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Kyles, Andrew Edward. "Evaluation of the spinal and supraspinal roles of antinociceptive drugs in sheep." Thesis, University of Bristol, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.389998.
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Rahman, Shazia. "Use of (2S)-pyroglutamic acid for the synthesis of glutamate agonists and antagonists and 1-#beta#-methylcarbapenams." Thesis, University of Sussex, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.264581.
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Sekhar, Gayathri Nair. "The transport of CNS-active cationic drugs across the blood-brain barrier." Thesis, King's College London (University of London), 2016. https://kclpure.kcl.ac.uk/portal/en/theses/the-transport-of-cnsactive-cationic-drugs-across-the-bloodbrain-barrier(41ff27df-17ce-4edc-82fe-c4169edf801c).html.
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The physical, transport, and metabolic barriers presented by the cerebral microvessel endothelium - the blood- brain barrier (BBB) - protect the brain from damage from toxic substances and ensure the delivery of nutrients required for the functioning of the brain thus creating a stable neuronal microenvironment. However, the BBB poses a challenge to many CNS-active drugs which must cross the BBB to reach their target. Of the drugs that target the brain, many are cationic at physiological pH making their transport into the brain even harder with the additional potential for drug-drug interactions. Therefore, this thesis has been an attempt to understand the transport characteristics of cationic therapeutic drugs across the BBB. One of the foci of this study has been the anti-human African trypanosomiasis (HAT) drugs pentamidine and e ornithine, both positively charged at physiological pH. Pentamidine is a stage 1 drug for HAT that was previously found in our laboratory to not cross the mouse BBB in vivo as it was a substrate for eux transporters, particularly P-glycoprotein. The present study observed that pentamidine is taken up by Organic Cation Transporter 1 (OCT1) in hCMEC/D3 (human) and bEnd.3 (mouse) cell lines where it accumulates and is euxed by ATP-dependent mechanisms out of the cell. In addition, the predominant localisation of OCT1 at the luminal membrane of the BBB may explain the low permeability of pentamidine into the brain. Considering pentamidine is a substrate for P-glycoprotein at the BBB, inhibitors of Pglycoprotein were used to increase pentamidine delivery into the brain. Pluronic® triblock polymers P85, P105, and F68 were thus chosen for their proven ability to inhibit P-glycoprotein and for their promising results from clinical trials. They were used at concentrations of 0.01%, 0.025%, 0.1%, and 0.5% along with pentamidine in an attempt to increase its delivery across the BBB, concomitantly reducing any side-e ects. In vitro assays carried out on MDCK-hMDR cell line suggested high concentrations of P85 and P105 were cytotoxic even though P85 was able to signi cantly increase pentamidine permeability at 0.5% and 0.1%. Greater speci city to a target could circumvent toxicity issues in the future. The second anti-HAT drug studied was e ornithine that treats stage 2 of HAT. To treat stage 2 of the disease it must cross the BBB, yet it was not found to cross the BBB in the in vivo study on mice carried out in our laboratory. Results obtained from assessing the accumulation of e ornithine in hCMEC/D3 and bEnd.3 cell lines, the in vitro models of the BBB, also suggested limited entry of e ornithine into the BBB. Nonetheless, the assays indicated that e ornithine could be a weak substrate for system y+ at the BBB. There was also evidence for its interaction with OCTs in the bEnd.3 cell line. Second part of the thesis focussed on the antipsychotic drugs haloperidol and amisulpride, both cationic drugs at physiological pH. Haloperidol, an extensively used drug both as an antipsychotic and for palliative care, has the potential to interact with other drugs at the BBB. Haloperidol was found to be a substrate for OCTs at the BBB in both hCMEC/D3 and bEnd.3 cell lines and was found to accumulate readily inside the BBB cells. Similarly, amisulpride is an antipsychotic that is also used to treat delusions and aggression in Alzheimer's disease (AD). Previous studies found increased central dopamine receptor occupancy in AD patients when amisulpride was administered at very low doses. Unlike haloperidol, amisulpride had very low accumulation inside the BBB cells. Results suggested amisulpride to be a substrate for the OCTs and the eux transporters MATE1 and PMAT at the BBB. Amisulpride entry into the brain was also tested in wildtype and transgenic AD mice to nd that amisulpride entry into the transgenic mice brains was signi cantly greater than wildtype mice brains and this was not due to a `leaky' BBB of the AD model. Changes to the expression levels of OCT1, 2, 3 and P-glycoprotein transporters in wildtype and AD model mice BBB were determined using Western blotting and no di erences were found. Further exploration of capillaries isolated from human brain samples from control and AD a ected patients was carried out and signi cant region-speci c changes to the expression levels of MATE1 was observed. There was also a tendency for region-speci c decrease in PMAT expression levels. MATE1 and PMAT are proton-dependent transporters that eux substrates out of the BBB. This decrease in eux transporter expression at the BBB of AD patients could explain the increased sensitivity in AD patients to amisulpride.
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Lloyd, Edward John, and mikewood@deakin edu au. "A common structural basis for central nervous system drug design." Deakin University. School of Biological Sciences, 1986. http://tux.lib.deakin.edu.au./adt-VDU/public/adt-VDU20050902.115505.
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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.
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Berggård, Cecilia. "Transcription Factor AP-2 in Relation to Personality and Antidepressant Drugs." Doctoral thesis, Uppsala University, Department of Neuroscience, 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4638.
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The CNS monoaminergic systems are considered as the head engine regulating neuropsychiatric functions and personality. Transcription factor AP-2 is known to be essential for the development of the brainstem including the monoaminergic nuclei, and has the ability to regulate many genes in the monoaminergic systems. The ability of transcription factors to regulate specific gene expression, has lately made them hot candidates as drug targets. In this thesis, results indicating a role of AP-2 in the molecular effects of the antidepressant drugs citalopram and phenelzine, are presented.
A polymorphism in the second intron of the gene encoding AP-2ß has previously been associated with anxiety-related personality traits as estimated by the Karolinska Scales of Personality (KSP). In this thesis, results confirming this association, gained by using a larger material and several different personality scales, are presented. Furthermore, data is presented showing an association between the activity of platelet monoamine oxidase, a trait-dependent marker for personality, and the genotype of the AP-2ß intron 2 polymorphism.
The functional importance of the AP-2ß intron 2 polymorphism has not yet been elucidated. Included in this thesis are results showing that the AP-2ß intron 2 polymorphism is not in linkage disequilibrium with the only other described polymorphism in the AP-2ß gene, i.e. in the AP-2ß promoter (-67 G/A). Introns have in several studies been shown to include binding sites for regulatory proteins, and thus, to be important in transcriptional regulation. Results are presented demonstrating that one human brain nuclear protein binds only to the long variant of the AP-2ß intron 2 polymorphism. If this protein is involved in the regulation of the AP-2ß gene, it would affect the expression levels of the AP-2ß protein.
In general, this thesis further establishes the role of transcription factor AP-2 as a regulatory factor of importance for personality and monoaminergic functions.
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Patel, Sulay H. "Effects of HIV-1 Tat and drugs of abuse on antiretroviral penetration inside different CNS cell types." VCU Scholars Compass, 2018. https://scholarscompass.vcu.edu/etd/5685.
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Human immunodeficiency (HIV) infection can result in neurocognitive deficits in about one-half of infected individuals. Despite excellent systemic effectiveness, restricted antiretroviral penetration across the blood-brain barrier (BBB) is a major limitation in fighting HIV infection within the central nervous system (CNS). Drug abuse exacerbates cognitive impairment and pathologic CNS changes in HIV-infected individuals. This work investigates the effects of the HIV-1 protein, Tat, and drugs of abuse on factors affecting drug penetration into the brain.
Firstly, an in vitro model of the blood-brain barrier was built to study effects of HIV-1 Tat and methamphetamine (Meth) on integrity and function of the BBB, in turn how HIV-1 Tat and meth will affect antiretroviral penetration into the brain. We found that co-exposure HIV-1 Tat and Meth results in inhibition or impairment of P-glycoprotein activity at the BBB. Also, simultaneous inhibition of P-glycoprotein (P-gp) and Multidrug Resistant Protein -1 (MRP-1), by verapamil and MK-571 causes an increase in accumulation of atazanavir inside the primary human brain endothelial cells.
Secondly, we developed and validated the method for simultaneous determination of tenofovir, emtricitabine, and dolutegravir in cell extracts of CNS cells. This method was used to study how HIV-1 Tat and/or morphine affects antiretroviral penetration in CNS cells like human brain microvascular endothelial cells, human astrocytes, human microglia, and human pericytes. We found that in untreated cells, accumulation of antiretroviral drugs was higher in hCMEC/D3 cells compared to other CNS cell types. Also, HIV-1 Tat and/or morphine had no significant effect on antiretroviral penetration amongst these cell types. Overall, the rank order of intracellular accumulation observed in treated and untreated cells was dolutegravir > emtricitabine > tenofovir.
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Garcia-Mijares, Miriam. "Efeito da administração aguda e repetida de fencanfamina sobre o valor reforçado do estímulo." Universidade de São Paulo, 2000. http://www.teses.usp.br/teses/disponiveis/47/47135/tde-14092006-114120/.
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A fencanfamina (FCF) é um agonista indireto do sistema dopaminérgico que tem efeitos neurais e comportamentais similares aos observados com outras drogas estimulantes como a anfetamina ou a cocaína (COC). O presente trabalho teve como objetivo avaliar o efeito da administração aguda e repetida de FCF sobre o valor reforçador dos estímulos (Re). Foi usada a equação de igualação proposta por Herrnstein (1970) para avaliar esse efeito motivacional Foi também medido o efeito dessa droga sobre a taxa de respostas e a capacidade motora (k). Três experimentos foram realizados. Nos três experimentos o efeito da FCF foi testado em ratos treinados em um esquema múltiplo de sete componentes de diferentes Vls. Nos Experimentos 1 e 2 (E1 e E2, respectivamente) três doses agudas de FCF (0,88 mg/kg, 1,75 mg/kg e 3,5 mg/kg) foram administradas i.p. No E1 o reforçador foi água e no E2 reforçador foi sacarose. Em ambos os experimentos, o efeito da droga sobre os parâmetros estudados foi semelhante: as três doses de FCF aumentaram a taxa de respostas e diminuíram Re, sem alterar k. No Experimento 3, seis injeções de veiculo (Grupo VEI) ou de 1,75 mg/kg de FCF (Grupo DROGA) foram administradas i.p. intermitentemente aos sujeitos a fim de promover sensibilização comportamental. Após sete dias de suspensão da droga, foi administrada uma dose de 0,88 mg/kg de FCF em animais de ambos os grupos e foi medido o efeito sobre a taxa de respostas, k e Re. Os resultados obtidos mostraram que a administração repetida de FCF não alterou o efeito dessa droga sobre os parâmetros estudados. Os resultados são consistentes com os dados que mostram que a FCF tem efeitos sobre o comportamento similares aos de outros estimulantes, e apoiam a hipótese de que o aumento da taxa de respostas observado após a administração da FCF está relacionado a mudanças no valor reforçador dos estímulos, o que sugere um efeito motivacional e não motor. Além disso, os resultados sustentam as hipóteses que relacionam o sistema dopaminérgico ao processo do reforço. A falha na obtenção de sensibilização após a administração repetida de FCF poderia estar relacionada à dose utilizada ou ao numero de injeções administradas.Fencanfamina (FCF) is an indirect dopaminergic agonist with neural and behavioral effects similar to those observed for other stimulant drugs such as the amphetamine or cocaine (COC). The aim of the present investigation was to evaluate the effect of acute and repeated administration of FCF on the reinforcing value (Re) taken as a motivational index. The Herrnstein hyperbole equation (1970) was used to evaluate this motivacional effect. The effects of FCF on response rate and motor capacity (k) where also observed. Three experiments were conducted. In all of them the effect of FCF was tested on rats trained on seven VI multiple schedule. In Experiments 1 and 2 (E1 and E2, respectively) three acute doses of FCF (0.88 mg/kg, 1.75 mg/kg and 3.5 mg/kg) were administered (i.p.) The reinforcer was water (E1) or sacarose (E2). In both experiments, the effect of the drug on the parameters studied was similar: the three doses of FCF increased the response rate, decreased Re and had no effect on k. In Experiment 3, six injections of vehicle (VEI Group) or 1.75 mg/kg of FCF (DROGA Group) were intermittently administered (i.p.) in order to promote sensitization. Seven days after drug withdrawal a single dose of 0.88 mg/kg of FCF was administered to animals in both groups and the effect on response rate, k and Re was measured. Results showed that repeated administration of FCF did not change the effect of this drug on the parameters investigated. These results are consistent with the evidence showing that FCF has behavioral effects similar to those reported for other stimulants and support the interpretation that increases in response rate are primarily related to changes in reinforcing value. Thus they probably reflect a motivational effect of the drug. Moreover, the results support the hypotheses that associate the dopaminergic system to the process of reinforcement. It is speculate that the failure to obtain sensitization after repeated administration of FCF could be related to dosage or number of injections.
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Mercolini, Laura <1979>. "Development of original analytical methods for the therapeutic drug monitoring of CNS druges: Antipsychotics, Antidepressants and Anxiolytics-hypnotics." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2010. http://amsdottorato.unibo.it/2713/.
