The Swedish drug expenses increased sharply during the 1990. The increase in cost of drug spending declined from year 2002, due to the introduction of generic substitution. ‘Generic substitution’ is a pharmaceutical term used to describe the substitution of a prescribed drug (that has an expired patent) with an equivalent alternative containing the same drug substance, formulation and strength. The substituted drug has similar bioavailability, and are approved as generics by “Läkemedelsverket” (compare EMA, FDA) This substitution of drugs has led to an eight million Swedish kronor reduction in annual costs on government drug spending. Money that can be allocated to other sectors in the healthcare system. Despite these huge savings, patients have been criticizing the generic exchange system due to perceived side effects, suspicion of a lower quality and uncertainty and confusion about what drugs to use. This might add up to poorer compliance, risk for double-medication and medicinal errors. Johan Wallér, CEO of Apoteksföreningen (a lobbying organization for pharmacy retailers), claims that an estimate of 200.000 people every year are making errors when medicating, and experience an inferior medical effect due to generic exchange. The aim of this study was to identify the problems and opportunities experienced by patients due to the introduction of generic substitution. A questionnaire study was performed including 280 customers, presenting prescriptions on drugs available for drug substitution in five different pharmacies, in Malmo (town in the southern part of Sweden). In the survey, questions were asked about what knowledge the customers had of generic substitution and from whom they had received this information. Questions were also asked about medical errors. The results from the questionnaire show that 5/280 had experienced problem with generic substitution that had had impact on their well-being. Also, patients over 56 on a long-term medication, and with multiple interchangeable medicines often run into problems with generic exchange. The patients in the survey reported a shortage/lack of communication and information from the doctors about the pros and cons with generic drugs. Some patients were confused about package looking different from what they were used to, different size, form and colour of tablets.  Approximately 46 % of the patients consider the shape of tablets to be important, and 23 % said the size. Changing the shape and size of tablets may therefore have negative consequences. There is a risk of medication errors associated with the use of generics. In this survey, few people experienced side effect, but on a national basis this problem cannot be ignored, since millions of prescriptions are subject to generic substitution. This calls for the need of informing the customers in pharmacies and by physicians in a proper way.

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Thesis (Ph. D.)--University of Wisconsin--Madison, 1980. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 149-154).

Th.--Droit--Lyon, 1909.

Les virus influenzae sont des pathogènes importants ayant un impact à la fois écologique et en santé publique humaine. En effet chez l’Homme, ces virus sont responsables de la grippe, qu’elle soit saisonnière, pandémique ou zoonotique. Face à ces infections très peu d’options thérapeutiques sont disponibles : seuls les inhibiteurs de neuraminidases (INA) sont recommandés par l’OMS mais des résistances ont été décrites. Les substitutions H274Y, E119V et R292K sont les substitutions de résistance retrouvées le plus fréquemment dans les neuraminidases des virus influenzae humains. Dans notre travail, l’étude des résistances aux INA a été organisée autour de deux axes, d’une part via le suivi clinique et biologique de la résistance chez les patients et d’autre part via l’étude de l’impact des substitutions de résistance dans des neuraminidases aviaires. La surveillance de ces résistances au sein du CNR des virus des infections respiratoires a permis la caractérisation du génome de virus influenza A(H1N1)pdm09 dans un contexte d’excrétion chronique en présence d’un traitement par INA chez un patient atteint de déficit immunitaire combiné sévère mais aussi le développement et l’évaluation de la PCR digitale pour le diagnostic de la substitution H274Y des virus A(H1N1). Au niveau mécanistique, notre travail a permis l’analyse des substitutions (H274Y, R292K, E119V±I222L) sur l’ensemble des sous-types de neuraminidases des virus influenzae A. La substitution H274Y se retrouve préférentiellement dans les N1 mais est responsable d’une diminution de la sensibilité à l’oseltamivir pour toutes les neuraminidases du groupe 1 (N1, N4, N5 et N8). La substitution E119V entraine une diminution de la sensibilité à l’oseltamivir variable en fonction des neuraminidases avec un impact plus important pour les N2, N7, N9 et N5. De plus l’association des substitutions E119V+I222L entraine un effet synergique sur le phénotype de résistance à l’oseltamivir. Enfin la substitution R292K entraine une diminution de la sensibilité à tous les INA dans toutes les neuraminidases du groupe 2 (N2, N3, N6, N7 et N9). La production d’une N9 recombinante portant la substitution R292K a montré un impact majeur de la substitution sur l’activité enzymatique. Un développement technologique toujours en cours au laboratoire va nous permettre d’aller plus loin dans l’analyse des mécanismes qui sous-tendent l’apparition de ces résistances / Influenza viruses are important human pathogens that are responsible for flu, whether seasonal, pandemic or zoonotic. Very few therapeutic options are available against these pathogens and neuraminidase inhibitors (NAI) are the only antiviral agents recommended by the WHO for treatment and prophylaxis of influenza virus infections. NAI resistance has already been described and the H274Y, E119V and R292K neuraminidase substitutions are the most frequently encountered substitutions responsible for oseltamivir resistance. During this work, we focused the NAI resistance study around two main objectives: first, we monitored clinical and biological resistance in treated patients and then we studied the impact of substitutions responsible for NAI resistance using avian neuraminidases. For NAI resistance monitoring, viral genomic diversity of a child's influenza A(H1N1)pdm09 was characterized in the context of a severe combined immunodeficiency and a chronic viral excretion despite antiviral treatment. For a better detection of H274Y substitution in A(H1N1) influenza viruses, a digital droplet PCR was developed and evaluated. At a more fundamental level, resistance substitutions (H274Y, R292K, E119V ± I222L) were analysed using all neuraminidase subtypes of influenza A viruses. To summarize, H274Y substitution is preferentially isolated in N1 but also decreases oseltamivir susceptibility in all group 1 neuraminidases (N1, N4, N5 and N8). The E119V substitution impact on oseltamivir susceptibility depends on the neuraminidase and decreases oseltamivir susceptibility especially within N2, N7, N9 and N5. Moreover, the E119V+I222L substitutions has a synergistic effect on oseltamivir resistance profile. The R292K substitution decreases all NAI susceptibility for all group 2 neuraminidases (N2, N3, N6, N7 and N9). The production of a recombinant N9 bearing the R292K substitution allows to highlight the substitution impact on the sialidasic activity. Development of new technological tools are still in progress to allow a more accurate analysis of the mechanisms that underlie the NAI resistance

