, and musk and some other components that are known to protect vessels and cells from injuries. Since different tissue injuries share many common cellular mechanisms, the protection by PTH to in nerves and the circulation systems may also be benefical to cerebrovascular conditions as well. In present experiments, PTH was used to treat hypertension rats that also developed chronic brain ischemia as a result of the bilateral carotid occlusion, and its protective role for neurons and blood vessels was investiaged.
From the data above, more severe damage could be caused by hypertension combined with chronic ischemia. The model of SHR with bilaterally occluded common carotid artery can be used to study pathological changes resulted from hypertension combined with chronic ischemia. PTH was able to protect neurons in stroke.
In the initial part of the work, patients from clinics in two cities in South and North China were compared and analysed; they had been suffering from brain ischemic stroke. About two thirds of the stroke patients were found to have hypertension before the onset of stroke. Their prognosis was significantly worse than those stroke patients without hypertension. In the hypertensive rats with occluded arteries, mean of functional magnetic resonance imaging (fMRI) examination showed that brain blood flow was very weak or even transiently became undetectable at the beginning of the acute stage of brain ischemia, but was restored one hour after the occlusion surgery. In addition, pathological changes in brains of hypertensive rats with induced brain ischemia (carotid occlusion) were examined by Nissl staining, TUNEL staining, cell death ELISA and anti-oxidation enzymes. At day 15 after ischemia, a large number of pyramid cells in the hippocampus of SHR were lost and a great deal of apoptotic cells were found in the CA1 of the hippocampus, while activities of some enzyme including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) were increased. At day 30 and 60, some degenerative changes appeared to have subsided and the cells appeared morphologically normal. The activities of the above enzymes were also decreased at day 60. In WKY control rats with normal blood pressure, neurons in the CA1 were found less damaged after the bilateral carotid occlusion. It was found that apoptotic and dead cells were significantly reduced in rats with hypertension combined with chronic brain ischemia if they had been pre-treated with PTH. Moreover, brain stroke damage was less severe in this pretreated rats.
Zhang, Lihong.
"March 2010."
Adviser: WH Kwong.
Source: Dissertation Abstracts International, Volume: 72-01, Section: B, page: .
Thesis (Ph.D.)--Chinese University of Hong Kong, 2010.
Includes bibliographical references (leaves 116-134).
Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Abstract also in Chinese.

Relatório de Estágio do Mestrado Integrado em Ciências Farmacêuticas apresentado à Faculdade de Farmácia
O estágio curricular em farmácia comunitária, inserido no segundo semestre do quinto ano, tem como finalidade colocar em prática os conhecimentos adquiridos ao longo de todo o curso. Prepara-nos para a realidade do que é o contacto direto com os doentes e ajuda-nos a perceber quais as nossas principais dúvidas, inseguranças e o que pode ser melhorado, a fim de um maior sucesso no início da carreira profissional.Este relatório é elaborado segundo uma análise SWOT, onde são discriminados os pontos fortes, pontos fracos, oportunidades e ameaças deparadas ao longo do estágio. O sistema nervoso central (SNC) é constituído por células neuronais que, entre outras funções, libertam neurotransmissores e neuromoduladores responsáveis pela comunicação química entre as células. Estas moléculas podem ser eletroativas e, portanto, serem detetadas por técnicas eletroquímicas como a amperometria e a voltametria cíclica de varrimento rápido.O estudo, deteção e monitorização no espaço extracelular foi possível com a descoberta, aperfeiçoamento e miniaturização de microelétrodos implantados in vivo, dado que permitem a deteção e monitorização da neurotransmissão em tempo real e com elevada resolução espacial.Os microelétrodos de fibra de carbono, dadas as vantagens que apresentam, foram os primeiros sensores químicos a revelar grande utilidade no estudo e monitorização de neurotransmissores e neuromoduladores ex vivo em fatias de cérebro e in vivo em animais anestesiados e acordados.
The curricular internship in a community pharmacy, inserted within the second semester of the fifth year has the purpose of putting into practice the knowledge acquired during the course. It prepares us for the reality of direct contact with patients and helps us understand which are our biggest doubts, insecurities and what can be improved in order to have greater success in the early stages of the professional career.This report is elaborated according to a SWOT analysis, where the strong points, weak points, opportunities and potential threats that might be experienced during the internship are discussed and evaluated. The central nervous system (CNS) is constituted by neuronal cells which, amongst other functions, release neurotransmitters and neuromodulators responsible for the chemical communication between cells. These molecules can be electroactive and, as such, be detected by electrochemical techniques such as amperometry and fast scanning cyclic voltammetry.The study, detection and monitorization in the extracellular space was made possible by the discovery, enhancement and miniaturization of microelectrodes implanted in vivo, given that these allow for detection and monitorization of neurotransmissions in real time and with high special resolution.The carbon fiber microelectrodes, given their advantages these allow for, were the first chemical sensors to reveal great utility in the study and monitorization of neurotransmitters and neuromodulators ex vivo in slices of brain and in vivo in anesthetized and awake animals.