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Great strides have been made in the last few years in the pharmacological treatment of neuropsychiatric disorders, with the introduction into the therapy of several new and more efficient agents, which have improved the quality of life of many patients. Despite these advances, a large percentage of patients is still considered “non-responder” to the therapy, not drawing any benefits from it. Moreover, these patients have a peculiar therapeutic profile, due to the very frequent application of polypharmacy, attempting to obtain satisfactory remission of the multiple aspects of psychiatric syndromes. Therapy is heavily individualised and switching from one therapeutic agent to another is quite frequent. One of the main problems of this situation is the possibility of unwanted or unexpected pharmacological interactions, which can occur both during polypharmacy and during switching. Simultaneous administration of psychiatric drugs can easily lead to interactions if one of the administered compounds influences the metabolism of the others. Impaired CYP450 function due to inhibition of the enzyme is frequent. Other metabolic pathways, such as glucuronidation, can also be influenced. The Therapeutic Drug Monitoring (TDM) of psychotropic drugs is an important tool for treatment personalisation and optimisation. It deals with the determination of parent drugs and metabolites plasma levels, in order to monitor them over time and to compare these findings with clinical data. This allows establishing chemical-clinical correlations (such as those between administered dose and therapeutic and side effects), which are essential to obtain the maximum therapeutic efficacy, while minimising side and toxic effects.
It is evident the importance of developing sensitive and selective analytical methods for the determination of the administered drugs and their main metabolites, in order to obtain reliable data that can correctly support clinical decisions. During the three years of Ph.D. program, some analytical methods based on HPLC have been developed, validated and successfully applied to the TDM of psychiatric patients undergoing treatment with drugs belonging to following classes: antipsychotics, antidepressants and anxiolytic-hypnotics. The biological matrices which have been processed were: blood, plasma, serum, saliva, urine, hair and rat brain. Among antipsychotics, both atypical and classical agents have been considered, such as haloperidol, chlorpromazine, clotiapine, loxapine, risperidone (and 9-hydroxyrisperidone), clozapine (as well as N-desmethylclozapine and clozapine N-oxide) and quetiapine. While the need for an accurate TDM of schizophrenic patients is being increasingly recognized by psychiatrists, only in the last few years the same attention is being paid to the TDM of depressed patients. This is leading to the acknowledgment that depression pharmacotherapy can greatly benefit from the accurate application of TDM. For this reason, the research activity has also been focused on first and second-generation antidepressant agents, like triciclic antidepressants, trazodone and m-chlorophenylpiperazine (m-cpp), paroxetine and its three main metabolites, venlafaxine and its active metabolite, and the most recent antidepressant introduced into the market, duloxetine. Among anxiolytics-hypnotics, benzodiazepines are very often involved in the pharmacotherapy of depression for the relief of anxious components; for this reason, it is useful to monitor these drugs, especially in cases of polypharmacy. The results obtained during these three years of Ph.D. program are reliable and the developed HPLC methods are suitable for the qualitative and quantitative determination of CNS drugs in biological fluids for TDM purposes.
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Jain, Anjana. "Delivery of Cdc42, Rac1, and Brain-derived Neurotrophic Factor to Promote Axonal Outgrowth After Spinal Cord Injury." Diss., Georgia Institute of Technology, 2007. http://hdl.handle.net/1853/16210.
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Injury severs the axons in the spinal cord causing permanent functional loss. After injury, a series of events occur around the lesion site, including the deposition of growth cone inhibitory astroglial scar tissue containing chondroitin sulfate proteoglycan (CSPG)- rich regions. It is important to encourage axons to extend through these inhibitory regions for regeneration to occur. The work presented in this dissertation investigates the effect of three proteins, constitutively active (CA)-Cdc42, CA-Rac1, and brain-derived neurotrophic factor (BDNF) on axonal outgrowth through CSPGs-rich inhibitory regions after spinal cord injury (SCI). Cdc42 and Rac1 are members of the Rho GTPase family and BDNF is a member of the neurotrophin sub-family. These three proteins affect the actin cytoskeleton dynamics. Therefore, Cdc42, Rac1, and BDNF promote axonal outgrowth.
The effect of CA-Cdc42 and CA-Rac1 on neurite extension through CSPG regions was determined in an in vitro model. Rac1 and Cdc42 s ability to modulate CSPG-dependent inhibition has yet to be explored. In this study, a stripe assay was utilized to examine the effects of modulating all three Rho GTPases on neurite extension across inhibitory CSPG lanes. Alternating laminin (LN) and CSPG lanes were created and NG108-15 cells and E9 chick dorsal root ganglions (DRGs), were cultured on the lanes. Using the protein delivery agent Chariot, the neuronal response to exposure of CA and dominant negative (DN) Rho GTPases, along with the bacterial toxin C3, was determined by quantifying the percent ratio of neurites crossing the CSPG lanes. CA-Cdc42, CA-Rac1, and C3 transferase significantly increased the number of neurites crossing into the CSPG lanes compared to the negative controls for both the NG108-15 cells and the E9 chick DRGs. We also show that these mutant proteins require the delivery vehicle, Chariot, to enter the neurons and affect neurite extension. Therefore, activation of Cdc42 and Rac helps overcome the CSPG-dependent inhibition of neurite extension.
In an in vivo study, CA-Cdc42 and CA-Rac1 were locally delivered into a spinal cord cavity. Additionally, BDNF was delivered to the lesion site, either individually or in combination with either CA-Cdc42 or CA-Rac1. The dorsal over-hemisection model was utilized, creating a ~2mm defect that was filled with an in situ gelling hydrogel scaffold containing lipid microtubules loaded with the protein(s) to encourage axons. The lipid microtubules enable slow release of proteins while the hydrogel serves to localize them to the lesion site and permit axonal growth. The results from this study demonstrate that groups treated with BDNF, CA-Cdc42, CA-Rac1, BDNF/CA-Cdc42, and BDNF/CA-Rac1 had significantly higher percentage of axons from the corticospinal tract (CST) that traversed the CSPG-inhibitory regions, as well as penetrate the glial scar compared to the untreated and agarose controls. Although axons from the CST tract did not infiltrate the scaffold-filled lesion, NF-160+ axons were observed in the scaffold. Treatment with BDNF, CA-Cdc42, and CA-Rac1 also reduced the inflammatory response, quantified by analyzing GFAP and CS-56 intensity for reactive astrocytes and CSPGs, respectively, at the interface of the scaffold and host tissue. Therefore, the local delivery of CA-Cdc42, CA-Rac1 and BDNF, individual and combination demonstrated the ability of axons to extend through CSPG inhibitory regions, as well as reduce the glial scar components.
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Fidanboylu, Mehmet. "Blood-CNS transport mechanisms in pathophysiology and drug delivery." Thesis, King's College London (University of London), 2013. https://kclpure.kcl.ac.uk/portal/en/theses/bloodcns-transport-mechanisms-in-pathophysiology-and-drug-delivery(2081d984-07fe-41aa-9f5b-54d1f33be9f2).html.
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The blood-CNS barriers form a highly selective biological firewall; regulating the passage of solutes between the blood and cerebral microenvironment. This thesis modelled the blood-CNS barriers in vivo to determine the transport of nutrients, metabolic products and drugs across these barriers, and was split into two main parts: 1. L-arginine and ADMA transport - Circulating levels of the cationic amino acid L-arginine and its endogenously produced homologue asymmetric dimethylarginine (ADMA) are in delicately poised equilibrium. Dysregulation of this balance has well-documented implications in cardiovascular disease and also more recently conditions of the brain, as ADMA is a potent inhibitor of nitric oxide synthase (NOS) enzymes, including the endothelial (eNOS) and neuronal (nNOS) isoforms. Until now it has been postulated that ADMA competes for transport across membranes via the same cationic transport system as L-arginine (system y+), however this hypothesis has surprisingly never been tested. The major contributors to transport of both amino acids were investigated to determine how their respective intracellular and extracellular concentrations affect transport across the blood-CNS barriers. These data also have strong relevance to other research areas due to the widespread influence of NO in physiological pathways in health and disease. At the time of writing, this study represents the first true characterisation of ADMA transport across any physiological membrane in vivo and reveals a likely mechanism for explaining ‘the L-arginine paradox’ – the clinical observation that NO-deficient patients respond well to oral supplementation with L-arginine even though [arginine]plasma is easily sufficient to saturate eNOS. 2. ‘NanoHAT’ - Efflux transporters expressed at the blood-CNS barriers remain one of the biggest hurdles for the efficient delivery of therapeutic agents to the brain. The anti-trypanosomal drug pentamidine was shown previously by our group to be a substrate for efflux from the blood-CNS barriers and does not ordinarily accumulate to pharmacologically relevant levels in the brain. Pluronic® copolymers are known biological response modifiers that are approved for use in humans and have generated a great deal of interest due to their ability to inhibit efflux transporters and spontaneously form micelles in solution. In this study, a coformulation of pentamidine and Pluronic® P85 was evaluated as a potential future treatment for CNS-stage Human African Trypanosomiasis, using a combination of in silico, in vitro, and in vivo methodologies. Combining our group’s knowledge and expertise in blood-brain barrier research with colleagues in Molecular Biophysics and Materials & Molecular Modelling has resulted in the creation of a ‘mini formulation-development pathway’ that can be utilised to optimise and develop formulations in the future.
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Arora, Priyanka. "Pharmacokinetic- Pharmacodynamic Investigations of Letrozole, a Potential Novel Agent for the Treatment of High-Grade Gliomas." University of Cincinnati / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1552398989110981.
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Svensson, Åsa. "Application of a New Logic to Old Drugs: Angiogenesis Inhibition in Neuroblastoma." Doctoral thesis, Uppsala University, Department of Medical Cell Biology, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3458.
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Neuroblastoma is one of the most common solid cancers of early childhood. In Sweden, approximately 10-15 cases occur annually. The overall five-year neuroblastoma survival in Europe is approximately 45%. Since cancer treatment involves drugs with risks of side effects in the growing child, there is a need for more effective and less toxic drugs. One new approach in cancer treatment is inhibition of tumor angiogenesis, i.e., of new blood vessel growth into the tumor. An angiogenesis inhibitor may be combined with cytostatic drugs to enhance the efficacy. The aim of this study was to investigate how drugs could be used to inhibit angiogenesis and tumor growth in a xenograft model of human neuroblastoma in nude mice.
The tumors express the angiogenesis stimulator vascular endothelial growth factor (VEGF) on both protein and mRNA levels. The angiogenesis inhibitors SU5416 (an inhibitor of VEGF signalling) and TNP-470 (an inhibitor of endothelial cell proliferation) inhibited angiogenesis in our model. TNP-470, however, inhibited angiogenesis without significant reduction of the tumor growth, in contrast to SU5416.
We also discovered that the cytostatic drug CHS 828 could cause regression of neuroblastoma tumors in the model when given orally at a low daily dose, alone or in combination with the angiogenesis inhibitor SU5416 or TNP-470.
Furthermore, a new use of the cardiac glycoside digoxin was found. Digoxin inhibited FGF-2 -stimulated bovine capillary endothelial cell growth in vitro, and inhibited angiogenesis in vivo in the chick chorioallantoic membrane assay (CAM). It also inhibited neuroblastoma growth by approximately 50% in our neuroblastoma model.
In conclusion, CHS 828 and digoxin represent two classes of drugs with potent antitumor effects that may be valuable in treatment of neuroblastoma, either alone or in combination with angiogenesis inhibitors.
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Ball, Kathryn. "Physiologically based pharmacokinetic modelling of the central nervous system : strategies for drug development." Thesis, Paris 5, 2014. http://www.theses.fr/2014PA05P630.