Made available in DSpace on 2014-06-12T18:28:46Z (GMT). No. of bitstreams: 2 arquivo4238_1.pdf: 678788 bytes, checksum: 1a19da235845c146881443f4bbcb79b9 (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2009 / Nós estudamos um novo tipo de processo estocástico a tempo discreto, que nós chamamos de processos de substituição. Como o tempo é discreto, nós podemos definir este processo através de um operador que transforma uma medida de probabilidade (em um certo espaço) em outra. Vale a pena notar que a maioria dos estudos de processos de partículas interagentes se baseia na suposição de que o conjunto de sítios, também chamado de espaço, não muda ao longo da interação. Existem apenas poucos trabalhos onde os sítios podem aparecer e desaparecer durante a realização do processo, e este trabalho é um deles. Considere então um conjunto finito não-vazio A chamado de alfabeto, cujos elementos são chamados de letras. Sequências finitas de letras são chamadas de palavras e o comprimento de uma palavra é o número de letras que existe nela. Os elementos de AZ (sequências bi-infinitas de letras) são chamados de configurações. Denotamos por M o conjunto de medidas de probabilidade invariantes por translação. Nós podemos definir um operador de substituição genérico como um operador de M em M que substitui cada ocorrência de uma palavra G (onde G precisa satisfazer uma certa condição) em uma configuração por outra palavra H com probabilidade ρ, onde ρ pertence a [0; 1], independentemente das outras ocorrências. A nossa maior contribuição é dada pela definição e estudo dos operadores de substituição em geral. O caso mais interessante do operador de substituição, na nossa opinião, é o caso em que G e H têm comprimentos diferentes; a própria definição do operador neste caso é não-trivial. De fato, foi preciso desenvolver uma teoria de aproximação de medidas por sequências de palavras para lidar com este caso. Uma dificuldade com este caso é que os operadores de substituição não são lineares. No entanto, foi possível provar que todos eles são finos, que nos parece ser a melhor propriedade depois da linearidade. Nós também provamos que todos os operadores de substituição são contínuos e nós utilizamos este fato para obter conclusões a respeito da existência de medidas invariantes por estes operadores, o que nos ajuda a estudar ergodicidade do processo de substituição. Por fim, nós esperamos que estas propriedades possam ser relacionadas com certas necessidades de ciências aplicadas

Nucleophilic substitution reactions involving phosphate monoesters have been investigated. Two general syntheses of O-alkyl or O-aryl [16O,18O] thiophosphate monoesters are reported. An independent and general method for the determination of the enantiomeric excess of isotopically chiral thiophosphate monoesters has been developed and the absolute configurations of the diastereoisomers of (2R)-O-(O-ethyl thiophosphoryl)-3, 4S-dimethyl-5S-phenyl-l,3,2-oxazaphos- pholidin-2-one have been assigned. The solvolysis of p-nitrophenyl [R-16O,18O] thiophosphate in ethanol gives rise to ethyl [16O, 18O] thiophosphate with a large degree of racemisation of configuration (~80%). This observation is consistent with the formation of a thiometaphosphate intermediate of finite life-time which is then trapped by ethanol with accompanying loss of stereochemical integrity. This study provides the first direct evidence for a monomeric thiometaphosphate in protic solvent. During the course of developing the stereochemical analysis, it was noted that O-ethyl thiophosphate reacts with cis-2-chloro-3, 4-dimethyl- 5-phenyl-l, 3, 2-oxazaphospholidin-2-one with ca. 10% inversion and 90% retention of configuration. This system also reacts with fluoride ion with complete loss of stereochemistry. Cis-2-chloro-3, 4-dimethyl-5- phenyl-l, 3, 2-oxazaphospholidin-2-one and the corresponding 2-thione are epimerised to the more stable trans isomers by pyridine and other nucleophilic catalysts. These reactions require an in-line exocyclic displacement at a phosphorus centre held in a five-membered ring. Nucleophilic substitution at di- and tri-esters have also been studied. The stereochemical course of the hydrolysis of the 1, 3, 2-dioxaphosphor- inan-2-one system involving good leaving groups such as chloride and fluoride occur with inversion of configuration via an in-line mechanism, whereas hydrolysis of this system involving poor leaving groups occurs with retention of configuration via a pseudorotation mechanism.

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