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Une étape critique au cours du développement de médicaments est la mesure ou la prédiction des concentrations du médicament dans un tissu cible, qui peuvent ensuite être liées à des mesures de leur efficacité ou leur toxicité. Les concentrations de médicaments ne pouvant être mesurées dans le cerveau humain, ils doivent être simulés ou prédits en utilisant des approches alternatives de modélisation. L'objectif de cette thèse est de développer in silico des approches de prédiction combinant à la fois des données précliniques in vitro et in vivo dans un modèle physiologique structuré, avec une stratégie translationnelle afin de permettre la simulation de concentrations totales et libres des médicaments dans le cerveau humain. Des modèles pharmacocinétiques physiologiques (PBPK) ont été développés dans cette thèse et évalués pour des médicaments de référence déjà sur le marché, et pour un médicament en cours de développement clinique dans l'industrie pharmaceutique. Ces modèles ont été développés à partir de stratégies de type « Bottom-up » sur la base de données in vitro pour la prédiction de la distribution des médicaments dans le cerveau et comparées à des méthodes de type «top-down » en utilisant des données in vivo. Cette thèse est une thèse sur article construite à partir de 5 articles scientifiques qui sont soit publiés soit en cours de soumission. Le premier article est une revue de la littérature publiée dans le Journal de l'AAPS. Cette revue discute les modèles PBPK disponibles actuellement et a permis d’élaborer des hypothèses de travail dans cette thèse afin de proposer des améliorations de ces modèles. Le deuxième article un article de recherche original publié dans Molecular Pharmaceutics. Cet article vise à démontrer l'élaboration d'une approche cohérente de modélisation pharmacocinétique chez le rat qui peut s’adapter en fonction de la quantité et de la qualité des données obtenues in vivo au cours du développement des médicaments. Un arbre de décision a été construit pour faciliter le paramétrage et la structure appropriée du modèle en fonction des données disponibles. Le troisième article est un article de recherche original publié dans Journal of Pharmaceutical Sciences. Cette étude porte sur le développement d'un modèle PBPK pour la prédiction de la pénétration cérébrale des médicaments, dans lequel son transfert à travers la BHE a été traité de façon mécanistique en séparant les paramètres régissant la quantité (perméabilité) à travers la BHE de sa liaison dans le tissu cérébral. Une stratégie de type vitro - vivo en fonction de la perméabilité des médicaments à travers les monocouches cellulaires in vitro a été proposé afin d'extrapoler la composante de transport actif du composé à l’aide de facteurs d’extrapolation (RAF). Deux autres articles sont en cours d’écriture ou soumis. Ces articles viennent compléter les approches de PBPK pour les médicaments du SNC décrites dans les deux autres articles originaux. Une dernière partie de la thèse constitue la discussion qui met très clairement en évidence l'importance du choix d’une approche de modélisation appropriée ou mieux encore la combinaison des approches fondées sur les connaissances physiologiques, les données expérimentales et les applications prévues dans le développement du médicament. L'avantage du paramétrage mécanistique dans ces modèles PBPK est qu’il améliore leur prédictivité et la simulation de différences inter-espèces. Cette thèse a considérablement contribué à démontrer la nécessité d’associer des données in vitro à des données in vivo dans la structuration des modèles PBPK qui se révèlent alors comme des outils précieux pour la prédiction de la pharmacocinétique cérébrale chez l'hommeA critical step during drug development is the measurement or the prediction of drug concentrations in the target tissue, which can then be linked to measures of drug efficacy or toxicity. Drug concentrations cannot be directly measured in the human brain, and must be simulated or predicted using alternative modeling approaches. The objective of this thesis is to develop in silico approaches to predict BBB penetration of drugs, combining in vitro and in vivo preclinical data in a physiologically structured model, with a translational strategy to allow the simulation of total and free drug concentrations in the human brain. Physiologically based pharmacokinetic (PBPK) models were developed and evaluated for reference molecules already on the market, as well as for a drug currently under clinical development within the pharmaceutical industry. These models were developed based on both ‘bottom-up’ (model parameter values predicted from in vitro data) and ‘top-down’ (model parameters estimated from in vivo data) strategies. This thesis is comprised of 5 scientific papers which are either published or submitted to peer-reviewed journals. The first article is a review of the literature, published in the AAPS journal. This review discusses the currently published PBPK models available for the mechanistic prediction of BBB penetration of drugs, and proposes a strategy for in vitro-in vivo (IVIVE) extrapolation. The second article is an original research article published in Molecular Pharmaceutics. This article aims to show the development of a coherent pharmacokinetic modeling approach in the rat which can be adapted based on the quantity and quality of data obtained in vivo during the development of new drugs. A decision tree was constructed to enable the appropriate parameterization and model structure based on the available data. The third article is an original research article published in Journal of Pharmaceutical Sciences. This article was based on the development of a PBPK model for the mechanistic prediction of BBB penetration of drugs, in which the active and passive components of permeability were considered separately, as well as the intra-brain tissue binding parameters. An in vitro-in vivo strategy was proposed to extrapolate the active transport component using a relative activity factor (RAF) to account for in vitro-in vivo differences in transporter activity and/or abundance. Two additional articles are either submitted or under preparation. These articles extend the PBPK approaches described in the previous two published original research articles. The final part of this thesis consists of a discussion which emphasizes clearly the importance of the appropriate choice of modeling approach, or even better, a combination of approaches based on physiological knowledge, experimental data and knowledge gathered during the course of drug development. The advantage of mechanistic parameterization of PBPK models is the improved ability for inter-species extrapolation for the subsequent simulation of free or total drug concentrations within the human brain. This thesis has considerably contributed to this rapidly evolving field of CNS drug research and development, showing the importance of combining in vitro and in vivo data within a physiologically based model structure, thus providing a valuable tool for the quantitative prediction of the penetration of drugs in the human brain
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Hassan, Saadia Bashir. "Methods for Preclinical Evaluation of Cytotoxic Drugs : With Special Reference to the Cyanoguanidine CHS 828 and Hollow Fiber Method." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4696.
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Oswald, Mira [Verfasser], and Achim [Akademischer Betreuer] Göpferich. "Targeted CNS Delivery via Nanoparticulate Drug Delivery Systems / Mira Oswald ; Betreuer: Achim Göpferich." Regensburg : Universitätsbibliothek Regensburg, 2017. http://d-nb.info/1139170708/34.
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Sahm, Ulrike Gisela. "Interaction of naturally occurring and synthetic MSH peptides with peripheral and CNS melanocortin receptors." Thesis, University of Bath, 1994. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.385312.
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O'Rourke, Catriona. "Development of novel, robust 3D CNS tissue models for neurobiological studies and drug discovery." Thesis, Open University, 2016. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.700133.
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Recreating the 3D spatial environment of the eNS allows neural cells in vitro to behave more like their counterparts in vivo, providing robust and controllable model systems that mimic key aspects of the cell biology of the nervous system. A simple, consistent and physiologically relevant model system, which uses a multi-well plate format and can potentially be used at a scale suitable for commercial R&D, has been developed. The model uses an engineered neural tissue which is prepared by a process of initial glial cell self-alignment within a tethered 3D collagen hydrogel and subsequent stabilisation of the gel. Stabilisation is achieved using RAFT technology which entails partial removal of interstitial fluid thereby increasing matrix and cell density. To establish viable production technology for the manufacture of eNS tissue models, the parameters that govern glial cell self-alignment were optimised via development of an assay system that requires a small number of cells. A CNS eo-culture system suitable for widespread adoption will require various combinations of cells to suit specific neuroscience research requirements. Both primary neuronal and glial cell types, relevant cell lines and stem cells were incorporated within engineered neural tissues and then assessed using a range of measures including neural cell survival, morphology, differentiation and sensitivity to stabilisation. In a bid to determine the limitations of these 3D eNS model, neuron-glial interactions, markers for myelination, electrophysiological responses and glial cell behaviour in response to injury and insult were also investigated. Initial studies reveal the new model system can be scaled down to facilitate increased throughput, be assembled quickly and reliably using various neural cell sources, and the eo-cultures exhibit characteristic behaviours that mimic in vivo scenarios.
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Ekelund, Sara. "Microphysiometry in the evaluation of cytotoxic drugs with special emphasis on the novel cyanoguanidine CHS 828." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2001. http://publications.uu.se/theses/91-554-5105-5/.
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Åleskog, Anna. "Application of In Vitro Chemosensitivity Testing for Evaluation of New Cytotoxic Drugs in Chronic Lymphocytic Leukaemia." Doctoral thesis, Uppsala University, Department of Medical Sciences, 2002. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3073.
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Despite major advances in the understanding of the biology of chronic lymphocytic leukaemia (CLL), progress in improving its treatment has been limited and it still remains an incurable disorder. In the present research, we have performed in vitro drug sensitivity testing of primary CLL cells for preclinical evaluation of cytotoxic drugs, using the fluorometric microculture cytotoxicity assay (FMCA).
The tumour type-specific activities of 14 standard drugs, evaluated in vitro on tumour cells from patients with CLL and acute leukaemias, were in good agreement with their known clinical activities. A correlation between drug treatment and development of cellular drug resistance was demonstrated in CLL, but not in the acute leukaemias. Moreover, the nucleoside analogues fludarabine, cladribine, cytarabine and gemcitabine, as well as the anthracycline idarubicin, were highly active in CLL cells.
A new cytotoxic drug candidate, CHS 828, was evaluated in primary cell cultures from a broad spectrum of tumours. CHS 828 was highly active against haematological malignancies in vitro, especially CLL, but also against some solid tumours. The drug appeared to be non cross-resistant with standard drugs.
In addition, the relationship between drug sensitivity in vitro and a recently described prognostic factor in CLL, the mutational status of the immunoglobulin variable heavy chain (IgVH) gene, was evaluated. Interestingly, cells with unmutated IgVH genes were more chemosensitive than the mutated cells.
In summary, our results indicate that in vitro studies on tumour cellsfrom leukaemia patients may yield considerable information regarding the activity, mechanisms of action and cross-resistance of cytotoxic drugs, as well as concerning the relationship between drug sensitivity and prognostic factors, which can be useful in the preclinical evaluation of new cytotoxic drugs. Furthermore, the results suggest that the pyrimidine analogues cytarabine and gemcitabine, as well as the anthracycline idarubicin, may have a role in the treatment of CLL. The new cyanoguanidine CHS 828 is highly active in CLL cells and appears to be non cross-resistant with standard drugs. The poorer prognosis in patients with CLL cells with unmutated IgVH genes can not be explained by increased chemoresistance.
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Gulmez, Sinem. "EPIHAM Drug-induced liver injury leading to hospital admission : a study in national healthcare insurance databases." Thesis, Bordeaux, 2017. http://www.theses.fr/2017BORD0592.
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L’objectif principal de l’étude était d’identifier les principaux médicaments associés aux hépatites aiguës (HA) associé aux médicaments (HAM) en France. Trois approches méthodologiques ont été définies. L’approche méthodologique principale est l’analyse cas-population. Les autres approches sont cas-propre témoin et cas témoins.Les cas ont été identifiés parmi les patients adultes présents dans le SNIIRAM, ayant une première hospitalisation entre 01/01/2010-31/12/2014 dont le diagnostic principal est une atteinte hépatique toxique (Classification Internationale des Maladies (CIM-10) K71.1, K71.2, K71.6, K71.9) ou une insuffisance hépatique(CIM-10 K72.0). La population de référence a été définie à partir de l’EGB. La date index (DI) considérée est la date de première hospitalisation pour HA. Les délivrances de l’ensemble des traitements précédant la DI ont été étudiées en considérant une exposition variant de 7 à 60 jours avant la DI. Les produits les plus fréquemment retrouvés sont classiques: antalgiques et en premier lieu le paracétamol, puis les produits à visée digestive symptomatique (inhibiteur de la pompe à protons, prokinétique, antispasmodique). Les suivants sont l’amoxicilline seule ou associée à l’acide clavulanique, l’ibuprofène, la codéine associée et le furosémide. L’ensemble de ces résultats pourra informer les autorités sanitaires, les praticiens et les patients sur le risque associé à chacune de ces molécules tant au plan individuel (risque absolu, risque attribuable), qu’au sein d’une famille de produits(risque relatif) ainsi que plus globalement pour la population et le système de santé(nombre absolu de cas attribuables)The main objective of EPIHAM study is to identify the main drugs associated with drug induced liver injury leading to hospital admission (DILIH) in France and the event rates associated with DILIH. Three methodological approaches were defined. Principal approach is case-population. The others are case-crossover and case control analyses. Cases were identified among adult patients present in SNIIRAM database having a first hospitalization between 01/01/2010-2010/31/12/1204, the main diagnosis of which is toxic liver disease (diagnostic codes according to the International Classification of Diseases (ICD-10) K71.1, K71.2, K71.6, K71.9) orK72.0. Reference population was defined from the EGB. Index date (ID) was considered as the date of hospital admission for DILI. The dispensations of all treatments preceding the ID were studied by considering an exposure windowvarying from 7 to 60 days before ID. The most frequently found are classical: analgesics and firstly paracetamol, followed by drugs acting on digestive system (proton pump inhibitors, prokinetics, antispasmodics). The following were amoxicillinalone or combined with clavulanic acid, ibuprofen, codeine combinations, and furosemide. These results can inform health authorities, practitioners and patients about the acute hepatitis risk leading to hospitalisation associated with each of these molecules, both individually (absolute risk, attributable risk) and within a therapeutic drug family (relative risk) as well as more generally for the population and the health system (absolute number of attributable cases)
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Miron, Veronique. "The effects of CNS-accessible multiple sclerosis-directed immuno-modulatory therapies on oligodendroglial lineage cells, myelin maintenance, and remyelination /." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=115701.
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Myelin and oligodendrocytes (OLGs) are the apparent targets of the immune-mediated injury that underlies the development of multiple sclerosis (M8). Recovery from M8 clinical relapses likely reflects remyelination attributed to recruitment and differentiation of oligodendrocyte progenitor cells (OPCs), rather than to new process formation by previously myelinating OLGs. Newly emerging M8-directed immuno-modulatory therapies (statins and FTY720) can readily cross the blood-brain barrier and have been shown to impact signaling pathways implicated in cytoskeletal regulation, differentiation, migration, and survival; these are cellular events presumably important for myelin integrity and remyelination.Statins inhibit the production of cholesterol (concentrated in the myelin membrane) and isoprenoids (post-translational attachments regulating the functions of proteins such as the Rho GTPases). We showed that treatment of human and rodent-derived OPCs with lipophilic statins induced an initial process extension associated with enhanced differentiation and impaired spontaneous migration, whereas prolonged treatment induced process retraction and cell death. Rodent and human mature OLGs demonstrated similar cytoskeletal and survival responses. Chronic simvastatin therapy of mice inhibited remyelination following demyelination induced by the OLG toxin, cuprizone, attributed to a block in OPC differentiation and consequent decrease in mature OLGs. Even fully myelinated animals treated with simvastatin over the long-term demonstrated a decrease in myelin in the brain by maintaining oligodendroglial cells in the pre-OLG state and preventing continual replacement of mature OLGs.
FTY720 is an agonist of G-protein-coupled receptors S1P1, 3, 4, and 5, that are associated with distinct receptor isotype-selective activation of Rho GTPases. In human OPCs, FTY720 could induce initial S1P3/5-dependent process retraction associated with an inhibition of differentiation, and subsequent S1P1-dependent process extension. Mature OLGs showed a dose-dependent cyclic modulation of process extension and retraction was observed over time. Both human OPCs and OLGs were rescued by FTY720 under death-promoting environments. Both cell types also demonstrated a cyclic and reciprocal modulation of S1P1 and S1P5 mRNA levels, reflected in the recurring receptor isotype-dependent functional responses over time. Studies using organotypic cerebellar slice cultures demonstrated that FTY720 did not impact myelin integrity under basal conditions, yet accelerated remyelination following lysolecithin-induced demyelination. Both treatment regimens were associated with an extension of OPC and mature OLG processes.
Our observations demonstrate that drug concentrations used to modulate immune function can have differential dose and time-dependent effects on OPCs, OLGs, as well as on myelin and remyelination processes. Our findings indicate the need to monitor the effects of putative immuno-modulatory therapies on myelin-related processes in MS patients.
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Duffett, Rodger Vincent. "The effect of cis-platinum alone or in combination with radiation on mouse lung." Master's thesis, University of Cape Town, 1999. http://hdl.handle.net/11427/26352.
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Cis-platinum is a widely used cytotoxic agent with known radiosensitising properties. It is used in the treatment of various types of lung cancer that may include radiation to the lung as part of the treatment protocol. There is little evidence and some conflict as to whether it sensitises pulmonary tissue to the effects of radiation treatment. This project investigates the effect of cis-platinum alone or in combination with radiation on mouse lung. Four end points were used to evaluate treatments. They were: the release of pulmonary surfactant, changes in breathing rate, a histology based score of damage and changes in TGF-β - a cytokine important in the development of fibrosis. Single doses of either cis-platinum or radiation, cis-platinum given immediately before a single dose of radiation, cis-platinum given immediately before the first of two fractions of radiation and cis-platinum given at various times before and after a single dose of radiation were investigated. Cis-platinum alone was observed to cause an increase in the phospholipid content of lavaged surfactant. Cis-platinum was observed to cause an early release in surfactant and a trend existed for it to induce an early increase in breathing rates as compared to that induced by radiation alone. Cis-platinum was observed to increase radiation damage as assessed using a histology based scoring system. Higher TGF-β levels in lavaged surfactant were observed in C57 /Bl mice as compared to Balb/C. No difference in TGF-β levels was seen in homogenised lung between the strains. Cis-platinum may cause changes in TGF-β in C57/Bl mice but further work is necessary to confirm this.
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Boehm, Michael. "EXPERIMENTAL INVESTIGATION OF TWO-PHASE PENETRATING FLOW OF NEWTONIAN AND NON-NEWTONIAN POLYMERIC FLUIDS AND DEVELOPMENT OF PRACTICAL APPLICATIONS IN DRUG/GENE DELIVERY." The Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1253548237.
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Hovstadius, Peter. "Preclinical and Clinical Development of the Novel Cyanoguanidine CHS 828 for Cancer Treatment." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-6178.
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Koukpo, Rachel Sainhoundé. "Le droit des produits de santé en Afrique de l'Ouest : le cas du Bénin et du Sénégal." Thesis, Bordeaux 4, 2012. http://www.theses.fr/2012BOR40008/document.
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Le médicament est un produit de consommation particulier ayant une multiple vocation.Biens spécifiques porteurs de risques par essence, sa répartition ne peut être laissée au seul jeudu marché. Ils doivent être évalués aussi bien à priori qu’à postéri et durant toute leur viecommerciale. Produit actif nécessaire à la santé, ils comportent de nombreux risques. Latotalité du cycle (production, dispensation, récupération) de tout produit de santé doit être trèsétroitement encadrée et confiée à la responsabilité de professionnels. Leur prise en chargerequiert donc l’attention de toute la collectivité, et doit faire l’objet d’une réglementationrigoureuse en raison des problèmes de santé publique résultant d’une mauvaise utilisation.Ces particularités du médicament entraînent un certain nombre de codification. Descontraintes réglementaires régissent la mise sur le marché et l’utilisation de ces biens, afind’assurer leur qualité, leur efficacité et leur innocuité. Les événements indésirables graves nesont pas toujours bien encadrés dans les pays, milieux médical et hospitalier africain. Et encas de dommages à la santé résultant d’une mauvaise utilisation, il importe de s’interroger surles droits et les responsabilités des différents acteurs (professionnels de santé, patient, Etat).On ne peut espérer prévenir les erreurs médicamenteuses si on n’implante pas dans les espritsla culture du risque et de la responsabilité, préalable indispensable à la réorganisation ducircuit des produits de santéDrugs are a particular consumer product having a multiple purposes. Specific goods carryrisks in themselves, and shouldn’t be distributed solely to the mainstream market. Rather, theymust be evaluated before, during and after their commercial life. Active products arenecessary for healthcare, but contain numerous risks. The entire cycle (production, delivery,recovery) of all health products must be very strictly supervised and entrusted to aprofessional’s responsibility. Their supervision therefore requires the attention of the wholehealth care community, and must be strictly regulated because health problems can resultfrom misuse. These features of the drug involve a certain codification system. Regulatoryrequirements govern the place on the market and use of these assets to ensure their quality,effectiveness and safety. Medical malpractice is not always well supervised in the medicaland hospital atmosphere of Africa. And in case of damage to health resulting from misuse, itis important to consider the rights and responsibilities of the various people involved(healthcare professionals, patients, government). Medical errors cannot be prevented if theculture of risk and responsibility is not instilled in the minds of the public. This is aprerequisite for the reorganisation of the distribution of health products
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Alterman, Julia F. "A CNS-Active siRNA Chemical Scaffold for the Treatment of Neurodegenerative Diseases." eScholarship@UMMS, 2019. https://escholarship.umassmed.edu/gsbs_diss/1027.
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Small interfering RNAs (siRNAs) are a promising class of drugs for treating genetically-defined diseases. Therapeutic siRNAs enable specific modulation of gene expression, but require chemical architecture that facilitates efficient in vivodelivery. siRNAs are informational drugs, therefore specificity for a target gene is defined by nucleotide sequence. Thus, developing a chemical scaffold that efficiently delivers siRNA to a particular tissue provides an opportunity to target any disease-associated gene in that tissue. The goal of this project was to develop a chemical scaffold that supports efficient siRNA delivery to the brain for the treatment of neurodegenerative diseases, specifically Huntington’s disease (HD).
HD is an autosomal dominant neurodegenerative disorder that affects 3 out of every 100,000 people worldwide. This disorder is caused by an expansion of CAG repeats in the huntingtin gene that results in significant atrophy in the striatum and cortex of the brain. Silencing of the huntingtin gene is considered a viable treatment option for HD. This project: 1) identified a hyper-functional sequence for siRNA targeting the huntingtin gene, 2) developed a fully chemically modified architecture for the siRNA sequence, and 3) identified a new structure for siRNA central nervous system (CNS) delivery—Divalent-siRNA (Di-siRNA). Di-siRNAs, which are composed of two fully chemically-stabilized, phosphorothioate-containing siRNAs connected by a linker, support potent and sustained gene modulation in the CNS of mice and non-human primates. In mice, Di-siRNAs induced potent silencing of huntingtin mRNA and protein throughout the brain one month after a single intracerebroventricular injection. Silencing persisted for at least six months, with the degree of gene silencing correlating to guide strand tissue accumulation levels. In Cynomolgus macaques, a bolus injection exhibited significant distribution and robust silencing throughout the brain and spinal cord without detectable toxicity. This new siRNA scaffold opens the CNS for RNAi-based gene modulation, creating a path towards developing treatments for genetically-defined neurological disorders.
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Djenna, Abdallah. "Brevet et développement : le cas de l'Algérie." Thesis, Grenoble, 2013. http://www.theses.fr/2013GREND004.
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La logique du nouveau système économique international s'appuie sur l'idée que le brevet est un mécanisme juridique d'incitation à la recherche et au développement. L'objet de notre étude est de savoir si les écarts de niveau de développement entre les pays pouvaient avoir des effets sur la fonction du brevet dans les pays en voie de développement. Dans cette perspective, nous avons consacré la première partie de notre recherche à l'étude du droit des brevets sur le plan international. Cette analyse est indispensable pour une meilleure compréhension des choix opérés par un pays en développement comme l'Algérie dans l'évolution de son propre système de protection des inventions. Ensuite, nous avons analysé le régime algérien des brevets et les changements qu'il a subi en vue de s'adapter au haut niveau de protection exigé par le système international, afin d'examiner les effets de telles exigences sur le développement. Il ressort de nos analyses, que pour remplir sa fonction universelle comme instrument d'incitation à l'innovation technologique et au développement, le système de brevet algérien doit connaitre plusieurs modifications sur le plan juridique, économique et institutionnelThe logic of the new international economic system is based on the idea that the patent is a legal mechanism to incentive research and development. The subject of our study is to know if the variations of the levels of development among between different countries could affect the function of the patent in the third world. In this perspective, we have to analyze the Algerian patent law and the changes they have undergone in order to adapt to the high level of protection required by the international system in order to examine the effects of the requirement of these conditions on reveal developments. Then we analyzed the Algerian regime of patents and the changes it has undergone in order to adapt to the level of protection required by the international system, to examine the effects of these requirements on you development. That the patent system in Algeria fulfills its universal function as an instrument for incentive technological innovation and development, several changes in the legal, institutional and economic should be performed
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Cowie, Philip David. "Analysis of the effects of disease-associated variation within a cis-regulatory element of the CNR1 locus on CNR1 promoter dynamics." Thesis, University of Aberdeen, 2014. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=225652.
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Genetic variation within the cannabinoid 1 receptor (CB1R) locus (CNR1) has been repeatedly associated with drug addiction pathologies. Genomic annotation of CNR1 indicates the vast majority of this genetic variation likely results in altered transcriptional regulation of the CNR1 gene as a mechanistic link to the disease phenotype. There is a lack of information describing the regulation of CNR1 transcription and the potential impact of disease-associated variation within the CNR1 locus on its transcriptional regulation. This study investigates the impact of an evolutionary conserved regulatory region of CNR1, termed ECR1, and the disease-associated variation contained within, on the transcriptional activity of the cognate CNR1 promoter region. Reporter assays conducted in primary hippocampal cells demonstrate that CNR1 promoter exhibits variable transcriptional activity during periods of CB1R signalling and cell depolarisation. Coupled to allelic variants of ECR1, the CNR1 promoter shows significant changes in transcriptional activity under resting conditions indicating that disease-associated variation within ECR1 may decrease CNR1 transcription. Further, alleles of ECR1 can drive allele-specific transcriptional responses from the CNR1 promoter during periods of CB1R stimulation and cell depolarisation. The results highlight the potential for disease-associated regulatory variation of the CNR1 locus to create stratified transcriptional responses to specific cell signalling scenarios and putatively to clinical strategies employing pharmacological agents. Furthermore, investigation of DNA-protein interactions at the allelic ECR1 region demonstrate that disease-associated variation within ECR1 alters DNA-protein interactions within the nucleus consistent with a decrease in transcriptional activity in the disease-associated allele variant. Collectively the current work supports the hypothesis that disease-associated variation within the ECR1 regulatory region of the CNR1 locus has the capacity to significantly impact on CNR1 promoter transcriptional activity. It is posited that allele-specific transcriptional effects may have a major impact on the susceptibility of individuals to drug addiction or on responses to clinical pharmacological treatments.
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Frost, Britt-Marie. "Chemotherapy in Childhood Acute Lymphoblastic Leukemia : In vitro cellular drug resistance and pharmacokinetics." Doctoral thesis, Uppsala University, Department of Women's and Children's Health, 2002. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-2664.
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The aims of the studies described in this thesis were to investigate the pharmacokinetics of and cellular resistance to chemotherapy as causes of treatment failure in childhood acute lymphoblastic leukemia (ALL).
Leukemic cells from 370 children with newly diagnosed ALL were tested by the Fluorometric Microculture Cytotoxicity Assay to measure their resistance to each of ten standard cytotoxic drugs. In the high-risk group, increased in vitro resistance to each of the drugs dexamethasone, etoposide and doxorubicin was associated with a worse clinical outcome. Combining the results for these drugs yielded a drug resistance score, showing a relative risk of relapse in the most resistant group that was 9.8 times higher than in the most sensitive group. In the standard-risk and intermediate-risk groups, final evaluation must await longer follow-up.
The new cytotoxic agent CHS 828 was equally active in vitro in samples from children with acute myeloblastic leukemia (AML) and ALL, with 50% cell kill at concentrations achievable in vivo. In AML samples CHS 828 also displayed high frequencies of synergistic interactions with four standard drugs. The well-known differences in clinical outcome between Down´s syndrome (DS) and non-DS children with acute leukemia may partly be explained by our finding of differences in drug resistance at the cellular level.
Pharmacokinetic studies were performed at the start of induction treatment of ALL. Doxorubicin was assayed by reversed-phase liquid chromatography with fluorometric detection, and vincristine by high performance liquid chromatography with electrochemical detection. Plasma doxorubicin concentrations were measured in 107 children after 23 h of a 24-h infusion. The median steady-state concentration in children 4-6 years old, a group known to have a favorable outcome of treatment, was about 50% higher than in those 1-2 and >6 years old Vincristine pharmacokinetics was evaluated in 98 children. There was no correlation between age and total body clearance or any other pharmacokinetic parameters.
In vitro testing of cellular drug resistance might be useful in predicting the outcome in high-risk ALL. The further exploration of CHS 828 in childhood leukemia seems warranted. There is no pharmacokinetic rationale for the common practice of administering relatively lower doses of vincristine to adolescents than to younger children.
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Sherwood, Alexander M. "Design, Synthesis and Biological Evaluation of Novel Compounds with CNS-Activity Targeting Cannabinoid and Biogenic Amine Receptors." ScholarWorks@UNO, 2014. http://scholarworks.uno.edu/td/1831.
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This work seeks to contribute to the discipline of neuropharmacology by way of structure activity relationship from the standpoint of an organic chemist. More specifically, we sought to develop robust synthetic methodology able to efficiently produce an array of compounds for the purpose of systematic evaluation of their interaction with specific sights within the central nervous system (CNS) in order to better understand the mind and to develop drugs that may have beneficial effects on neurological function.
The focus of these studies has been toward the development of novel molecules, using a structure-activity relationship approach, that exhibit binding affinity at specific targets within the CNS. The merit of such studies is twofold: primarily, new compounds are produced that provide valuable scientific insight about their physiological targets, and secondarily, new synthetic methodologies that may arise in order to produce these compounds, thereby contributing to the whole of organic chemistry.
As a result of the research described herein, the development of one high affinity and several moderate affinity compounds at the cannabinoid receptor subtype 1 (CB1) has been accomplished. The research demonstrates that a diaryl ether molecular scaffold represents a successful motif in the cannabinoid pharmacophore. The production of the compounds in the SAR studies also introduced a novel general synthetic methodology for the synthesis of diaryl ethers around a phloroglucinol core.
A second project was initiated in order to explore the synthetic methods required to develop a general process for the synthesis of rigid aminobenzocyclobutane analogs of known phenethylamines with activity at monoaminergic neurotransmitter sites. Using the synthetic approach devised here, four novel aminobenzocyclobutane isomeric analogs of a known pharmacologically active phenethylamine, (RS)-phenylpropan-amine were synthesized and are currently being evaluated for pharmacological potential.
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Nsarhaza, Bishikwabo Kizito. "La restructuration du secteur de santé et le marché informel: cas de la République Démocratique du Congo." Doctoral thesis, Universite Libre de Bruxelles, 1997. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/212128.
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Little, James L., Curtis D. Cleven, and Stacy D. Brown. "Identification of “Known Unknowns” Utilizing Accurate Mass Data and Chemical Abstracts Service Databases." Digital Commons @ East Tennessee State University, 2011. https://dc.etsu.edu/etsu-works/5300.
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Pinto, Alexandre. "Common scaffolds for the enantioselective synthesis of marine, plant, and amphibian cis-decahydroquinoline alkaloids." Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/457969.
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Chiral amino alcohol derived lactams are a valuable scaffold for the enantioselective synthesis of alkaloids. In the present thesis the potential of this methodology was expanded and to demonstrate the synthetic utility of chiral tricyclic lactams obtainedthe enantioselective total synthesis complex cis-decahydroquinoline alkaloids was carried out. The alkaloids that were targeted for synthesis using the developed methodology were the lepadin alkaloids (marine alkaloids) and tricyclic cis-decahydroquinoline alkaloids such as cermizine B (Lycopodium alkaloids). To accomplish these objectives further studies on the functionalization of the decahydroquinoline system were required in order to install the appropriate substituents and functionalities for the synthesis of each target. During the present PhD thesis it was possible to complete the total synthesis of (+)-gephyrotoxin 287C, (−)-cermizine B, (−)-lepadin B and (+)-lepadin D and the formal total synthesis of (−)-lepadins A and C.
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Robert, i. Sabaté Laia. "Creació d’un instrument de verificació i guiatge per millorar la qualitat informativa en la comunicació farmacoterapèutica. Cas pràctic amb els inhibidors de la bomba de protons." Doctoral thesis, Universitat de Barcelona, 2020. http://hdl.handle.net/10803/671211.
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La comunicació en salut i la millora de l’alfabetització per a la salut són aspectes clau en les polítiques sanitàries. L’èxit d’un tractament farmacològic no només depèn de l’eficàcia del medicament sinó també del coneixement que el pacient té sobre aquest medicament i del seu grau d’alfabetització en salut.
Les fonts d’informació sobre medicaments que tenen els pacients avui en dia a mà són múltiples i variades però no totes elles són de qualitat i fiables. Actualment els actors implicats en la comunicació i disseminació d’informació sobre medicaments, ja siguin organitzacions sanitàries, professionals de la salut, periodistes, experts en comunicació o qualsevol persona a títol individual, són múltiples, però tots ells comparteixen la responsabilitat de garantir i proporcionar una bona informació sobre els medicaments.
L’objectiu d’aquest treball és crear una metodologia que permeti avaluar i millorar la qualitat informativa dels temes relacionats amb els medicaments i la farmacoteràpia que contribueixi a millorar el grau d’alfabetització en salut de la societat i que pugui ser utilitzada pels diferents agents implicats en la comunicació farmacoterapèutica
Per fer-ho, s’ha fet primerament un estudi sobre la llegibilitat i qualitat de la informació de medicaments dirigida a la ciutadania d’una web institucional. I posteriorment s’ha realitzat un segon estudi sobre la llegibilitat i la qualitat de la informació escrita sobre els medicaments i necessitats reals de la ciutadania, a partir d’un pràctic amb els inhibidors de la bomba de protons. En aquest segon estudi s’ha fet una aproximació de tota aquella informació escrita que pot rebre un pacient sobre els IBP, ja sigui el prospecte, les fonts oficials o de referència, les notícies de premsa o la informació provinent de la cerca a internet. També s’ha volgut conèixer les necessitats d’informació sobre els medicaments a través d’entrevistes personals a pacients que prenen algun dels principis actius dels IBP.
S’ha observat que, malgrat que els resultats en llegibilitat són positius, el marge de millora en termes de qualitat dels documents no considerats de referència
–com ara la informació d’internet o les notícies de premsa– és ampli. Per altra banda, la informació que més interessa als pacients que prenen tractaments crònics, com el cas dels que prenen IBP, són els aspectes de seguretat i eficàcia.
A mésa més, aquests pacients consideren que els prospectes contenen massa informació, són pesats de llegir i massa llargs.
A partir dels dos estudis sobre la llegibilitat i la qualitat de la informació escrita sobre medicaments on s’hi inclouen les entrevistes ad hoc i una sòlida revisió bibliogràfica, es proposa un nou instrument que permet verificar la qualitat de la informació escrita sobre medicaments i alhora ser una guia per l’elaboració d’aquesta informació. Aquest instrument inclou deu ítems clau: “beneficis”, “riscos”, “alternatives terapèutiques”, “efectes sobre la qualitat de vida”, “evidència científica”, “bibliografia i fonts complementàries”, “informació de suport”, “autoria”, “data de publicació” i “llenguatge planer”. D’aquesta manera, els agents implicats en la comunicació farmacoterapèutica tindran una nova eina per controlar i millorar la qualitat de la seva informació escrita.Health communication and improving health literacy are key issues in healthcare policies. Treatment benefits and success depend not only on the efficacy of the drug, but also on the patient's knowledge about medicines and his or her level of health literacy. Nowadays, sources of medicines information available to patients are many and varied, but not all of them are of high quality and reliable. Currently, many actors can communicate and disseminate information about medicines, for example healthcare professionals, journalists, healthcare organizations, communication experts or anyone on an individual basis. All of them share the responsibility to guarantee and provide accurate medicines information. The aim of this work is to create a methodology to evaluate and improve the informative quality of subjects related to medicines and pharmacotherapy. This methodology will help to improve the degree of health literacy from the society and it is intended to be used by different agents involved in pharmacotherapeutic communication. To accomplish this, quality and readability of written information about medicines published on an institutional website has been analyzed. A second study of the quality and readability of all the written information that a patient may receive about a group of drugs of widespread use such as PPI (leaflet, official or sources of reference, news and internet information) has been carried out. In this second study, patients taken PPI have also been interviewed in order to know their information’s needs about drugs. Although results in readability are positive, the margin for improvement in quality of the documents not classified as reference one’s (internet information, news .) is wide. What matters most to patients is drug safety and drug effectiveness and they think that medicine’s’ leaflets have too much information, are long and not easy to read. From data of the two performed studies and from a solid literature review, it is proposed a new instrument that will allow to verify the quality of written information about medicines, and at the same time, to guide through the elaboration process. This instrument consists of 10 items: benefits, risks, therapeutic alternatives, effects on quality of life, scientific evidence, bibliography and complementary sources, supporting information, authorship, publication date and plain language. With this instrument, agents involved in the pharmacotherapeutic communication will have a new tool to control and improve the quality of their written information.
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Amonkou, Anne Cinthia. "Les bases législatives et réglementaires du développement de l'industrie pharmaceutique en Afrique : le cas de la Côte d'Ivoire." Thesis, Strasbourg, 2018. http://www.theses.fr/2018STRAJ115/document.
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Une industrie pharmaceutique locale forte est l’une des assises d’un système sanitaire efficace. L’objectif de ce travail est de contribuer à l’optimisation du cadre juridique en vue de l’essor de ce secteur d’activités en Côte d’Ivoire. Partant d’une description des textes législatifs et réglementaires applicables à l’industrie pharmaceutique, nous avons recherché et analysé les facteurs qui conditionnent le développement du secteur et enfin avons formulé des axes d’optimisation. Le corpus juridique ivoirien sur l’industrie pharmaceutique en vigueur définit un cadre normatif, institutionnel et professionnel organisé. L’ouverture du capital aux non pharmaciens par la législation de 2015 est à saluer. Toutefois, il conviendrait d’adopter de véritables mesures de promotion à l’implantation de laboratoires pharmaceutiques et une certaine protection du marché pour soutenir les premiers pas de développement. La volonté politique et l’ambition des acteurs du secteur sont primordiales. Une coordination des mécanismes juridiques à travers une politique attractive permettra de relever le défi de l’industrialisation pharmaceutiqueA strong local pharmaceutical industry is one of the foundations of an effective health system. The aim of this work was to contribute to the optimization of the legal framework for the development of the pharmaceutical industry. Starting from a description of the legislative and regulatory texts applicable to the pharmaceutical industry in Côte d'Ivoire, we have researched and analyzed the factors that condition the development of this sector of activity and finally formulated axes of optimization. The Ivorian legal corpus on the pharmaceutical industry in force defines an organized normative, institutional and professional framework. The opening of the capital to the non-pharmacists by the legislation of 2015 is to be welcomed. However, genuine promotion measures for the establishment of pharmaceutical laboratories and some protection of the market should be adopted to support the first steps of development of the sector. The political will and ambition of the players in the sector are paramount. Coordination of legal mechanisms through an attractive policy will make it possible to meet the challenge of pharmaceutical industrialization
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Roux, Perrine. "Observance thérapeutique des patients multitraités : le cas de la toxicomanie." Thesis, Aix-Marseille 2, 2010. http://www.theses.fr/2010AIX20651/document.
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L’épidémie du VIH a bouleversé le rapport de la médecine à l’individu et inversement. D’une part, la forte stigmatisation associée à la contamination par le virus a rendu le vécu de la maladie plus complexe que pour toute autre pathologie. D’autre part, la chronicisation de l’infection impliquant une prise en charge complexe à base d’une multithérapie au long cours a contraint les soignants à s’interroger plus en profondeur sur la relation intime du patient à son traitement, et tout particulièrement sur l’observance thérapeutique. L’idée de ce travail de thèse est de poursuivre une argumentation en faveur d’une nouvelle approche moins paternaliste de l’observance aux antirétroviraux, incluant un partage des savoirs entre le médecin et le patient, et de l’appliquer à des populations de patients dont les comorbidités compliquent la prise en charge telles que la dépendance aux opiacés et l’infection par le virus de l’hépatite C. A travers une série d’articles, nous avons montré que la prise en compte de la perception du patient vis-à-vis des soins permettait de mieux comprendre la non-observance aux traitements. Chez les personnes traitées pour leur dépendance, la non-observance peut être définie comme l’injection du traitement de substitution ou la consommation d’opiacés illicites. La diminution ou l’arrêt de ces pratiques est un processus long, souvent ponctué de rechutes et elles peuvent être le reflet d’une prise en charge inadaptée. Les résultats de ce travail ont permis de mettre en évidence l’effet positif d’un accès à des soins adaptés, à travers une prise en charge de la pathologie mais aussi la réduction des risques liés à la non-observance. Il s’agit là de promouvoir une relation plus délibérative entre le médecin et le patientThe epidemic of Human Immunodeficiency Virus (HIV) has profoundly changed the relationship between medicine and humans and vice versa. On the one hand, the intense stigmatization associated with HIV infection has made the disease more complex than for any other pathology. On the other hand, the chronicization of infection has forced care providers to investigate in greater detail the intimate relationship between patient and treatment, and more particularly, the therapeutic adherence. My research work aimed to investigate this latter argument in greater detail, favoring a less paternalistic approach toward therapeutic adherence in HIV-infected patients and applying this approach to multi-treated populations with comorbidities such as drug dependence and hepatitis C. Through several articles, we tried to put in evidence that a model of care that includes patient’s perception about care may lead to better understand non-adherence to treatment (ongoing drug use, drug injection or treatment diversion). In fact, injection cessation or reduction of opioid consumption in dependent individuals is a non-linear process which could take a long time, and which is often punctuated with relapse. Our findings showed the positive impact of access to adequate care to treat not only the disease but also the harm related to non adherence to treatment. The idea is to promote a more deliberative relationship between physician and patient, including a harm reduction approach
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Rojas, Diana. "Les transformations de l´intervention à l'ère de la mondialisation : le cas des Etats-Unis en Colombie (1961-2010)." Thesis, Paris Est, 2012. http://www.theses.fr/2012PEST0055/document.
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Cette recherche part de la volonté de comprendre et d‘expliquer l‘interaction entre la politique intérieure et la politique internationale dans les processus de construction étatique des pays les moins développés et avec une histoire de forte dépendance extérieure. Son objectif central consiste donc à étudier les transformations du phénomène de l‘intervention internationale dans le contexte de la mondialisation à partir de l‘analyse du cas colombien. C‘est pourquoi, en premier lieu, y sont examinés les théories qui, selon les relations internationales, ont rendu compte de l‘intervention comme partie de la dynamique de la politique internationale contemporaine. Un type spécifique d‘intervention, la construction étatique, est analysé dans le cadre de la politique extérieure nord-américaine au XXe siècle. En second lieu, l‘étude de cas présentée analyse l‘intervention des États-Unis en Colombie lors de trois moments distincts : l‘Alliance pour le progrès (1961-1972), la lutte contre les drogues (1975-1994) et le Plan Colombie (2000-2010). A travers ceux-ci est exposé de quelle manière l‘intervention de la superpuissance dans le pays sud-américain a changé tant dans sa conception que dans sa mise en place au long d‘un demi-siècle. L‘examen détaillé de ces trois périodes permet d‘identifier les point de comparaison afin d‘établir s‘il s‘agit ou non d‘une intervention orientée vers la construction étatiqueThis research project emerges from an interest in understanding and explaining the interaction between domestic and international politics in the processes of state-building in less developed countries that also have histories of strong3foreign dependence. The main objective of this work is to study the transformation of the phenomena of foreign intervention in the context of globalization through the analysis of the Colombian case. Thus, theories from the discipline of international relations that study intervention as part of the dynamics of contemporary international politics are examined first. Specifically, the intervention related to statebuilding, which is presented in the context of American foreign policy in the 20th century, is analyzed. Second, the intervention of the United States in Colombia in three different periods is explored: the Alliance for Progress (1961-1972), the War on Drugs (1975-1994) and Plan Colombia (2000-2010). Throughout these periods, this study establishes how the intervention of this superpower in this South American country was changing in both its conception and implementation for half of a century. Also, by a detailed examination, the study identifies points of comparison in order to assess whether or not the intervention was oriented towards statebuilding
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Constant, Chloé. "Trajectoires et dynamiques carcérales au féminin. Le cas de Lima." Phd thesis, Paris 3, 2013. http://tel.archives-ouvertes.fr/tel-00979203.
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Cette thèse propose d'étudier la trajectoire des femmes incarcérées dans la prison péruvienne Chorrillos I à Lima et d'analyser l'influence des inégalités sociales et du parcours de vie des détenues sur les dynamiques carcérales de cet établissement. Les entretiens menés avec les détenues révèlent un ensemble de similitudes dans leur parcours avant l'incarcération, parmi lesquelles ressortent des schémas de domination genrée, des situations de précarité socioéconomique, des expériences de mères célibataires, ainsi que la recherche de stratégies de survie. Le croisement de l'étude de leur trajectoire et de l'analyse des rapports sociaux, ethniques et genrés permet de comprendre leurs formes d'adaptation au milieu carcéral ainsi que les relations qui lient l'ensemble des acteurs en présence, pour dévoiler les ressorts d'un univers carcéral particulier.
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Martin, Benoît. "La production des statistiques internationales : le cas de l'Office des Nations unies contre la drogue et le crime (UNODC)." Thesis, Paris, Institut d'études politiques, 2018. http://www.theses.fr/2018IEPP0030.
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Comment les organisations internationales produisent-elles leurs statistiques ? Cette thèse dévoile ces activités singulières à partir du cas de l’Office des Nations unies contre la drogue et le crime (UNODC). La démonstration suit une double approche sociologique (des relations internationales et des quantifications) en s’appuyant sur des entretiens menés au siège (à Vienne, en Autriche), la littérature méthodologique (interne et publiée) et les documents onusiens (normatifs et analytiques). Quantifier à l’échelle internationale consiste en un processus complexe organisé en étapes successives : accord d’un mandat, définition d’une méthode, collecte puis traitement et validation des données et, enfin, publication d’un rapport mondial. L’entreprise s’avère collective, impliquant le secrétariat de l’UNODC, les États-membres et des experts. En revanche, la tâche est inégalement répartie, les fonctionnaires internationaux réalisent ou coordonnent l’essentiel ; tout comme les interactions entre les acteurs sont asymétriques, l’UNODC dépend de ses États-membres à plusieurs égards et sans véritable pouvoir de les contraindre. Enjeux bureaucratiques, politiques, financiers, voire autocensure affectent alors le travail statistique routinier. De plus, les sources nationales officielles mais administratives – aux biais pourtant documentés et délicats à surmonter – restent majoritairement utilisées car légitimes. Le recours aux images satellites et aux enquêtes sur le terrain fait figure d’exception. Élaborées dans de telles conditions, les statistiques onusiennes de la drogue et du crime fournissent davantage un inventaire international consensuel que le diagnostic mondial prétenduHow do international organizations produce their statistics? This thesis unveils these singular activities from the case of the United Nations Office on Drugs and Crime (UNODC). The demon-stration follows a double sociological approach (of international relations and of quantification) based on interviews conducted at headquarters (in Vienna, Austria), methodological literature (internal and published) and UN documents (normative and analytical). Quantifying internationally is a complex process organized in successive steps: agreeing a mandate, defining a method, collecting and then processing and validating the data, and finally publishing a world report. The enterprise is collective, involving the UNODC secretariat, member states and experts. However, the task is unequally distributed, the international civil servants realizes or coordinates a large part of the work; just as the interactions between actors are asymmetrical, UNODC depends on its member states in many respects and has no real power to constrain them. Bureaucratic, political, financial and even self-censorship issues affect routine statistical work. In addition, official but administrative national sources – with their documented and delicate biases to overcome – remain mostly used because of their legitimacy. The use of satellite imagery and field surveys is an exception. Developed under such conditions, UN drug and crime statistics provide a more consensual international inventory than the so-called global diagnosis
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Pirson, Magali. "Apports de la comptabilité analytique par cas et par pathologie à la gestion hospitalière." Doctoral thesis, Universite Libre de Bruxelles, 2006. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/210867.
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Le calcul des coûts des séjours et des pathologies peut être abordé selon différentes perspectives :les coûts à charge des systèmes sociaux, des patients ou des hôpitaux. La thèse est centrée sur cette dernière approche.Les DRGs représentent la tentative la plus récente de maîtriser la croissance des dépenses des hôpitaux en introduisant une médicalisation partielle des mécanismes de financement.
La connaissance des coûts des pathologies peut permettre aux hôpitaux de participer à l’élaboration des tarifs par pathologie en faisant partie d’un échantillon de référence des coûts hospitaliers. En cas de financement basé sur les pathologies, les hôpitaux doivent pouvoir comparer le coût des séjours au chiffre d’affaires octroyé et s’y adapter. Cet intérêt s’accroît en cas de financement forfaitaire, évolution qui semble se profiler en Belgique tout comme dans d’autres pays. En décrivant une méthodologie de calcul des coûts par pathologie et en indiquant la manière dont ceux-ci pourraient contribuer à la création d’une échelle de cost-weights, notre thèse incite les hôpitaux à adopter une politique proactive dans le domaine du financement des hôpitaux.
Les comparaisons de coûts hospitaliers pour évaluer la gestion sont pratiquées depuis de nombreuses années. Cependant, ce « benchmarking » est imparfait car il ne prend pas en compte la lourdeur des patients pris en charge. La standardisation des coûts sur base du case-mix de l’hôpital suppose un préalable important :l’existence d’une échelle de cost-weights issue d’un échantillon représentatif d’hôpitaux. Si cette situation n’est pas encore totalement rencontrée en Belgique, il est néanmoins possible de suggérer une voie de réflexion. La simulation inspirée de la méthodologie suisse à partir d’un échantillon de quatre hôpitaux belges présentée dans le cadre de cette thèse, est une première avancée en ce sens.
Un des problèmes majeurs de la gestion hospitalière est d’intéresser les prescripteurs et les prestataires à un contrôle de gestion essentiellement financier. Depuis quelques années, de nombreux efforts visent à intégrer de nouveaux indicateurs de performance dans les tableaux de bord. L’analyse des coûts des pathologies et de la variabilité des cas permet d’entamer un dialogue entre gestionnaire et corps médical. En abordant différentes études (apport des nomenclatures dans le calcul des coûts par pathologie, mesure des coûts associés aux bactériémies nosocomiales, analyse des facteurs médico-sociaux expliquant les surcoûts des patients outliers, analyse de la relation entre le coût et la sévérité des cas, comparaison des coûts de production et des pratiques médicales), nous avons voulu montrer l’importance d’associer une approche médicalisée à des raisonnements économiques. Si elle se développe, cette approche est susceptible de représenter un moyen de communication idéal entre le personnel médical et soignant et le monde de la gestion.
Comme nous le rappelions au début de cette thèse, les concepteurs des DRGs (Fetter et Thompson) ont regretté le manque d'intérêt manifesté par les gestionnaires d'hôpitaux pour l'utilisation de leur concept dans le management hospitalier. Au terme de cette thèse, nous pensons que, si l'analyse des coûts par pathologie reste encore d'un abord difficile, elle peut rendre d'importants services en associant médecins et managers à l'élaboration d'un contrôle de gestion enfin adapté à la spécificité de leurs institutions.
Doctorat en Sciences de la santé publique
info:eu-repo/semantics/nonPublished
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Ferchakhi, Widiane. "Influence du risque percu sur l'intention d'achat d un produit générique : le cas du médicament." Thesis, Lyon, 2016. http://www.theses.fr/2016LYSE3070.
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Cette thèse vise à comprendre les freins à l’achat des médicaments génériques chez les patients-consommateurs. Plus particulièrement, notre recherche vise par le biais d’une étude qualitative et quantitative à améliorer l’efficacité des communications des acteurs de santé pour réduire le risque perçu à l’achat des génériques. Il s’agit plus précisément d’étudier les variables susceptibles d’expliquer l’attitude envers la substitution, mais aussi de comprendre les mécanismes impliqués, et de mettre en lumière les variables les plus à même à expliquer l’intention d’achat d’un médicament générique (vs princeps). Ainsi, nous avons cherché à explorer les facteurs explicatifs de la perception et de la réduction du risque envers les génériques à travers des entretiens semi-directifs individuels menés auprès de 24 patients-consommateurs. Les résultats de l’étude quantitative menée auprès de 303 personnes, soulignent que (1) le risque perçu envers la substitution et l’attitude envers les génériques médiatisent la relation entre le risque perçu envers les génériques et l’attitude envers la substitution, (2) la confiance dans la source d’informations (pharmacien et médecin) modère la relation entre l’attitude envers la substitution et l’intention d’achat d’un médicament générique (vs princeps) et (3) l’effet d’interaction entre le capital marque du médicament générique : faible (vs fort), la chronicité de la maladie : non chronique (vs chronique) et le taux de remboursement : 65% (vs 100%) sur l’intention d’achat d’un médicament générique (vs princeps) est validé. Sur un plan théorique, la recherche permet d’éclairer la littérature sur le risque perçu en matière de santé, notamment en mobilisant un concept issu de la médecine « l’effet nocebo». Les implications managériales sont multiples, tant pour les laboratoires pharmaceutiques génériqueurs, d’une part, que pour les pharmaciens, les médecins et enfin les pouvoirs publics décideurs des politiques de communication en faveur des médicaments génériques, d’autre partThis thesis aims to understand the obstacles to the purchase of generic drugs in patients-consumers. More specifically, it aims, through a qualitative and a quantitative study, to improve the efficiency of communication of health actors to reduce the perceived risk in buying generics. More precisely, it intends to examine the variables that explain the patients-consumers attitudes towards the substitution, to understand the mechanisms involved in this process and to highlight the most likely variables that explain the intention of purchasing a generic (vs brand name) drug. Thus, we aimed to explore the factors that explain the perception and reduction of risks towards the generic drugs by conducting individual semi-structured interviews with 24 patients-consumers. The results of the quantitative study of 303 individuals point out that (1) the perceived risk towards the substitution and the attitude towards generic drugs mediate the relationship between the perceived risk towards generic drugs and attitude towards substitution, (2) the trust in the information source (pharmacist and physician) moderates the relationship between the attitude towards substitution and the intention of purchasing a generic (vs brand name) drug and (3) the interaction effect between the brand equity of generic drug : low (vs strong ), the chronicity of disease : non chronic (vs chronic) and the repayment rate : 65% (vs 100%) on the intention purchase generic (vs brand name) drug is validated. Theoretically, the research sheds light on the literature on the perceived risk in health, including mobilizing a concept from the medicine "Nocebo effect". The managerial implications are manifold for generic pharmaceutical industry as well as for pharmacists, physicians, and, finally government makers of communications policies for generic drugs
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Toulemon, Léa. "Job quality, health insurance and the price of medical products : essays in applied economics." Thesis, Paris, Institut d'études politiques, 2016. http://www.theses.fr/2016IEPP0041/document.
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Cette thèse étudie deux facteurs majeurs pour le bien-être individuel, la qualité de l'emploi et l'accès aux soins. Dans le premier chapitre, nous étudions l'effet de la perte d’emploi suite à une fermeture d’usine sur un large panel d’indicateurs mesurant la qualité de l'emploi retrouvé. Nous utilisons une stratégie d’appariement exact par tranche qui prend en compte les inobservables fixes dans le temps. Nos résultats principaux montrent une dégradation de la qualité de l’emploi suite au licenciement, dont la durée et l’ampleur dépendent de la dimension considérée. Le second chapitre étudie l'impact d'une assurance maladie publique plus généreuse sur la consommation de soins de santé. Nous utilisons la coexistence de deux systèmes d'assurance maladie en France, tous deux publics et obligatoires : le système national, et le régime local d'Alsace Moselle, donc les taux de remboursement sont plus élevés. Nous évaluons comment les personnes déménageant en Alsace Moselle modifient leur consommation de soins, en utilisant les personnes déménageant entre d’autres régions françaises comme groupe de contrôle. En étudiant plusieurs postes de santé, nous trouvons qu’au total, le régime d’Alsace Moselle n’engendre pas de hausse des dépenses. Le dernier chapitre s'intéresse à l'effet de l'achat groupé sur les prix des médicaments dans les hôpitaux français, en utilisant les créations de groupements entre 2009 et 2014. Nos données contiennent les prix d’achat des médicaments innovants dans les hôpitaux publics. Nos résultats montrent que l'achat groupé baisse les prix des médicaments en oligopole, mais n'a aucun impact sur les prix des médicaments qui n'ont pas de concurrentsThis thesis focuses on two major aspects of individual well-being : job quality and the availability of medical care. We first investigate the long-term effects of job displacement on several dimensions of job quality. We use a coarsened exact matching method that takes into account time-invariant unobservables. Our main findings point to a deterioration of job quality after displacement. The magnitude and duration of the observed negative impact depends on the dimension considered. The second chapter studies the impact of a more generous public health insurance. We use the coexistence of two compulsory public health insurance systems in France, the national system, and the Alsace Moselle local system, which offers higher reimbursement rates. We investigate how moving to Alsace Moselle affects healthcare consumption, taking individuals who move between other French regions as a control group. Overall, we show that the Alsace Moselle local system does not increase healthcare consumption. The third chapter estimates the impact of group purchasing on medicine prices in French hospitals. We take advantage of the creation of regional purchasing groups between 2009 and 2014. We use a unique database that provides information on the average annual prices paid by public hospitals for all innovative medicines. Using a fixed effects model controlling for medicine-specific bargaining abilities of hospitals and medicine-specific price trends, we find that group purchasing reduces prices of medicines in oligopoly markets, but has no impact on prices of medicines for which there exist no competitors
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Ngo, Nguene Marie Rosaire. "Les consommations de substances psychoactives sur le lieu de travail : le cas d’usagers et salariés des bars-restaurants et de chantiers du bâtiment parisiens." Thesis, Paris 10, 2020. http://www.theses.fr/2020PA100102.
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Cette recherche a pour objectif d’élucider les liens entre consommations de produits psychoactifs et milieux professionnels à partir des formes différenciées d’usages d’alcool, de tabac, de cocaïne et de cannabis de salariés de bars restaurants et de chantiers du bâtiment parisiens. Il s’agit de sortir d’une mesure purement quantitative des consommations de substances psychoactives, d’élaborer des catégories proprement sociologiques pour les penser dans l’espace du travail et du hors travail, en les articulant à l’organisation du travail et la gestion de la main-d’œuvre, aux conditions de travail proprement dites (travail de nuit dans les bars-restaurants, pénibilité physique dans les chantiers du bâtiment par exemple), aux propriétés des produits consommés et à leurs représentations, ainsi qu’aux caractéristiques sociales et professionnelles des salariésThis research aims to explain the relationship between the consumption of psychoactive products and professional environments, based on the differentiated forms of alcohol, tobacco, cocaine and cannabis use by Parisian employees of restaurants, bars and building sites. We are moving away from a purely quantitative measure of the consumption of psychoactive substances. We develop strictly sociological categories to consider these practices in and outside the workplace, by taking jointly into account: the organization of work, the management of the workforce, the working conditions themselves (for example night work in bars and restaurants, physical difficulties of work in building sites), the properties of the products consumed and their representations, as well as the social and professional characteristics of employees
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Bouzillé, Guillaume. "Enjeux et place des data sciences dans le champ de la réutilisation secondaire des données massives cliniques : une approche basée sur des cas d’usage." Thesis, Rennes 1, 2019. http://www.theses.fr/2019REN1B023/document.
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La dématérialisation des données de santé a permis depuis plusieurs années de constituer un véritable gisement de données provenant de tous les domaines de la santé. Ces données ont pour caractéristiques d’être très hétérogènes et d’être produites à différentes échelles et dans différents domaines. Leur réutilisation dans le cadre de la recherche clinique, de la santé publique ou encore de la prise en charge des patients implique de développer des approches adaptées reposant sur les méthodes issues de la science des données. L’objectif de cette thèse est d’évaluer au travers de trois cas d’usage, quels sont les enjeux actuels ainsi que la place des data sciences pour l’exploitation des données massives en santé. La démarche utilisée pour répondre à cet objectif consiste dans une première partie à exposer les caractéristiques des données massives en santé et les aspects techniques liés à leur réutilisation. La seconde partie expose les aspects organisationnels permettant l’exploitation et le partage des données massives en santé. La troisième partie décrit les grandes approches méthodologiques en science des données appliquées actuellement au domaine de la santé. Enfin, la quatrième partie illustre au travers de trois exemples l’apport de ces méthodes dans les champs suivant : la surveillance syndromique, la pharmacovigilance et la recherche clinique. Nous discutons enfin les limites et enjeux de la science des données dans le cadre de la réutilisation des données massives en santéThe dematerialization of health data, which started several years ago, now generates na huge amount of data produced by all actors of health. These data have the characteristics of being very heterogeneous and of being produced at different scales and in different domains. Their reuse in the context of clinical research, public health or patient care involves developing appropriate approaches based on methods from data science. The aim of this thesis is to evaluate, through three use cases, what are the current issues as well as the place of data sciences regarding the reuse of massive health data. To meet this objective, the first section exposes the characteristics of health big data and the technical aspects related to their reuse. The second section presents the organizational aspects for the exploitation and sharing of health big data. The third section describes the main methodological approaches in data sciences currently applied in the field of health. Finally, the fourth section illustrates, through three use cases, the contribution of these methods in the following fields: syndromic surveillance, pharmacovigilance and clinical research. Finally, we discuss the limits and challenges of data science in the context of health big data
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Ouedraogo, Wendkouni Adelphe Sabine. "Étude comparée de l’intégration juridique de la tradimédecine dans les systèmes de santé publique en Afrique de l’Ouest : les cas du Ghana et du Burkina Faso." Thesis, Aix-Marseille, 2019. http://www.theses.fr/2019AIXM0009.
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La médecine et la pharmacopée traditionnelles ouest-africaine constituent encore aujourd'hui, l'unique moyen de prise en charge des maladies pour des milliers de personnes vivant en zone rurale et même en zone urbaine. Cette réalité est souvent présentée comme découlant uniquement de la faiblesse du système allopathique de santé, cependant, elle peut être le fruit d'un choix socioculturel. En effet, les conceptions traditionnelles des maladies, c’est-à-dire la distinction entre maladies naturelles et maladies provoquées influencent encore le choix thérapeutique dans les communautés africaines surtout en zone rurale. Pendant longtemps, ce retour à la médecine et à la pharmacopée traditionnelle s'est fait sans la mise en place des mesures d'encadrement et d'accompagnement nécessaires. Ce qui engendre d’énormes risques sanitaires. De plus, la multiplication des bio-prospections sans contrôle des États a conduit à une forte croissance des appropriations illicites des savoirs tradimédicaux. Cet état des faits a fait émerger au sein des institutions internationales compétentes de nouvelles questions : celles des droits des communautés locales et autochtones sur leurs ressources et leurs savoirs tradimédicaux associés, et la nécessité de la construction d'un système équitable d'exploitation des ressources et des savoirs médicaux traditionnels à des fins de recherches et de développement. Les États burkinabè et ghanéen ont, pour pallier ces difficultés, adopté des législations encadrant les pratiques traditionnelles de soins ainsi que la production et la mise sur leurs marchés nationaux de médicaments traditionnels et néo traditionnelsTraditional medicine and pharmacopeia are still nowadays for thousands of people in West Africa, the unique healthcare solution. If this fact is often considered as arising solely from the weakness of the allopathic health system, it could also be a result of socio-cultural choices. Indeed, people especially in rural areas are strongly influenced by traditional vision and beliefs about diseases’ origins, which could have natural or induced causes in this traditional conception. For a long time, this resort to traditional medicine was done without the supervision and support of the appropriate measures and regulations. This has generated high public healthcare risks. Moreover, the multiplication of bioprospection’s without states control has led to a sharp increase in illicit appropriation of traditional medicine knowledge for the purposes of pharmaceutical innovation. This has created new issues in the South, especially about local populations’ intellectual property on their traditional knowledge. Highlighting these facts has raised new concerns within the competent international and regional institutions: the need of protection for local and indigenous communities’ rights over their genetic resources and associated tradimedical knowledge, and the need of building a fair system of exploitation of resources and medical indigenous knowledge for purposes of research and development. The Burkinabe and Ghanaian states have, in order to overcome these issues, adopted legislations to regulate traditional care practices as well as the production and placement on their national markets of traditional and neo-traditional medicines
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Berger, Tristan. "L'accès aux informations environnementales et sanitaires : le cas des substances chimiques, des OGM et des médicaments." Thesis, Paris 1, 2020. http://www.theses.fr/2020PA01D006.
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Thalidomide, amiante, tabac, PCB, benzène, valproate, dexfenfluramine, ECB, implants PIP, chlordécone, BPA, glyphosate, etc. La liste est désormais longue d’atteintes à l’environnement et à la santé qui ont miné la confiance du public à l’égard du mode de gestion des risques et des institutions. Pour ces raisons, l’exigence de transparence en matière de risque environnemental et sanitaire n’a cessé de croître, non seulement dans un but d’information directe des citoyens, mais aussi dans l’objectif de construire une contre-expertise, un nombre croissant d’associations ou de chercheurs ambitionnant ainsi de contrôler la véracité des expertises officielles et entendant contester l’action ou l’inertie des autorités publiques ou des entreprises. Aussi les agences d’expertise font-elles de plus en plus régulièrement l’objet de demandes d’accès aux informations environnementales et sanitaires, y compris à des données des plus précises et techniques en vue d’éprouver leur fiabilité. Malgré l’amélioration des droits d’accès du public aux informations durant quarante années et l’affichage constant d’une politique d’open data, la présente thèse met en évidence les difficultés du public à accéder à ces informations avant tout parce que celles-ci, qui viennent à l’appui des demandes d’autorisation, sont produites par les entreprises. Ne négligeant pas les causes classiquement analysées par la doctrine (longueur des délais, culture du secret, complexité des règles et des situations), la thèse s’attache à identifier les limites systémiques à l’accès du public aux informations environnementales et sanitaires. Elle met notamment en relief trois séries de facteurs structurels. D’une part, le dispositif d’évaluation de la sécurité des produits, confié aux entreprises, intrinsèquement porteur d’un risque de conflits d’intérêts, qui nuit ainsi à la fiabilité des données à l’accès desquelles le public a droit. D’autre part, l’existence de droits de propriété intellectuelle sur les données produites par les entreprises, qui entraîne leur privatisation. Enfin, le manque de pouvoir des agences publiques d’expertise, prises en étau entre les entreprises, qui entendent protéger leurs informations, et le public, qui en revendique l’accès. Trois types de cas – substances chimiques, OGM et médicaments – sont étudiés pour mettre en lumière ces limites structurelles aux droits d’accès et, du même coup, à l’approfondissement de la démocratie du risqueThalidomide, asbestos, tobacco, PCB, benzene, valproate, dexfenfluramine, ECB, PIP implants, chlordecone, BPA, glyphosate, etc., there is now a long list of environmental and health risks that both affected risk management and undermined the public’s trust towards institutions. In this context, the issue of transparency related to environmental and health risks has continued to grow, not only for the purpose of directly informing citizens, but also for the purpose of building a counterexpertise, with a growing number of organizations or researchers seeking to review and check official expertise, and to challenge the action or the inertia of public authorities or companies. As a result, expert agencies increasingly receive requests to access environmental and health information, including to detailed datasets and techniques to test their reliability. Despite the progress that has characterized public rights to access information over the past forty years and the display of an open data policy, this thesis is based on the observation that access to information regimes are not effective. Going beyond the causes traditionally analyzed by doctrine (length of the delays, culture of secrecy, complexity), the thesis seeks to identify systemic limits to public access to environmental and health information. In particular, it highlights three sets of structural factors. First, the system for assessing product safety, entrusted to companies, inherently carries a risk of conflicts of interest and therefore undermines the reliability of the data to which the public is entitled. Second, the claim of intellectual property rights on data produced by companies, subjects them to a privatization process. Third, the lack of enforcement power of expert agencies, caught in a stranglehold between the exclusive rights of companies and the rights of public access. Three case studies – chemicals, GMOs and medicines – are used to highlight these structural limitations to access rights and, simultaneously, to deepen ecological and health democracy
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Aïssaoui, Mohammed Amine. "Des modalités de fixation aux déterminants du prix des médicaments innovants : le cas des anticancéreux dans les pays de l’OCDE." Thesis, Paris Sciences et Lettres (ComUE), 2018. http://www.theses.fr/2018PSLED026.
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Cette thèse se propose d’étudier les déterminants des prix des médicaments innovants de l’oncologie, en s’interrogeant à la fois sur le rôle des caractéristiques propres à chaque produit, en particulier sa valeur thérapeutique ajoutée, et sur l’influence d’éléments structurels, notamment les modalités des politiques de fixation des prix appliqués par les Etats.Une revue de la littérature nous permet tout d’abord de spécifier les modalités de fixation des prix ainsi que les nouveaux instruments mis en place par les décideurs pour réguler leur montant. Nous montrons que la détermination des prix des traitements innovants passe par l’évaluation de la valeur ajoutée et donc la mise en place de politiques d’évaluation de type Health Technology Assessment (HTA). Toutefois, nous mettons en lumière que les politiques de prix se réfèrent à des doctrines différentes tant dans les démarches évaluatives que dans la fixation des prix. Dès lors, nous proposons un cadre théorique de détermination des prix qui permet de prendre en compte ces différences. En complément, la constitution d’une base de données incluant les caractéristiques des anticancéreux et leurs prix fixés dans huit pays de l’OCDE, nous permet d’entreprendre différentes analyses statistiques.A partir des études empiriques, nous examinons dans un premier temps la relation entre les prix et le caractère innovant des anticancéreux. Nous commençons pour cela par nous intéresser à l’accès au marché de ces produits dans les pays retenus avant d’examiner les disparités de prix entres les pays.Si l’on constate qu’une majorité des médicaments de notre échantillon étaient bien disponibles dans ces pays, il apparaît néanmoins des différences en matière réglementaire, notamment concernant l’octroi du statut de médicament orphelin ou encore en matière de délais d’enregistrement. Une étude comparative plus fine des évaluations faites par le NICE et la HAS confirme l’existence de divergences sur les décisions et/ou recommandations de prise en charge malgré une appréciation similaire de la valeur ajoutée. Enfin lorsqu’on procède à la comparaison des prix, on constate un écart de prix considérable selon les modalités de fixation des prix appliqués par les Etats.Ce dernier constat nous conduit ensuite à rechercher des éléments d’explication à partir d’une approche économétrique permettant de mesurer l’effet de la valeur ajoutée, définie par la survie incrémentale, sur le prix des anticancéreux. De façon complémentaire, nous montrons que cette influence se manifeste même lorsque l’estimation de cette valeur ajoutée reste incertaine au regard du niveau de preuve obtenu.De façon complémentaire, les analyses économétriques confirment que les écarts de prix entre pays reflètent les différences internationales sur les choix de politique de prix. En effet, nous montrons que les prix les plus élevés sont relevés dans les pays exerçant une politique de prix libres. A l’inverse, les prix les plus bas sont retrouvés dans les pays pratiquant une évaluation économique. Et l’on retrouve à un niveau intermédiaire les pays ayant recours à la négociation et au référencement internationalThis PhD thesis focused on the regulation and the determinants of innovative drugs prices in oncology. First, with a literature review we provided a comprehensive description examining the pricing mechanisms of innovative drugs in OECD countries. This approach shows us that most of the countries determine their prices according the assessment of the added value of the pharmaceutical product, and use HTA policies in their decisions making. Based on that conclusions and regarding the differences observed between the policies’ countries we assumed a framework to describe the pricing mechanism.In addition, we developed an original database which contains the anticancer drugs characteristics and their prices in 8 OECD countries. From empirical studies, we examined the relationship between the prices and the drugs characteristics. Before assessing prices disparities between the selected countries, we focused on the market approval of these medicines in each country. Nevertheless, even if most of the products were available in all studied countries, we observed differences between their regulations notably concerning the orphan status designation as well as for the time to market authorization.Thereafter, we achieved a comparative study to assess the discordance between the NICE and HAS. This analysis shows that despite a similar estimation of the added value, there is divergences between these HTA bodies in term of decisions making. Then, when we investigated the trends in prices across the selected countries, the level of pricing disparities observed, in most cases, seems to reflect the differences in pricing regulations.Finally, in order to highlight the determinants of these disparities between countries with respect to anticancer drug prices, we used the econometric approaches, we assessed both the effects on the prices of the added value (the incremental survival) and the pharmaceutical policy: It appears that the incremental survival impacts on the prices, independently of its uncertainties and its level of evidence provided in the clinical trials. In addition, the analysis confirms that the prices disparities reflect the pricing policy applied. Indeed, the countries using a free pricing policy have the highest-level prices, followed by the countries using the pricing negotiation and external reference pricing. Lastly, the countries using economic evaluation have the lowest prices
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Leroy, Fanny. "Etude des délais de survenue des effets indésirables médicamenteux à partir des cas notifiés en pharmacovigilance : Problème de l'estimation d'une distribution en présence de données tronquées à droite." Phd thesis, Université Paris Sud - Paris XI, 2014. http://tel.archives-ouvertes.fr/tel-01011262.
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Ce travail de thèse porte sur l'estimation paramétrique du maximum de vraisemblance pour des données de survie tronquées à droite, lorsque les délais de troncature sont considérés déterministes. Il a été motivé par le problème de la modélisation des délais de survenue des effets indésirables médicamenteux à partir des bases de données de pharmacovigilance, constituées des cas notifiés. Les distributions exponentielle, de Weibull et log-logistique ont été explorées.Parfois le caractère tronqué à droite des données est ignoré et un estimateur naïf est utilisé à la place de l'estimateur pertinent. Une première étude de simulations a montré que, bien que ces deux estimateurs - naïf et basé sur la troncature à droite - puissent être positivement biaisés, le biais de l'estimateur basé sur la troncature est bien moindre que celui de l'estimateur naïf et il en va de même pour l'erreur quadratique moyenne. De plus, le biais et l'erreur quadratique moyenne de l'estimateur basé sur la troncature à droite diminuent nettement avec l'augmentation de la taille d'échantillon, ce qui n'est pas le cas de l'estimateur naïf. Les propriétés asymptotiques de l'estimateur paramétrique du maximum de vraisemblance ont été étudiées. Sous certaines conditions, suffisantes, cet estimateur est consistant et asymptotiquement normal. La matrice de covariance asymptotique a été détaillée. Quand le délai de survenue est modélisé par la loi exponentielle, une condition d'existence de l'estimation du maximum de vraisemblance, assurant ces conditions suffisantes, a été obtenue. Pour les deux autres lois, une condition d'existence de l'estimation du maximum de vraisemblance a été conjecturée.A partir des propriétés asymptotiques de cet estimateur paramétrique, les intervalles de confiance de type Wald et de la vraisemblance profilée ont été calculés. Une seconde étude de simulations a montré que la couverture des intervalles de confiance de type Wald pouvait être bien moindre que le niveau attendu en raison du biais de l'estimateur du paramètre de la distribution, d'un écart à la normalité et d'un biais de l'estimateur de la variance asymptotique. Dans ces cas-là, la couverture des intervalles de la vraisemblance profilée est meilleure.Quelques procédures d'adéquation adaptées aux données tronquées à droite ont été présentées. On distingue des procédures graphiques et des tests d'adéquation. Ces procédures permettent de vérifier l'adéquation des données aux différents modèles envisagés.Enfin, un jeu de données réelles constitué de 64 cas de lymphomes consécutifs à un traitement anti TNF-α issus de la base de pharmacovigilance française a été analysé, illustrant ainsi l'intérêt des méthodes développées. Bien que ces travaux aient été menés dans le cadre de la pharmacovigilance, les développements théoriques et les résultats des simulations peuvent être utilisés pour toute analyse rétrospective réalisée à partir d'un registre de cas, où les données sur un délai de survenue sont aussi tronquées à droite.
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Santoro, Alice. "Métallothionéines et biomolécules capables de chélater et/ou de réduire le Cu et leur impact sur l'activité rédox et sur la stabilité des complexes de Cu d’intérêt médicinal : étude de cas sur des complexes de Cu-peptide amyloïde ou sur des principes actifs à base de Cu." Thesis, Strasbourg, 2019. http://www.theses.fr/2019STRAF067.
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Les dérèglements dans l'homéostasie du cuivre (Cu) ont été liés à la maladie d'Alzheimer (MA) et au cancer. Dans la MA le Cu se lie au peptide Aβ dans les plaques amyloïdes, impactant sur la production d'espèces oxygénées réactives (ROS). L'augmentation de la présence de Cu a également été impliquée dans la croissance tumorale. Ceci a conduit au développement de thérapies à base de Cu. L'utilisation de complexes de Cu pro-oxydants semble être une stratégie prometteuse pour le cancer. Dans la MA, des chélateurs qui bloquent l’activité redox du Cu sont nécessaires. Dans un environnement biologique, la stabilité d’un complex de Cu par rapport à ses concurrents physiologiques, est un aspect essentiel à considerer. Spécialement, le rôle des biomolécules liant/réductrices de Cu (telles que les métallothioneines, le glutathion et la cystéine) est très important. Cette thèse vise à étudier l’impact de ces molécules sur l’activité redox/stabilité de complexes de Cu médicinaux. Les études montrent que ces molécules sont des acteurs essentiels, car elles peuvent conduire à des réactions de dissociation, transmétallation, supprimant ainsi la production de ROSDefects in copper (Cu) homeostasis have been linked to Alzheimer’s disease (AD) and Cancer. In AD, Cu has been found to bind to Aβ-peptides in extracellular amyloid-plaques, likely impacting the production of reactive oxygen species (ROS). Increased Cu levels have also been implicated in tumor growth. This has led to the development of Cu-based drugs. Particularly, the use of pro-oxidant Cu-complexes appears to be a promising strategy in cancer. Contrarily, in AD, redox silencing chelators are warranted. In a biological environment, the kinetic/thermodynamic stability of a Cu-complex against physiological competitors, is a key aspect to consider. In particular, the role of Cu-binding and reducing biomolecules (including metallothioneins, gluathione and cystein) is of pivotal importance. Within this context, this thesis aims to investigate the impact of these molecules on the redox-activity and stability of medicinal Cu-complexes. The studies carried out show that these molecules are key players for the fate of a Cu-complex, as they could lead to reactions of dissociation or transmetallation, abolishing the Cu-dependent ROS production
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Beccaria, Kévin. "Evaluation de la diffusion intracérébrale des drogues antinéoplasiques après ouverture de la barrière hémato-encéphalique induite par ultrasons : Application aux gliomes malins de l’enfant Brainstem Blood-Brain Barrier Disruption and Enhanced Drug Delivery with an Unfocused Ultrasound Device – A Preclinical Study in Healthy and Tumor-Bearing Mice Ultrasound-Induced Blood-Brain Barrier Disruption for the Treatment of Gliomas and other Primary CNS Tumors Blood-Brain Barrier Disruption with Low-Intensity Pulsed Ultrasound for the Treatment of Pediatric Brain Tumors: A Review and Perspectives." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASS044.
Full textAbstract:
Les gliomes de haut grade représentent près de 15% de l’ensemble des tumeurs cérébrales de l’enfant. Aucun progrès thérapeutique n’a été fait depuis 30 ans et leur pronostic reste effroyable. La barrière hémato-encéphalique (BHE) est l’une des causes de l’échec des traitements médicaux car elle limite le passage de la majorité des molécules vers le cerveau, empêchant la plupart des drogues antinéoplasiques d’atteindre le tissu tumoral. L’ouverture de la BHE par les ultrasons pulsés de faible intensité en association avec des microbulles injectées par voie intraveineuse est une technique qui permet d’ouvrir transitoirement la BHE de manière localisée et sécurisée. Dans cette étude, nous avons confirmé la capacité d’un nouvel agent de contraste (microbulles) à ouvrir la BHE avec des ultrasons. Nous avons par ailleurs montré qu’il était possible d’ouvrir la BHE dans le tronc cérébral avec un dispositif ultrasonore non focalisé (SonoCloud®), à la fois sur des souris saines et des modèles murins de DIPG. Nous avons pu augmenter la distribution de l’irinotécan et du panobinostat dans le tronc cérébral de souris saines et de modèles de DIPG après ouverture de la BHE, sans cependant améliorer la survie de notre modèle de DIPG. Des études préliminaires ont été réalisées avec des inhibiteurs de chekpoints et des cellules natural killer, qui n’ont pas permis d’améliorer la survie d’un modèle murin de gliome malin sus-tentoriel. Enfin, nous avons mis au point le premier essai clinique pédiatrique qui visera, dès le premier semestre 2020, à évaluer la faisabilité et la tolérance de l’ouverture de la BHE avec le dispositif SonoCloud® chez l’enfant et l’adolescentHigh-grade gliomas represent about 15% of pediatric brain tumors. No progress has been made in the treatment of these tumors during the last decades, and their prognosis remains dismal. The blood-brain barrier (BBB) plays a major role in the failure of medical treatments since it prevents most molecules to reach the brain, thus limiting the delivery of antineoplastic drugs to brain tumors. Disruption of the BBB (BBBD) with low intensity pulsed ultrasound in association with intravenous microbubbles is a technique that allows for safe, transient, and localized opening of the BBB. In this thesis, we confirmed the capacity of a new microbubble contrast agent to induce BBBD with ultrasound. We showed that opening of the BBB in the brainstem is possible with a nonfocused ultrasound device (SonoCloud®), in both healthy mice and a murine model of DIPG. We were able to increase irinotecan and panobinostat delivery in the brainstem of both healthy and tumor-bearing mice after BBBD, but we did not observe increased in overall survival. Preliminary studies have also been performed with checkpoints inhibitors and natural killer cells in a murine model of supra-tentorial high-grade glioma, but we were not able to increase survival in these models anymore. Finally, we prepared the first clinical trial that will evaluate the feasibility and tolerance of ultrasound-induced BBBD with the SonoCloud® device in the pediatric population. This trial will begin during the first semester of 2020